RNAi抑制PTN对人增生性瘢痕成纤维细胞作用的实验研究
|
摘要
由于缺乏有效的防治手段，皮肤创伤后形成的病理性瘢痕是目前整形手术面临的临床难题之一。增生性瘢痕（hypertrophic scar，HS)的形成机理目前尚不十分明确，一般观点认为，是由于皮肤受到创伤后，由于各种因素引起成纤维细胞（Fibroblast，Fb)的增殖异常，使胶原蛋白合成失控，进而导致胶原在细胞外基质中的大量沉积所形成的。因此，研究增生性瘢痕形成过程中与成纤维细胞异常增殖有关因子的表达，对于阐明增生性瘢痕的形成机制，以及临床上探索增生性瘢痕的新的治疗手段均具有十分重要的意义。一些研究表明，主要是由Fb、生长因子和ECM的共同作用导致了HS的发生以及发展，因此如何控制生长因子的调控作用，有效的抑制成纤维细胞的过度增殖并诱导细胞凋亡是增生性瘢痕（HS）防治研究的重要途径。
多效生长因子pleiotrophin（PTN）是由Milner等人于1989年从围产期鼠脑组织中纯化得到的一种肝素结合蛋白[1]。此后的研究表明PTN也存在于一些非神经组织，如子宫，心脏，软骨组织等，其主要生理功能是刺激细胞增殖与迁移，促进血管生成，促进神经系统及骨发育等[2]。最近，Paddock等人利用表达谱芯片发现PTN在增生性瘢痕中也呈现高表达[3]，但是PTN对瘢痕成纤维细胞增殖及凋亡的影响尚不清楚。
基于以上研究背景，本研究通过检测PTN在增生性瘢痕组织及正常皮肤组织中的表达，进一步验证PTN的过表达是否参与了增生性瘢痕的形成。此外还通过体外培养瘢痕成纤维细胞，利用RNA干扰技术下调PTN的表达，并检测PTN表达下调对瘢痕成纤维细胞增殖及凋亡的影响，探讨PTN是否通过促进瘢痕成纤维细胞增殖参与病理性瘢痕的形成。
一、临床样本病理检测
目的：增生性瘢痕（Hypertrophic scar，HS）发病机制尚未明确，普遍认为是成纤维细胞的增生及细胞外基质蛋白沉积等共同作用的结果，Pleiotrophin（PTN）是一种高度保守的细胞外基质相关的分泌蛋白，作为一种原癌基因具有多种生物功能，本实验通过比较正常皮肤组织和增生性瘢痕组织中PTN是否存在差异表达，探讨PTN在增生性瘢痕形成过程中起到的作用及意义。
方法：随机抽取术后的增生性瘢痕患者，以相应正常皮肤组织作为对照，通过病理学HE和Masson染色观察组织形态变化，通过RT-PCR、Western Blot和免疫组织化学方法检测PTN在增生性瘢痕组织的表达量与表达位置。
结果：RT-PCR和Western Blot结果显示，与正常皮肤组织相比，PTN在病理性瘢痕组织中表达量有所升高，且与皮肤正常组织之间存在显著性差异（P<0.01）。免疫组化结果显示，PTN在皮肤真皮和表皮细胞中均有表达，且在增生性瘢痕组织中表达呈现阳性。
结论：依据分子和蛋白水平检测结果推断PTN可能参与了增生性瘢痕组织的形成过程。从病理免疫组化结果和染色结果显示，PTN极有可能参与到细胞外基质蛋白的沉积和成纤维细胞的增殖过程中，从而促进增生性瘢痕的形成。有望将PTN作为增生性瘢痕治疗的靶点，为增生性瘢痕的治疗提供新的途径
二、 PTN siRNA重组质粒的构建、制备、鉴定以及干扰片段的筛选
目的：筛选PTN可能的干扰靶点，构建、制备PTN siRNA重组质粒。体外分离并培养增生性瘢痕成纤维细胞，向其转染PTN siRNA重组质粒，筛选干扰效率最佳的一组，大量纯化用于转染实验，进行后续检测。
方法：参照siRNA设计原则，选择的PTN特异性干扰靶点，设计并构建重组质粒（经测序验证），转化于大肠杆菌DH5α中扩大培养，以无内毒素质粒大提试剂盒提取高纯度重组质粒，脂质体法转染进瘢痕成纤维细胞，Western Blot、RT-PCR方法检测PTN表达水平变化，选择干扰效果最佳的一组质粒进行后续细胞水平实验。
结果：测序结果证明质粒构建成功，质粒提取量达到细胞转染所需剂量。编号pGCsi-PTN-sh3的干扰质粒对PTN表达的抑制率达70%以上，选择其进行后续转染实验。
结论：体外成功构建了PTN siRNA重组质粒，并能提供细胞转染所需足量高纯度质粒。筛选出干扰效果符合实验要求的目标质粒，可以进行后续转染实验。
三、 RNAi法下调PTN表达对增生性瘢痕成纤维细胞的影响
目的：将经实验筛选的PTN干扰质粒转染进瘢痕成纤维细胞，经过一系列细胞、分子、蛋白水平检测分析PTN表达下调对瘢痕成纤维细胞生长、增殖及相关基因的影响。
方法：MTT、细胞周期及凋亡实验检测PTN表达下调对细胞生长的影响，RT-PCR，Western Blot检测PTN siRNA重组质粒对靶基因PTN的干扰效果，细胞内I型、III型胶原mRNA及蛋白表达的变化。
结果：将RT-PCR，Western Blot筛选出对PTN干扰效果达到70%以上的重组质粒，转染至瘢痕成纤维细胞后，可有效抑制PTN表达，同未转染组相比，转染干扰质粒的瘢痕成纤维细胞生长、增殖受到抑制（P＜0.05）。流式细胞仪检测结果显示，PTN干扰质粒转染后瘢痕成纤维细胞的凋亡比率明显高于对照组（P＜0.05）。RT-PCR，Western Blot检测结果显示，PTN表达下调后，细胞内I、III型胶原含量较对照组显著降低。
结论：PTN是一种分泌性生长因子，在多种肿瘤组织中发现表达上调，研究发现PTN能够刺激细胞增殖、迁移、促进血管生成，瘢痕成纤维细胞转染PTN siRNA重组质粒后，PTN表达明显下调，细胞增殖被抑制，细胞内胶原蛋白的合成相比对照细胞下调明显。实验结果为我们提供了抑制增生性瘢痕形成的可能靶点，为基因治疗增生性瘢痕提供了的部分依据。
Pathologic scar is one of the most difficult clinical problems during plastic surgerydue to lacking of effective treatment. The formation mechanism of Hypertrophic scarhowever is not very clear. Generally speaking, it is caused by the abnormal proliferation offibroblast, making large number of collagen deposited in the extracellular matrix.Therefore, it is useful to study the expression of factors associating with proliferation offibroblast in elucidating the formation mechanism of hypertrophic scar and meaningful toexplore new methods on clinical treatment to hypertrophic scar.
Pleiotrophin (PTN) is a heparin-binding protein which was purified from the perinatalrat brain tissues by Milner in1989. Some studies indicated that PTN was also present inseveral non-neural tissues, such as uterine, heart, cartilage tissues. The main physiologicalfunctions are simulating the cell proliferation, migration, angiogenesis and promoting thedevelopment of bone and nervous system. Recently, Paddock found that PTN had a highexpression in the hypertrophic scar by Microarray profiling expression technology. But theeffect on the proliferation and apoptosis of fibroblast cells is still unclear.
Based on the results of these studies above, this study is to further validate whetherPTN had an expression difference between normal skins and hypertrophic scar tissues. Inaddition, fibroblast cells of scars were cultured in vitro and then down–regulated theexpression of PTN by RNA interference technology. At last, we detected the influences ofthe low expression of PTN on the proliferation and apoptosis of fibroblast cells, and makesure whether PTN was participate in the formation of Hypertrophic scars.
Part I experiment: Pathological Detection of ClinicalSamples
Objective：The formation mechanism of Hypertrophic scar is not very clear. Generallyspeaking, it is caused by the joint efforts of the abnormal proliferation of fibroblast anddeposition of collagen in the extracellular matrix. PTN is a highly conserved extracellularmatrix secretion protein, and has multiple biological functions as an oncogene. The aim ofthis study was to discuss whether PTN has an effect on the formation of hypertrophic scarbased on the different PTN expression between normal skin tissues and hypertrophic scars.
Methods：Patients with hypertrophic scars after surgery operation were randomlyselected, normal skin tissues were corresponded as control, HE and Masson staining wereused to observe the changes of morphology, RT-PCR, Western Blot andimmunohistochemistry were used to evaluate the expression and location of PTN in thehypertrophic scars.
Results：RT-PCR and Western Blot results showed that the expression of PTN in thehypertrophic scars were more higher than that in normal skin tissues, and had a significantdifference. The immunohistochemistry results showed that PTN expressed both in thedermal and epidermal cells, and had a positive expression in hypertrophic scars.
Conclusion：According to the results, we could infer that PTN may participate in theformation of hypertrophic scars. As it showed in the immunohistochemistry and stainingresults, PTN is likely to take part in the abnormal proliferation of fibroblast and depositionof collagen in the extracellular matrix. PTN could be expected as the therapeutic targets ofhyperplastic scar during the treatment.
Part II experiment PTN siRNA recombinant plasmidconstruction, preparation, identification and screening ofinterfering fragments
Objective：To screen the possible interfering targets of PTN, constructing andpreparing the recombinant plasmid of PTN. Fibroblast cells of scars were separated andcultured in vitro, then transfected the siRNA recombinant plasmid of PTN into the cells.The one had the most maximum efficiency was selected to do following research.
Methods：According to the designing principles of siRNA, selected the specialinterfering targets to design and construct the recombinant plasmid (verification bysequencing), then transfected into E. coli DH5α for culture. High purity recombinantplasmid was extracted by endotoxin-free plasmid extracting kit. Liposome method wasused to transfect the fibroblast cells. RT-PCR and Western Blot were used to test theexpression of PTN, choosing the most maximum interfering efficiency one to do followingcell research.
Results：Recombinant plasmid was successful constructed by sequencing verification.The extracted concentration of plasmid is enough for transfecting. PTN-sh3was conferredto had inhibition rate of70%to the expression of PTN in the experiment, which wasselected to do the following cell research..
Conclusion：PTN siRNA recombinant plasmid was successfully constructed in vitro,and the concentration and purity of the plasmid were enough for transfecting. Theinterfering effect of siRNA is consistent with expected and could be used for the followingresearch.
Part III experiment Effects of Down-regulation of PTNexpression by RNAi on hypertrophic scar fibroblasts
Objective：Transfect the screening recombinant plasmid into the fibroblast cells fromscars. To analysis the effect of down-regulated expression of PTN on fibroblastproliferation and the relationship with other associated genes at the level of cell, molecularand protein.
Methods：Evaluate the effect of down-regulated expression of PTN on cell growth byMTT, cell cycle and apoptosis experiment. Detect the interfering efficiency of siRNA tothe target gene and the changes of expression of ColⅠand ColⅢ by RT-PCR and WesternBlot.
Results：The selected recombinant plasmid by detection of RT-PCR and Western Blotcould inhibit the expression of PTN effectively, as well as the growth of fibroblast cellscomparing to the cell without transfection (P＜0.05). The results of RT-PCR and WesternBlot showed that the expression of ColⅠand ColⅢ had a significant decrease after theexpression of PTN being down regulated.
Conclusion：As a secreted growth factor, PTN had a higher expression in variouskinds of cancers. It could stimulate cell proliferation, migration and angiogenesis. Scarfibroblasts tansfected by PTN siRNA recombinant plasmid had a low expression of PTN,and cell proliferation was inhibited as well as the expression of ColⅠand ColⅢ. Theresults indicated that the PTN may be a candidate target for inhibiting the formation ofhypertrophic scars, and provide theoretical basis of gene therapy.
多效生长因子pleiotrophin（PTN）是由Milner等人于1989年从围产期鼠脑组织中纯化得到的一种肝素结合蛋白[1]。此后的研究表明PTN也存在于一些非神经组织，如子宫，心脏，软骨组织等，其主要生理功能是刺激细胞增殖与迁移，促进血管生成，促进神经系统及骨发育等[2]。最近，Paddock等人利用表达谱芯片发现PTN在增生性瘢痕中也呈现高表达[3]，但是PTN对瘢痕成纤维细胞增殖及凋亡的影响尚不清楚。
基于以上研究背景，本研究通过检测PTN在增生性瘢痕组织及正常皮肤组织中的表达，进一步验证PTN的过表达是否参与了增生性瘢痕的形成。此外还通过体外培养瘢痕成纤维细胞，利用RNA干扰技术下调PTN的表达，并检测PTN表达下调对瘢痕成纤维细胞增殖及凋亡的影响，探讨PTN是否通过促进瘢痕成纤维细胞增殖参与病理性瘢痕的形成。
一、临床样本病理检测
目的：增生性瘢痕（Hypertrophic scar，HS）发病机制尚未明确，普遍认为是成纤维细胞的增生及细胞外基质蛋白沉积等共同作用的结果，Pleiotrophin（PTN）是一种高度保守的细胞外基质相关的分泌蛋白，作为一种原癌基因具有多种生物功能，本实验通过比较正常皮肤组织和增生性瘢痕组织中PTN是否存在差异表达，探讨PTN在增生性瘢痕形成过程中起到的作用及意义。
方法：随机抽取术后的增生性瘢痕患者，以相应正常皮肤组织作为对照，通过病理学HE和Masson染色观察组织形态变化，通过RT-PCR、Western Blot和免疫组织化学方法检测PTN在增生性瘢痕组织的表达量与表达位置。
结果：RT-PCR和Western Blot结果显示，与正常皮肤组织相比，PTN在病理性瘢痕组织中表达量有所升高，且与皮肤正常组织之间存在显著性差异（P<0.01）。免疫组化结果显示，PTN在皮肤真皮和表皮细胞中均有表达，且在增生性瘢痕组织中表达呈现阳性。
结论：依据分子和蛋白水平检测结果推断PTN可能参与了增生性瘢痕组织的形成过程。从病理免疫组化结果和染色结果显示，PTN极有可能参与到细胞外基质蛋白的沉积和成纤维细胞的增殖过程中，从而促进增生性瘢痕的形成。有望将PTN作为增生性瘢痕治疗的靶点，为增生性瘢痕的治疗提供新的途径
二、 PTN siRNA重组质粒的构建、制备、鉴定以及干扰片段的筛选
目的：筛选PTN可能的干扰靶点，构建、制备PTN siRNA重组质粒。体外分离并培养增生性瘢痕成纤维细胞，向其转染PTN siRNA重组质粒，筛选干扰效率最佳的一组，大量纯化用于转染实验，进行后续检测。
方法：参照siRNA设计原则，选择的PTN特异性干扰靶点，设计并构建重组质粒（经测序验证），转化于大肠杆菌DH5α中扩大培养，以无内毒素质粒大提试剂盒提取高纯度重组质粒，脂质体法转染进瘢痕成纤维细胞，Western Blot、RT-PCR方法检测PTN表达水平变化，选择干扰效果最佳的一组质粒进行后续细胞水平实验。
结果：测序结果证明质粒构建成功，质粒提取量达到细胞转染所需剂量。编号pGCsi-PTN-sh3的干扰质粒对PTN表达的抑制率达70%以上，选择其进行后续转染实验。
结论：体外成功构建了PTN siRNA重组质粒，并能提供细胞转染所需足量高纯度质粒。筛选出干扰效果符合实验要求的目标质粒，可以进行后续转染实验。
三、 RNAi法下调PTN表达对增生性瘢痕成纤维细胞的影响
目的：将经实验筛选的PTN干扰质粒转染进瘢痕成纤维细胞，经过一系列细胞、分子、蛋白水平检测分析PTN表达下调对瘢痕成纤维细胞生长、增殖及相关基因的影响。
方法：MTT、细胞周期及凋亡实验检测PTN表达下调对细胞生长的影响，RT-PCR，Western Blot检测PTN siRNA重组质粒对靶基因PTN的干扰效果，细胞内I型、III型胶原mRNA及蛋白表达的变化。
结果：将RT-PCR，Western Blot筛选出对PTN干扰效果达到70%以上的重组质粒，转染至瘢痕成纤维细胞后，可有效抑制PTN表达，同未转染组相比，转染干扰质粒的瘢痕成纤维细胞生长、增殖受到抑制（P＜0.05）。流式细胞仪检测结果显示，PTN干扰质粒转染后瘢痕成纤维细胞的凋亡比率明显高于对照组（P＜0.05）。RT-PCR，Western Blot检测结果显示，PTN表达下调后，细胞内I、III型胶原含量较对照组显著降低。
结论：PTN是一种分泌性生长因子，在多种肿瘤组织中发现表达上调，研究发现PTN能够刺激细胞增殖、迁移、促进血管生成，瘢痕成纤维细胞转染PTN siRNA重组质粒后，PTN表达明显下调，细胞增殖被抑制，细胞内胶原蛋白的合成相比对照细胞下调明显。实验结果为我们提供了抑制增生性瘢痕形成的可能靶点，为基因治疗增生性瘢痕提供了的部分依据。
Pathologic scar is one of the most difficult clinical problems during plastic surgerydue to lacking of effective treatment. The formation mechanism of Hypertrophic scarhowever is not very clear. Generally speaking, it is caused by the abnormal proliferation offibroblast, making large number of collagen deposited in the extracellular matrix.Therefore, it is useful to study the expression of factors associating with proliferation offibroblast in elucidating the formation mechanism of hypertrophic scar and meaningful toexplore new methods on clinical treatment to hypertrophic scar.
Pleiotrophin (PTN) is a heparin-binding protein which was purified from the perinatalrat brain tissues by Milner in1989. Some studies indicated that PTN was also present inseveral non-neural tissues, such as uterine, heart, cartilage tissues. The main physiologicalfunctions are simulating the cell proliferation, migration, angiogenesis and promoting thedevelopment of bone and nervous system. Recently, Paddock found that PTN had a highexpression in the hypertrophic scar by Microarray profiling expression technology. But theeffect on the proliferation and apoptosis of fibroblast cells is still unclear.
Based on the results of these studies above, this study is to further validate whetherPTN had an expression difference between normal skins and hypertrophic scar tissues. Inaddition, fibroblast cells of scars were cultured in vitro and then down–regulated theexpression of PTN by RNA interference technology. At last, we detected the influences ofthe low expression of PTN on the proliferation and apoptosis of fibroblast cells, and makesure whether PTN was participate in the formation of Hypertrophic scars.
Part I experiment: Pathological Detection of ClinicalSamples
Objective：The formation mechanism of Hypertrophic scar is not very clear. Generallyspeaking, it is caused by the joint efforts of the abnormal proliferation of fibroblast anddeposition of collagen in the extracellular matrix. PTN is a highly conserved extracellularmatrix secretion protein, and has multiple biological functions as an oncogene. The aim ofthis study was to discuss whether PTN has an effect on the formation of hypertrophic scarbased on the different PTN expression between normal skin tissues and hypertrophic scars.
Methods：Patients with hypertrophic scars after surgery operation were randomlyselected, normal skin tissues were corresponded as control, HE and Masson staining wereused to observe the changes of morphology, RT-PCR, Western Blot andimmunohistochemistry were used to evaluate the expression and location of PTN in thehypertrophic scars.
Results：RT-PCR and Western Blot results showed that the expression of PTN in thehypertrophic scars were more higher than that in normal skin tissues, and had a significantdifference. The immunohistochemistry results showed that PTN expressed both in thedermal and epidermal cells, and had a positive expression in hypertrophic scars.
Conclusion：According to the results, we could infer that PTN may participate in theformation of hypertrophic scars. As it showed in the immunohistochemistry and stainingresults, PTN is likely to take part in the abnormal proliferation of fibroblast and depositionof collagen in the extracellular matrix. PTN could be expected as the therapeutic targets ofhyperplastic scar during the treatment.
Part II experiment PTN siRNA recombinant plasmidconstruction, preparation, identification and screening ofinterfering fragments
Objective：To screen the possible interfering targets of PTN, constructing andpreparing the recombinant plasmid of PTN. Fibroblast cells of scars were separated andcultured in vitro, then transfected the siRNA recombinant plasmid of PTN into the cells.The one had the most maximum efficiency was selected to do following research.
Methods：According to the designing principles of siRNA, selected the specialinterfering targets to design and construct the recombinant plasmid (verification bysequencing), then transfected into E. coli DH5α for culture. High purity recombinantplasmid was extracted by endotoxin-free plasmid extracting kit. Liposome method wasused to transfect the fibroblast cells. RT-PCR and Western Blot were used to test theexpression of PTN, choosing the most maximum interfering efficiency one to do followingcell research.
Results：Recombinant plasmid was successful constructed by sequencing verification.The extracted concentration of plasmid is enough for transfecting. PTN-sh3was conferredto had inhibition rate of70%to the expression of PTN in the experiment, which wasselected to do the following cell research..
Conclusion：PTN siRNA recombinant plasmid was successfully constructed in vitro,and the concentration and purity of the plasmid were enough for transfecting. Theinterfering effect of siRNA is consistent with expected and could be used for the followingresearch.
Part III experiment Effects of Down-regulation of PTNexpression by RNAi on hypertrophic scar fibroblasts
Objective：Transfect the screening recombinant plasmid into the fibroblast cells fromscars. To analysis the effect of down-regulated expression of PTN on fibroblastproliferation and the relationship with other associated genes at the level of cell, molecularand protein.
Methods：Evaluate the effect of down-regulated expression of PTN on cell growth byMTT, cell cycle and apoptosis experiment. Detect the interfering efficiency of siRNA tothe target gene and the changes of expression of ColⅠand ColⅢ by RT-PCR and WesternBlot.
Results：The selected recombinant plasmid by detection of RT-PCR and Western Blotcould inhibit the expression of PTN effectively, as well as the growth of fibroblast cellscomparing to the cell without transfection (P＜0.05). The results of RT-PCR and WesternBlot showed that the expression of ColⅠand ColⅢ had a significant decrease after theexpression of PTN being down regulated.
Conclusion：As a secreted growth factor, PTN had a higher expression in variouskinds of cancers. It could stimulate cell proliferation, migration and angiogenesis. Scarfibroblasts tansfected by PTN siRNA recombinant plasmid had a low expression of PTN,and cell proliferation was inhibited as well as the expression of ColⅠand ColⅢ. Theresults indicated that the PTN may be a candidate target for inhibiting the formation ofhypertrophic scars, and provide theoretical basis of gene therapy.
引文
[1] Milner PG, Li YS, Hoffman RM, Kodner CM, Siegel NR, Deuel TF. A novel17kDheparin-binding growth factor (HBGF-8) in bovine uterus: purification and N-terminal amino acidsequence. Biochem Biophys Res Commun[J].1989Dec29;165(3):1096-103.
[2] Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY. Pleiotrophin: a cytokine with diversefunctions and a novel signaling pathway. Arch Biochem Biophys[J].2002Jan15;397(2):162-71.
[3] Paddock HN, Schultz GS, Baker HV, Varela JC, Beierle EA, Moldawer LL, Mozingo DW.Analysis of gene expression patterns in human postburn hypertrophic scars. J Burn Care Rehabil[J].2003Nov-Dec;24(6):371-7.
[4] Zhao Y, He Q, Niu X.[Expression of alpha1-4integrins in hypertrophic scar fibroblasts][J].Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plasticsurgery.2000;16(1):37-9.
[5] Akaishi S, Ogawa R, Hyakusoku H. Keloid and hypertrophic scar: neurogenic inflammationhypotheses[J]. Medical hypotheses.2008;71(1):32-8.
[6] Ding J, Hori K, Zhang R, Marcoux Y, Honardoust D, Shankowsky HA, et al. Stromal cell-derivedfactor1(SDF-1) and its receptor CXCR4in the formation of postburn hypertrophic scar (HTS)[J].Wound repair and regeneration: official publication of the Wound Healing Society [and] the EuropeanTissue Repair Society.2011;19(5):568-78.
[7] Burd A, Huang L. Hypertrophic response and keloid diathesis: two very different forms of scar[J].Plastic and reconstructive surgery.2005;116(7):150e-7e.
[8] Liu JY, Li SR, Ji SX.[Expression of connective tissue growth factor gene in the hypertrophic scarand keloid tissue][J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waikezazhi=Chinese journal of reparative and reconstructive surgery.2003;17(6):436-8.
[9] Garver RI, Jr., Chan CS, Milner PG. Reciprocal expression of pleiotrophin and midkine in normalversus malignant lung tissues[J]. American journal of respiratory cell and molecular biology.1993;9(5):463-6.
[10] Souttou B, Raulais D, Vigny M. Pleiotrophin induces angiogenesis: involvement of thephosphoinositide-3kinase but not the nitric oxide synthase pathways[J]. Journal of cellular physiology.2001;187(1):59-64.
[11] Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY. Pleiotrophin: a cytokine with diversefunctions and a novel signaling pathway[J]. Archives of biochemistry and biophysics.2002;397(2):162-71.
[12] Rumsby M, Suggitt F, Haynes L, Hughson E, Kidd D, McNulty S. Substratum of pleiotrophin(HB-GAM) stimulates rat CG-4line oligodendrocytes to adopt a bipolar morphology and disperse:primary O-2A progenitor glial cells disperse similarly on pleiotrophin[J]. Glia.1999;26(4):361-7.
[13] Chung HW, Wen Y, Choi EA, Hao L, Moon HS, Yu HK, et al. Pleiotrophin (PTN) and midkine(MK) mRNA expression in eutopic and ectopic endometrium in advanced stage endometriosis[J].Molecular human reproduction.2002;8(4):350-5.
[14] Sato H, Funahashi M, Kristensen DB, Tateno C, Yoshizato K. Pleiotrophin as a Swiss3T3cell-derived potent mitogen for adult rat hepatocytes[J]. Experimental cell research.1999;246(1):152-64.
[15] Weber D, Klomp HJ, Czubayko F, Wellstein A, Juhl H. Pleiotrophin can be rate-limiting forpancreatic cancer cell growth[J]. Cancer research.2000;60(18):5284-8.
[16] Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, et al. Identification of anaplasticlymphoma kinase as a receptor for the growth factor pleiotrophin[J]. The Journal of biologicalchemistry.2001;276(20):16772-9.
[17] Ochiai K, Muramatsu H, Yamamoto S, Ando H, Muramatsu T. The role of midkine andpleiotrophin in liver regeneration[J]. Liver international: official journal of the InternationalAssociation for the Study of the Liver.2004;24(5):484-91.
[18] Grzelinski M, Bader N, Czubayko F, Aigner A. Ribozyme-targeting reveals the rate-limiting roleof pleiotrophin in glioblastoma[J]. International journal of cancer Journal international du cancer.2005;117(6):942-51.
[19] Feng ZJ, Gao SB, Wu Y, Xu XF, Hua X, Jin GH. Lung cancer cell migration is regulated viarepressing growth factor PTN/RPTP beta/zeta signaling by menin[J]. Oncogene.2010;29(39):5416-26.
[20] Satyamoorthy K, Oka M, Herlyn M. An antisense strategy for inhibition of human melanomagrowth targets the growth factor pleiotrophin[J]. Pigment cell research/sponsored by the EuropeanSociety for Pigment Cell Research and the International Pigment Cell Society.2000;13Suppl8:87-93.
[21] Christman KL, Fang Q, Kim AJ, Sievers RE, Fok HH, Candia AF, et al. Pleiotrophin inducesformation of functional neovasculature in vivo[J]. Biochemical and biophysical researchcommunications.2005;332(4):1146-52.
[22] Mourlevat S, Debeir T, Ferrario JE, Delbe J, Caruelle D, Lejeune O, et al. Pleiotrophin mediatesthe neurotrophic effect of cyclic AMP on dopaminergic neurons: analysis of suppression-subtractedcDNA libraries and confirmation in vitro[J]. Experimental neurology.2005;194(1):243-54.
[23] Taravini IR, Ferrario JE, Delbe J, Ginestet L, Debeir T, Courty J, et al. Immunodetection ofheparin-binding growth associated molecule (pleiotrophin) in striatal interneurons[J]. Brain research.2005;1066(1-2):196-200.
[24] Roger J, Brajeul V, Thomasseau S, Hienola A, Sahel JA, Guillonneau X, et al. Involvement ofPleiotrophin in CNTF-mediated differentiation of the late retinal progenitor cells[J]. Developmentalbiology.2006;298(2):527-39.
[25] Li SR, Liu JY, Ji SX.[Collagen synthesis and expression of connective tissue growth factor in thecultured fibroblasts of human hypertrophic scar][J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2004;20(2):124-7.
[26] Tao L, Liu JY, Li SR, Dai X, Li Z.[Function of STAT1in proliferation and differentiation ofhuman hypertrophic scar fibroblast induced by connective tissue growth factor][J]. Zhonghua yi xue zazhi.2009;89(16):1093-7.
[27] Lang Q, Liu Q, Xu N, Qian KL, Qi JH, Sun YC, et al. The antifibrotic effects of TGF-beta1siRNAon hepatic fibrosis in rats[J]. Biochemical and biophysical research communications.2011;409(3):448-53.
[28] Li Y, Yang K, Mao Q, Zheng X, Kong D, Xie L. Inhibition of TGF-beta receptor I by siRNAsuppresses the motility and invasiveness of T24bladder cancer cells via modulation of integrins andmatrix metalloproteinase[J]. International urology and nephrology.2010;42(2):315-23.
[29] Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma:new approaches to treatment[J]. PLoS medicine.2007;4(9): e234.
[30] Matsumoto K, Wanaka A, Takatsuji K, Muramatsu H, Muramatsu T, Tohyama M. A novel familyof heparin-binding growth factors, pleiotrophin and midkine, is expressed in the developing rat cerebralcortex[J]. Brain research Developmental brain research.1994;79(2):229-41.
[31] Lai S, Czubayko F, Riegel AT, Wellstein A. Structure of the human heparin-binding growth factorgene pleiotrophin[J]. Biochemical and biophysical research communications.1992;187(2):1113-22.
[32] Vanderwinden JM, Mailleux P, Schiffmann SN, Vanderhaeghen JJ. Cellular distribution of thenew growth factor pleiotrophin (HB-GAM) mRNA in developing and adult rat tissues[J]. Anatomy andembryology.1992;186(4):387-406.
[33] Muramatsu T. Midkine (MK), the product of a retinoic acid responsive gene, and pleiotrophinconstitute a new protein family regulating growth and differentiation[J]. The International journal ofdevelopmental biology.1993;37(1):183-8.
[34] Garver RI, Jr., Radford DM, Donis-Keller H, Wick MR, Milner PG. Midkine and pleiotrophinexpression in normal and malignant breast tissue[J]. Cancer.1994;74(5):1584-90.
[35] Mailleux P, Preud'homme X, Albala N, Vanderwinden JM, Vanderhaeghen JJ.delta-9-Tetrahydrocannabinol regulates gene expression of the growth factor pleiotrophin in theforebrain[J]. Neuroscience letters.1994;175(1-2):25-7.
[36] Mitsiadis TA, Salmivirta M, Muramatsu T, Muramatsu H, Rauvala H, Lehtonen E, et al.Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associatedwith epithelial-mesenchymal interactions during fetal development and organogenesis[J]. Development.1995;121(1):37-51.
[37] Sharifi BG, Zeng Z, Wang L, Song L, Chen H, Qin M, et al. Pleiotrophin inducestransdifferentiation of monocytes into functional endothelial cells[J]. Arteriosclerosis, thrombosis, andvascular biology.2006;26(6):1273-80.
[38] Nakagawara A, Milbrandt J, Muramatsu T, Deuel TF, Zhao H, Cnaan A, et al. Differentialexpression of pleiotrophin and midkine in advanced neuroblastomas[J]. Cancer research.1995;55(8):1792-7.
[39] Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer[J].Cancer letters.2004;204(2):127-43.
[40] Petersen W, Wildemann B, Pufe T, Raschke M, Schmidmaier G. The angiogenic peptidepleiotrophin (PTN/HB-GAM) is expressed in fracture healing: an immunohistochemical study in rats[J].Archives of orthopaedic and trauma surgery.2004;124(9):603-7.
[41] Wu H, Barusevicius A, Babb J, Klein-Szanto A, Godwin A, Elenitsas R, et al. Pleiotrophinexpression correlates with melanocytic tumor progression and metastatic potential[J]. Journal ofcutaneous pathology.2005;32(2):125-30.
[42]Hunter CP. Gene silencing: shrinking the black box of RNAi[J]. Current biology: CB.2000;10(4):R137-40.
[43] Barstead R. Genome-wide RNAi[J]. Current opinion in chemical biology.2001;5(1):63-6.
[44] Ishizuka A, Siomi MC, Siomi H. A Drosophila fragile X protein interacts with components ofRNAi and ribosomal proteins[J]. Genes&development.2002;16(19):2497-508.
[45] Grishok A, Mello CC. RNAi (Nematodes: Caenorhabditis elegans)[J]. Advances in genetics.2002;46:339-60.
[46] Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T. Single-stranded antisense siRNAsguide target RNA cleavage in RNAi[J]. Cell.2002;110(5):563-74.
[47] Fan Y, Xin XY, Chen BL, Ma X. Knockdown of RAB25expression by RNAi inhibits growth ofhuman epithelial ovarian cancer cells in vitro and in vivo[J]. Pathology.2006;38(6):561-7.
[48] Ushida C.[RNA interference (RNAi): gene suppression by dsRNA][J]. Tanpakushitsu kakusankoso Protein, nucleic acid, enzyme.2001;46(10):1381-6.
[49] Carthew RW. Synthesis of dsRNA for RNAi in Drosophila: PCR Template Method[J]. CSHprotocols.2006;2006(3).
[50] Dallas A, Johnston BH. Design and chemical modification of synthetic short shRNAs as potentRNAi triggers[J]. Methods Mol Biol.2013;942:279-90.
[51] Siolas D, Lerner C, Burchard J, Ge W, Linsley PS, Paddison PJ, et al. Synthetic shRNAs as potentRNAi triggers[J]. Nature biotechnology.2005;23(2):227-31.
[52] Zenke K, Kim KH. Novel fugu U6promoter driven shRNA expression vector for efficient vectorbased RNAi in fish cell lines[J]. Biochemical and biophysical research communications.2008;371(3):480-3.
[53] Zhao Y, He Q.[Study on the expression of calreticulin in hypertrophic scar-derived fibroblasts][J].Zhonghua zheng xing shao shang wai ke za zhi=Zhonghua zheng xing shao shang waikf [ie waike]zazhi=Chinese journal of plastic surgery and burns/[Chung-hua cheng hsing shao shang wai k'o tsachih pien1999;15(3):167-9.
[54] Zhang Z, Garron TM, Li XJ, Liu Y, Zhang X, Li YY, et al. Recombinant human decorin inhibitsTGF-beta1-induced contraction of collagen lattice by hypertrophic scar fibroblasts[J]. Burns: journal ofthe International Society for Burn Injuries.2009;35(4):527-37.
[55] Zhang LQ, Laato M, Muona P, Penttinen R, Oikarinen A, Peltonen J. A fibroblast cell line culturedfrom a hypertrophic scar displays selective downregulation of collagen gene expression: barelydetectable messenger RNA levels of the pro alpha1(III) chain of type III collagen[J]. Archives ofdermatological research.1995;287(6):534-8.
[56] Zhao Y, Niu X, Xiao J.[Study on the activity of fibroblast in hypertrophic scar][J]. Zhongguo xiufu chong jian wai ke za zhi=Zhongguo xiufu chongjian waike zazhi=Chinese journal of reparativeand reconstructive surgery.1998;12(2):108-12.
[57] Yang P, Wang AL, Liu DW, Xu S, Gu YH, Huang J, et al.[Effect of transfection of recombinanthuman endothelial nitric oxide synthase gene on hypertrophic scar fibroblasts in vitro][J]. Zhonghuashao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2008;24(4):275-7.
[58] Xiao Z, Zhang F, Lin W, Zhang M, Liu Y. Effect of botulinum toxin type A on transforminggrowth factor beta1in fibroblasts derived from hypertrophic scar: a preliminary report[J]. Aestheticplastic surgery.2010;34(4):424-7.
[59] Tabara H, Grishok A, Mello CC. RNAi in C. elegans: soaking in the genome sequence[J]. Science.1998;282(5388):430-1.
[60] Fire A. Nucleic acid structure and intracellular immunity: some recent ideas from the world ofRNAi[J]. Quarterly reviews of biophysics.2005;38(4):303-9.
[61] Pak J, Maniar JM, Mello CC, Fire A. Protection from Feed-Forward Amplification in an AmplifiedRNAi Mechanism[J]. Cell.2012;151(4):885-99.
[62] Agami R. RNAi and related mechanisms and their potential use for therapy[J]. Current opinion inchemical biology.2002;6(6):829-34.
[63] Bilanges B, Stokoe D. Direct comparison of the specificity of gene silencing using antisenseoligonucleotides and RNAi[J]. The Biochemical journal.2005;388(Pt2):573-83.
[64] Binnie U, Wong K, McAteer S, Masters M. Absence of RNASE III alters the pathway by whichRNAI, the antisense inhibitor of ColE1replication, decays[J]. Microbiology.1999;145(Pt11):3089-100.
[65] Byers HR, Boissel SJ, Tu C, Park HY. RNAi-mediated knockdown of protein kinase C-alphainhibits cell migration in MM-RU human metastatic melanoma cell line[J]. Melanoma research.2010;20(3):171-8.
[66] Caplen NJ, Mousses S. Short interfering RNA (siRNA)-mediated RNA interference (RNAi) inhuman cells[J]. Annals of the New York Academy of Sciences.2003;1002:56-62.
[67] Wang J, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE. Improvement in postburnhypertrophic scar after treatment with IFN-alpha2b is associated with decreased fibrocytes[J]. Journal ofinterferon&cytokine research: the official journal of the International Society for Interferon andCytokine Research.2007;27(11):921-30.
[68] Blondet B, Carpentier G, Lafdil F, Courty J. Pleiotrophin cellular localization in nerve regenerationafter peripheral nerve injury[J]. The journal of histochemistry and cytochemistry: official journal of theHistochemistry Society.2005;53(8):971-7.
[69] Clark DE, Lord EA, Suttie JM. Expression of VEGF and pleiotrophin in deer antler[J]. Theanatomical record Part A, Discoveries in molecular, cellular, and evolutionary biology.2006;288(12):1281-93.
[70] Gonzalez-Gonzalez E, Lopez-Casas PP, del Mazo J. The expression patterns of genes involved inthe RNAi pathways are tissue-dependent and differ in the germ and somatic cells of mouse testis[J].Biochimica et biophysica acta.2008;1779(5):306-11.
[71] Bai H, Palli SR. Functional characterization of bursicon receptor and genome-wide analysis foridentification of genes affected by bursicon receptor RNAi[J]. Developmental biology.2010;344(1):248-58.
[72] Baker N, Alsford S, Horn D. Genome-wide RNAi screens in African trypanosomes identify thenifurtimox activator NTR and the eflornithine transporter AAT6[J]. Molecular and biochemicalparasitology.2011;176(1):55-7.
[73] Kossi J, Vaha-Kreula M, Peltonen J, Risteli J, Laato M. Effect of sucrose on collagen metabolismin keloid, hypertrophic scar, and granulation tissue fibroblast cultures[J]. World journal of surgery.2001;25(2):142-6.
[74] Chu Y, Guo F, Li Y, Li X, Zhou T, Guo Y. A novel truncated TGF-beta receptor II downregulatescollagen synthesis and TGF-beta I secretion of keloid fibroblasts[J]. Connective tissue research.2008;49(2):92-8.
[75] Ju-Lin X, Shao-Hai Q, Tian-Zeng L, Chao-Quan L, Hou-Dong L, Ying-Bin X, et al. Attenuation ofalpha1collagen production with antisense ribonucleic acid in cultured hypertrophic scar fibroblasts[J].Journal of cutaneous medicine and surgery.2009;13(3):129-33.
[76] Krotzsch-Gomez FE, Furuzawa-Carballeda J, Reyes-Marquez R, Quiroz-Hernandez E, Diaz deLeon L. Cytokine expression is downregulated by collagen-polyvinylpyrrolidone in hypertrophicscars[J]. The Journal of investigative dermatology.1998;111(5):828-34.
[77] Kischer CW. Collagen and dermal patterns in the hypertrophic scar[J]. The Anatomical record.1974;179(1):137-45.
[78] Isaac C, Mathor MB, Bariani G, Paggiaro AO, Herson MR, Goldenstein-Schainberg C, et al.Pentoxifylline modifies three-dimensional collagen lattice model contraction and expression of collagentypes I and III by human fibroblasts derived from post-burn hypertrophic scars and from normal skin[J].Burns: journal of the International Society for Burn Injuries.2009;35(5):701-6.
[79] Berthod F, Germain L, Li H, Xu W, Damour O, Auger FA. Collagen fibril network and elasticsystem remodeling in a reconstructed skin transplanted on nude mice[J]. Matrix biology: journal of theInternational Society for Matrix Biology.2001;20(7):463-73.
[80] Callahan LA, Ganios AM, McBurney DL, Dilisio MF, Weiner SD, Horton WE, Jr., et al. ECMproduction of primary human and bovine chondrocytes in hybrid PEG hydrogels containing type Icollagen and hyaluronic acid[J]. Biomacromolecules.2012;13(5):1625-31.
[81] Wang L, Murthy SK, Barabino GA, Carrier RL. Synergic effects of crypt-like topography andECM proteins on intestinal cell behavior in collagen based membranes[J]. Biomaterials.2010;31(29):7586-98.
[82] Ramtani S. Mechanical modelling of cell/ECM and cell/cell interactions during the contraction of afibroblast-populated collagen microsphere: theory and model simulation[J]. Journal of biomechanics.2004;37(11):1709-18.
[83] Colwell AS, Phan TT, Kong W, Longaker MT, Lorenz PH. Hypertrophic scar fibroblasts haveincreased connective tissue growth factor expression after transforming growth factor-betastimulation[J]. Plastic and reconstructive surgery.2005;116(5):1387-90; discussion91-2.
[84] Cao C, Li S, Dai X, Chen Y, Feng Z, Zhao Y, et al. Genistein inhibits proliferation and functionsof hypertrophic scar fibroblasts[J]. Burns: journal of the International Society for Burn Injuries.2009;35(1):89-97.
[85] Cao B, Jiang MC, Lei ZY, Bai SF, Chen H. Effects of PLAB on apoptosis and Smad signalpathway of hypertrophic scar fibroblasts[J]. Journal of Asian natural products research.2008;10(1-2):147-57.
[86] Mi L, Li YY, Lin WH, Li G, Sun JE, Dai LB, et al.[The effect of intergrin-linked kinase on VEGFexpression in fibroblasts from human hypertrophic scar][J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2011;27(4):289-93.
[87] Wang Q, Wu Z.[A study on the detection of apoptosis of hypertrophic scar and its relatedmodulating factors][J]. Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal ofburns.2001;17(1):25-8.
[1] Chvapil M, Koopmann CF, Jr. Scar formation: physiology and pathological states[J].Otolaryngologic clinics of North America.1984;17(2):265-272.
[2] Wu WY, Zhu SZ, Wu RL, Zou CH, Wang ZY, Huang ZX. Expression and significance of Skp2and p27kip1protein in pathological scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxingwaike zazhi=Chinese journal of plastic surgery.2005;21(6):448-451.
[3] Yamada N, Kusumoto M, Maeshima A, Suzuki K, Matsuno Y. Correlation of the solid part onhigh-resolution computed tomography with pathological scar in small lung adenocarcinomas[J].Japanese journal of clinical oncology.2007;37(12):913-917.
[4] Liu Y, Cen Y, Ying T, Xu X. The role of myofibroblast in the development of pathological scar[J].Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waike zazhi=Chinese journal ofreparative and reconstructive surgery.2005;19(1):39-41.
[5] Akaishi S, Ogawa R, Hyakusoku H. Keloid and hypertrophic scar: neurogenic inflammationhypotheses[J]. Medical hypotheses.2008;71(1):32-38.
[6] Burd A, Huang L. Hypertrophic response and keloid diathesis: two very different forms of scar[J].Plastic and reconstructive surgery.2005;116(7):150e-157e.
[7] Jin PS, Chen JJ, Cen Y, Zhang AJ, Tao CB, Li XY. The effect of recombinant HSP47siRNA onthe pathological scar in nude mice: in vivo study[J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2009;25(5):377-380.
[8] Yang L, Scott PG, Dodd C, Medina A, Jiao H, Shankowsky HA, et al. Identification of fibrocytesin postburn hypertrophic scar[J]. Wound repair and regeneration: official publication of the WoundHealing Society [and] the European Tissue Repair Society.2005;13(4):398-404.
[9] Tan J, Peng X, Luo G, Ma B, Cao C, He W, et al. Investigating the role of P311in the hypertrophicscar[J]. PloS one.2010;5(4): e9995.
[10] Dasu MR, Hawkins HK, Barrow RE, Xue H, Herndon DN. Gene expression profiles fromhypertrophic scar fibroblasts before and after IL-6stimulation[J]. The Journal of pathology.2004;202(4):476-485.
[11] Ghahary A, Shen YJ, Nedelec B, Scott PG, Tredget EE. Enhanced expression of mRNA forinsulin-like growth factor-1in post-burn hypertrophic scar tissue and its fibrogenic role by dermalfibroblasts[J]. Molecular and cellular biochemistry.1995;148(1):25-32.
[12] Sidgwick GP, Bayat A. Extracellular matrix molecules implicated in hypertrophic and keloidscarring[J]. Journal of the European Academy of Dermatology and Venereology: JEADV.2012;26(2):141-152.
[13] Leng XF, Wang DC, Huo R, Zhang Q, Xue WJ. Expression and significance of TRAIL receptorsin fibroblasts of hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waikezazhi=Chinese journal of plastic surgery.2005;21(6):444-7.
[14] Cheng YC, Kuo WW, Wu HC, Lai TY, Wu CH, Hwang JM, et al. ZAK induces MMP-2activityvia JNK/p38signals and reduces MMP-9activity by increasing TIMP-1/2expression in H9c2cardiomyoblast cells[J]. Molecular and cellular biochemistry.2009;325(1-2):69-77.
[15] Garner WL, Rittenberg T, Ehrlich HP, Karmiol S, Rodriguez JL, Smith DJ, et al. Hypertrophic scarfibroblasts accelerate collagen gel contraction[J]. Wound repair and regeneration: official publication ofthe Wound Healing Society [and] the European Tissue Repair Society.1995;3(2):185-191.
[16] Kossi J, Laato M. Different metabolism of hexose sugars and sucrose in wound fluid and infibroblast cultures derived from granulation tissue, hypertrophic scar and keloid[J]. Pathobiology:journal of immunopathology, molecular and cellular biology.2000;68(1):29-35.
[17] Guo S, Zhang L, Wang Z, Liu J. Effects of conditioned medium derived from differentkeratinocytes on proliferation and collagen synthesis of hypertrophic scar fibroblasts[J]. Zhonghuazheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2002;18(2):83-85.
[18] Tao L, Liu JY, Li SR, Dai X, Li Z. Function of STAT1in proliferation and differentiation ofhuman hypertrophic scar fibroblast induced by connective tissue growth factor[J]. Zhonghua yi xue zazhi.2009;89(16):1093-1097.
[19] Ghahary A, Shen YJ, Scott PG, Gong Y, Tredget EE. Enhanced expression of mRNA fortransforming growth factor-beta, type I and type III procollagen in human post-burn hypertrophic scartissues[J]. The Journal of laboratory and clinical medicine.1993;122(4):465-473.
[20] Ghahary A, Ghaffari A. Role of keratinocyte-fibroblast cross-talk in development of hypertrophicscar[J]. Wound repair and regeneration: official publication of the Wound Healing Society [and] theEuropean Tissue Repair Society.2007;15Suppl1: S46-53.
[21] Fumagalli M, Musso T, Vermi W, Scutera S, Daniele R, Alotto D, et al. Imbalance between activinA and follistatin drives postburn hypertrophic scar formation in human skin[J]. Experimentaldermatology.2007;16(7):600-610.
[22] Varkey M, Ding J, Tredget EE. Differential collagen-glycosaminoglycan matrix remodeling bysuperficial and deep dermal fibroblasts: potential therapeutic targets for hypertrophic scar[J].Biomaterials.2011;32(30):7581-7591.
[23] van der Veer WM, Bloemen MC, Ulrich MM, Molema G, van Zuijlen PP, Middelkoop E, et al.Potential cellular and molecular causes of hypertrophic scar formation[J]. Burns: journal of theInternational Society for Burn Injuries.2009;35(1):15-29.
[24] Chen L, Wang Z, Li S, Zhao G, Tian M, Sun Z. SFRP2and Slug Contribute to Cellular Resistanceto Apoptosis in Hypertrophic Scars[J]. PloS one.2012;7(12): e50229.
[25] Guan B, Xu S, Bao W. Study on apoptosis of fibroblasts from abnormal scars in media containinglow level of serum and interleukin1beta[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxingwaike zazhi=Chinese journal of plastic surgery.2001;17(5):279-281.
[26] Bao W, Xu S. Mechanism of abnormal scars with treatment of steroid[J]. Zhonghua wai ke za zhi
[Chinese journal of surgery].2000;38(5):378-381.
[27] Ding J, Hori K, Zhang R, Marcoux Y, Honardoust D, Shankowsky HA, et al. Stromal cell-derivedfactor1(SDF-1) and its receptor CXCR4in the formation of postburn hypertrophic scar (HTS)[J].Wound repair and regeneration: official publication of the Wound Healing Society [and] the EuropeanTissue Repair Society.2011;19(5):568-578.
[28] Mi L, Li YY, Lin WH, Li G, Sun JE, Dai LB, et al. The effect of intergrin-linked kinase on VEGFexpression in fibroblasts from human hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2011;27(4):289-293.
[29] Kuhn MA, Moffit MR, Smith PD, Lyle WG, Ko F, Meltzer DD, et al. Silicone sheeting decreasesfibroblast activity and downregulates TGFbeta2in hypertrophic scar model[J]. International journal ofsurgical investigation.2001;2(6):467-474.
[30] Chen W, Fu XB, Sun TZ. Gene expression of stress activated protein kinase and its MAPKs inhypertrophic scar[J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waikezazhi=Chinese journal of reparative and reconstructive surgery.2004;18(1):1-3.
[31] Reid RR, Roy N, Mogford JE, Zimmerman H, Lee C, Mustoe TA. Reduction of hypertrophic scarvia retroviral delivery of a dominant negative TGF-beta receptor II[J]. Journal of plastic, reconstructive&aesthetic surgery: JPRAS.2007;60(1):64-72; discussion3-4.
[32] Schmid P, Itin P, Cherry G, Bi C, Cox DA. Enhanced expression of transforming growthfactor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar[J]. TheAmerican journal of pathology.1998;152(2):485-493.
[33] Dabiri G, Tumbarello DA, Turner CE, Van de Water L. Hic-5promotes the hypertrophic scarmyofibroblast phenotype by regulating the TGF-beta1autocrine loop[J]. The Journal of investigativedermatology.2008;128(10):2518-2525.
[34] Hou XH, Cao B, Liu HQ, Wang YZ, Bai SF, Chen H. Effects of osthole on apoptosis andTGF-beta1of hypertrophic scar fibroblasts[J]. Journal of Asian natural products research.2009;11(7):663-669.
[35] Zunwen L, Shizhen Z, Dewu L, Yungui M, Pu N. Effect of tetrandrine on the TGF-beta-inducedsmad signal transduction pathway in human hypertrophic scar fibroblasts in vitro[J]. Burns: journal ofthe International Society for Burn Injuries.2012;38(3):404-413.
[36] Zhang GY, He B, Liao T, Luan Q, Tao C, Nie CL, et al. Caveolin1inhibits transforming growthfactor-beta1activity via inhibition of Smad signaling by hypertrophic scar derived fibroblasts in vitro[J].Journal of dermatological science.2011;62(2):128-131.
[37] Zhang Z, Finnerty CC, He J, Herndon DN. Smad ubiquitination regulatory factor2expression isenhanced in hypertrophic scar fibroblasts from burned children[J]. Burns: journal of the InternationalSociety for Burn Injuries.2012;38(2):236-246.
[38] Zhang Y, Qiu L, Li MY. Effects of radix astragali on expression of transforming growth factorbeta1and Smad3signal pathway in hypertrophic scar of rabbit[J]. Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2010;26(5):366-370.
[39] Zhang CD, Tian Y, Song L, Zhang CP. The influence of adrenaline on the expression ofTGF-beta1, bFGF and I procollagen for hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2005;21(6):440-444.
[40] Wang R, Ghahary A, Shen Q, Scott PG, Roy K, Tredget EE. Hypertrophic scar tissues andfibroblasts produce more transforming growth factor-beta1mRNA and protein than normal skin andcells[J]. Wound repair and regeneration: official publication of the Wound Healing Society [and] theEuropean Tissue Repair Society.2000;8(2):128-137.
[41] Song B, Lu K, Zhang Y, Guo S, Han Y, Ma F, et al. Angiogenesis in hypertrophic scar of rabbitears and effect of extracellular protein with metalloprotease and thrombospondin1domains onhypertrophic scar[J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waikezazhi=Chinese journal of reparative and reconstructive surgery.2008;22(1):70-74.
[42] Ting-An W, Hong-Xiang Z. PTK-pathways and TGF-beta signaling pathways in schistosomes[J].Journal of basic microbiology.2009;49(1):25-31.
[43] Tredget EE, Wang R, Shen Q, Scott PG, Ghahary A. Transforming growth factor-beta mRNA andprotein in hypertrophic scar tissues and fibroblasts: antagonism by IFN-alpha and IFN-gamma in vitroand in vivo[J]. Journal of interferon&cytokine research: the official journal of the InternationalSociety for Interferon and Cytokine Research.2000;20(2):143-151.
[44] Wang J, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE. Improvement in postburnhypertrophic scar after treatment with IFN-alpha2b is associated with decreased fibrocytes[J]. Journal ofinterferon&cytokine research: the official journal of the International Society for Interferon andCytokine Research.2007;27(11):921-930.
[45] Cao C, Li SR, Dai X, Chen YQ, Feng Z, Qin X, et al. The effects of genistein on tyrosine proteinkinase-mitogen activated protein kinase signal transduction pathway in hypertrophic scar fibroblasts[J].Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2008;24(2):118-121.
[46] Acarin L, Gonzalez B, Castellano B. STAT3and NFkappaB activation precedes glial reactivity inthe excitotoxically injured young cortex but not in the corresponding distal thalamic nuclei[J]. Journalof neuropathology and experimental neurology.2000;59(2):151-163.
[47] Shimizu T, Kanai K, Kyo Y, Asano K, Hisamitsu T, Suzaki H. Effect of tranilast on matrixmetalloproteinase production from neutrophils in-vitro[J]. The Journal of pharmacy and pharmacology.2006;58(1):91-99.
[48] Van Tassell BW, Seropian IM, Toldo S, Salloum FN, Smithson L, Varma A, et al. Pharmacologicinhibition of myeloid differentiation factor88(MyD88) prevents left ventricular dilation andhypertrophy after experimental acute myocardial infarction in the mouse[J]. Journal of cardiovascularpharmacology.2010;55(4):385-390.
[49] De Felice B, Ciarmiello LF, Mondola P, Damiano S, Seru R, Argenziano C, et al. Differential p63and p53expression in human keloid fibroblasts and hypertrophic scar fibroblasts[J]. DNA and cellbiology.2007;26(8):541-547.
[50] Oku T, Takigawa M, Fukamizu H, Inoue K, Yamada M. Growth kinetics of fibroblasts derivedfrom normal skin and hypertrophic scar[J]. Acta dermato-venereologica.1987;67(6):526-528.
[51] Song W, Sun G, Guan Z. Comparative study on biological characteristics and ultrastructure of thefibroblasts derived from normal skin, hypertrophic scar and keloidin in vitro culture[J]. Zhonghua zhengxing shao shang wai ke za zhi=Zhonghua zheng xing shao shang waikf [ie waike] zazhi=Chinesejournal of plastic surgery and burns/[Chung-hua cheng hsing shao shang wai k'o tsa chih pien1998;14(6):410-413.
[52] Colwell AS, Phan TT, Kong W, Longaker MT, Lorenz PH. Hypertrophic scar fibroblasts haveincreased connective tissue growth factor expression after transforming growth factor-betastimulation[J]. Plastic and reconstructive surgery.2005;116(5):1387-90; discussion91-92.
[53] Linares HA, Kischer CW, Dobrkovsky M, Larson DL. The histiotypic organization of thehypertrophic scar in humans[J]. The Journal of investigative dermatology.1972;59(4):323-331.
[54] Phan TT, Sun L, Bay BH, Chan SY, Lee ST. Dietary compounds inhibit proliferation andcontraction of keloid and hypertrophic scar-derived fibroblasts in vitro: therapeutic implication forexcessive scarring[J]. The Journal of trauma.2003;54(6):1212-1224.
[55] Peck GL. Hypertrophic scar after cryotherapy and topical tretinoin[J]. Archives of dermatology.1973;108(6):819-822.
[56] Li-Tsang CW, Feng BB, Li KC. Pressure therapy of hypertrophic scar after burns and relatedresearch[J]. Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2010;26(6):411-415.
[57] Harrop AR, Ghahary A, Scott PG, Forsyth N, Uji-Friedland A, Tredget EE. Regulation of collagensynthesis and mRNA expression in normal and hypertrophic scar fibroblasts in vitro byinterferon-gamma[J]. The Journal of surgical research.1995;58(5):471-477.
[58] Ketchum LD, Smith J, Robinson DW, Masters FW. The treatment of hypertrophic scar, keloid andscar contracture by triamcinolone acetonide[J]. Plastic and reconstructive surgery.1966;38(3):209-218.
[59] Saulis AS, Chao JD, Telser A, Mogford JE, Mustoe TA. Silicone occlusive treatment ofhypertrophic scar in the rabbit model[J]. Aesthetic surgery journal/the American Society for AestheticPlastic surgery.2002;22(2):147-153.
[60] Gilman TH. Silicone sheet for treatment and prevention of hypertrophic scar: a new proposal forthe mechanism of efficacy[J]. Wound repair and regeneration: official publication of the WoundHealing Society [and] the European Tissue Repair Society.2003;11(3):235-236.
[61] Lee SJ, Kim JH, Lee SE, Chung WS, Oh SH, Cho SB. Hypertrophic scarring after burn scartreatment with a10,600-nm carbon dioxide fractional laser[J]. Dermatologic surgery: officialpublication for American Society for Dermatologic Surgery [et al].2011;37(8):1168-1172.
[62] Iannello S, Milazzo P, Bordonaro F, Belfiore F. Low-dose enalapril in the treatment of surgicalcutaneous hypertrophic scar and keloid--two case reports and literature review[J]. MedGenMed:Medscape general medicine.2006;8(4):60.
[63] Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Valle CA, Roy M. Normal skin wound andhypertrophic scar myofibroblasts have differential responses to apoptotic inductors[J]. Journal ofcellular physiology.2004;198(3):350-358.
[64] Gu H, He Q, Lin Z, Liu Q, Zhang X. Effects of microfilaments on the expression of collagenasesand tissue inhibitor of metalloproteinases-1in fibroblasts[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2002;18(3):163-164.
[65] Deten A, Holzl A, Leicht M, Barth W, Zimmer HG. Changes in extracellular matrix and intransforming growth factor beta isoforms after coronary artery ligation in rats[J]. Journal of molecularand cellular cardiology.2001;33(6):1191-1207.
[66] Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH. Macrophagesin skin injury and repair[J]. Immunobiology.2011;216(7):753-762.
[67] Schultze-Mosgau S, Blaese MA, Grabenbauer G, Wehrhan F, Kopp J, Amann K, et al. Smad-3andSmad-7expression following anti-transforming growth factor beta1(TGFbeta1)-treatment in irradiatedrat tissue[J]. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiologyand Oncology.2004;70(3):249-259.
[68] Ghahary A, Shen YJ, Nedelec B, Wang R, Scott PG, Tredget EE. Collagenase production is lowerin post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-likegrowth factor-1[J]. The Journal of investigative dermatology.1996;106(3):476-481.
[69] Li SR, Liu JY, Ji SX. Collagen synthesis and expression of connective tissue growth factor in thecultured fibroblasts of human hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2004;20(2):124-127.
[70] Guoyou Z, Chenggang Y, Chengyue M, Xuan L, Yan Z, Wei X, et al. Modulation of transforminggrowth factor-beta1production by vector-based RNAi in hypertrophic scar fibroblasts: a therapeuticpotential strategy for hypertrophic scar[J]. Journal of dermatological science.2007;48(1):67-70.
[71] Ha X, Yuan B, Li Y, Lao M, Wu Z. Gene therapy for pathological scar with hepatocyte growthfactor mediated by recombinant adenovirus vector[J]. Science in China Series C, Life sciences/ChineseAcademy of Sciences.2003;46(3):320-327.
[72] Anderson WF, Fletcher JC. Sounding boards. Gene therapy in human beings: when is it ethical tobegin?[J]. The New England journal of medicine.1980;303(22):1293-1297.
[73] Anderson WF, Blaese RM, Culver K. The ADA human gene therapy clinical protocol: Points toConsider response with clinical protocol, July6,1990[J]. Human gene therapy.1990;1(3):331-362.
[74]王健民，韩风来，杨建民，血友病B基因治疔临床研究中华血液学杂志[J]，1994，15；282—285
[75] Diao JS, Zhang X, Ren J, Zeng HF, Liu B, Ma FC, et al. Blocking of Notch signaling decreasedscar formation in rabbit ear hypertrophic scar model[J]. Zhonghua yi xue za zhi.2009;89(16):1088-1092.
[76] Arakawa M, Hatamochi A, Mori Y, Mori K, Ueki H, Moriguchi T. Reduced collagenase geneexpression in fibroblasts from hypertrophic scar tissue[J]. The British journal of dermatology.1996;134(5):863-868.
[77] Qui L, Jin X, Kingston PA, Luo X, Ding X.[Experimental study on BMSCs transfected byendogene inhibiting hypertrophic scar][J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufuchongjian waike zazhi=Chinese journal of reparative and reconstructive surgery.2008;22(2):212-216.
[78] Qi S, Li T, Shan Y. Inhibiting effect of antisense oligodeoxynucleotide of alpha1(I) Precollagengene on hypertrophic scar in an animal model[J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2000;16(5):295-297.
[79] Lu F, Gao J, Ogawa R, Hyakusoku H, Ou C. Fas-mediated apoptotic signal transduction in keloidand hypertrophic scar[J]. Plastic and reconstructive surgery.2007;119(6):1714-1721.
[80] Liu YB, Gao JH, Liu XJ, Lu F, Liu HW. The effect of tunicamycin on Fas protein expression andits function in fibroblasts from hypertrophic scar and keloid[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2009;25(3):213-216.
[81] Sun Z, Li S, Cao C, Wu J, Ma B, Tran V. shRNA targeting SFRP2promotes the apoptosis ofhypertrophic scar fibroblast[J]. Molecular and cellular biochemistry.2011;352(1-2):25-33.
[1] Milner PG`, Li YS，Hoffinan RM`, et aL. A novel l7kDa heparin-binding growth factor(HBGF-8)in bovine uterus: purifieationand N-terminal amino amino acid sequence.[J]. Bioehem BioPhys ResCommun. I989`;165:1096-1103
[2] Rauvala H.M18-kd heparin-binding protein of developing brain that is distinct from fibrobIastgrowth factors [J]. EMBO J.1989`;8:2933-2941.
[3] Huber D`, Gautschi-Sova P. Amino-teminal sequences of a novel heparin-binding protein fromhuman`, bovine`, rat`, and chick brain: high interspecies homology [J]. NeuroChem Res.1990`;15:435-439.
[4] Courty J, Dauchel MC, Caruelle D, Perderiset M, Barritault D. Mitogenic properties of a newendothelial cell growth factor related to pleiotrophin [J]. Biochemical and biophysical researchcommunications.1991Oct15;180(1):145-151.
[5] Tezuka K`, Takeshita S`, HakedaY`, et aI. Isolation of mouse and human Cdna clones eneodind aprotein expressed specifically in osteoblast and brain tissues [J]. Biochem BioPhys Res Commun.1990`;173:246-251.
[6] Bohlen P, Kovesdi I. HBNF and MK, members of a novel gene family of heparin-binding proteinswith potential roles in embryogenesis and brain function [J]. Progress in growth factor research.1991;3(2):143-157.
[7] Hampton BS, Marshak DR, Burgess WH. Structural and functional characterization of full-lengthheparin-binding growth associated molecule [J]. Molecular biology of the cell.1992Jan;3(1):85-93.
[8] Li YS, Gurrieri M, Deuel TF. Pleiotrophin gene expression is highly restricted and is regulated byplatelet-derived growth factor [J]. Biochemical and biophysical research communications.1992Apr15;184(1):427-432.
[9] Svensson SL, Pasupuleti M, Walse B, Malmsten M, Morgelin M, Sjogren C, et al. Midkine andpleiotrophin have bactericidal properties: preserved antibacterial activity in a family of heparin-bindinggrowth factors during evolution [J]. J Biol Chem.2010May21;285(21):16105-16115.
[10] Roth TM`, Klett C`, Cowan BD`, et al. Ecpression profile of several genes in human myometriumand uterine leiomyoma [J]. Fertil Steril.2007Mar`;87(3):635-641.
[11] Vanderwinden JM, Mailleux P, Schiffmann SN, Vanderhaeghen JJ. Cellular distribution of thenew growth factor pleiotrophin (HB-GAM) mRNA in developing and adult rat tissues [J]. AnatEmbryol (Berl).1992Sep;186(4):387-406.
[12] Deuel T F`, Zhang N`, Yeh H J`, et al. Pleiotrophin: a cylokine wish diverse functions and a novelsignaling pathway [J]. Arch. Biochem Biophys.2002`;397:162-171.
[13] Fabri L`, Nice E C`, Ward L D`, et al. Characerization of bovine heparin-binding neurotrophicfactor(HBNF)-assignment of disulfide honds [J]. Biochem Int.1992`;28:1-9.
[14] Park T J`, Jeong BR`, Tateno C`, et al. Pleiotrophin inhibits transforming growth factorbetal-induced apoptosis in hepatoma cell lines [J]. Mol Careinog.2008Oct:47(10):784-796.
[15] Jung CG, Hida H, Nakahira K, Ikenaka K, Kim HJ, Nishino H. Pleiotrophin mRNA is highlyexpressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotesproduction of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells [J]. FASEBJ.2004Aug;18(11):1237-1239.
[16] Fukazawa N, Yokoyama S, Eiraku M, Kengaku M, Maeda N. Receptor type protein tyrosinephosphatase zeta-pleiotrophin signaling controls endocytic trafficking of DNER that regulatesneuritogenesis [J]. Mol Cell Biol.2008Jul;28(14):4494-4506.
[17] Soh BS, Song CM, Vallier L, Li P, Choong C, Yeo BH, et al. Pleiotrophin enhances clonal growthand long-term expansion of human embryonic stem cells [J]. Stem Cells.2007Dec;25(12):3029-3037.
[18] Jin L, Jianghai C, Juan L, Hao K. Pleiotrophin and peripheral nerve injury [J]. Neurosurg Rev.2009Oct;32(4):387-933.
[19] Yao J, Ma Q, Wang L, Zhang M. Pleiotrophin expression in human pancreatic cancer and itscorrelation with clinicopathological features, perineural invasion, and prognosis [J]. Dig Dis Sci.2009Apr;54(4):895-901.
[20] Achour A, M'Bika J P, Baudouin F, Caruelle D, Courty J. Pleiotrophin induces expression ofinflammatory cytokines in peripheral blood mononuclear cells [J]. Biochimie.2008Nov-Dec;90(11-12):1791-1795.
[21] Mashour GA, Ratner N, Khan GA, Wang HL, Martuza RL, Kurtz A. The angiogenic factormidkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen forneurofibroma-derived cells [J]. Oncogene.2001Jan4;20(1):97-105.
[22] Ezquerra L, Alguacil LF, Nguyen T, Deuel TF, Silos-Santiago I, Herradon G. Different pattern ofpleiotrophin and midkine expression in neuropathic pain: correlation between changes in pleiotrophingene expression and rat strain differences in neuropathic pain [J]. Growth Factors.2008Feb;26(1):44-48.
[23] Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer [J].Cancer Lett.2004Feb20;204(2):127-143.
[24] Hamma-Kourbali Y, Bernard-Pierrot I, Heroult M, Dalle S, Caruelle D, Milhiet PE, et al.Inhibition of the mitogenic, angiogenic and tumorigenic activities of pleiotrophin by a synthetic peptidecorresponding to its C-thrombospondin repeat-I domain [J]. Journal of cellular physiology.2008Jan;214(1):250-259.
[25] Rosenfield SM, Bowden ET, Cohen-Missner S, Gibby KA, Ory V, Henke RT, et al. Pleiotrophin(PTN) expression and function and in the mouse mammary gland and mammary epithelial cells [J].PLoS One.2012;7(10):e47876.
[26] Weng T, Gao L, Bhaskaran M, Guo Y, Gou D, Narayanaperumal J, et al. Pleiotrophin regulateslung epithelial cell proliferation and differentiation during fetal lung development via beta-catenin andDlk1[J]. J Biol Chem.2009Oct9;284(41):28021-28032.
[27] Neidlinger-Wilke C, Liedert A, Wuertz K, Buser Z, Rinkler C, Kafer W, et al. Mechanicalstimulation alters pleiotrophin and aggrecan expression by human intervertebral disc cells andinfluences their capacity to stimulate endothelial migration [J]. Spine (Phila Pa1976).2009Apr1;34(7):663-669.
[28] Heiss C, Wong ML, Block VI, Lao D, Real WM, Yeghiazarians Y, et al. Pleiotrophin inducesnitric oxide dependent migration of endothelial progenitor cells [J]. J Cell Physiol.2008May;215(2):366-373.
[29] Orr B, Vanpoucke G, Grace OC, Smith L, Anderson RA, Riddick AC, et al. Expression ofpleiotrophin in the prostate is androgen regulated and it functions as an autocrine regulator ofmesenchyme and cancer associated fibroblasts and as a paracrine regulator of epithelia [J]. The Prostate.2011Feb15;71(3):305-317.
[30] Chang Y, Berenson JR, Wang Z, Deuel TF. Dominant negative pleiotrophin induces tetraploidyand aneuploidy in U87MG human glioblastoma cells [J]. Biochem Biophys Res Commun.2006Dec15;351(2):336-339.
[31] Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R. Expression of pleiotrophin, anembryonic growth and differentiation factor, in rheumatoid arthritis [J]. Arthritis and rheumatism.2003Mar;48(3):660-667.
[32] Li G, Bunn JR, Mushipe MT, He Q, Chen X. Effects of pleiotrophin (PTN) over-expression onmouse long bone development, fracture healing and bone repair [J]. Calcif Tissue Int.2005Apr;76(4):299-306.
[33] Imai S, Heino TJ, Hienola A, Kurata K, Buki K, Matsusue Y, et al. Osteocyte-derived HB-GAM(pleiotrophin) is associated with bone formation and mechanical loading [J]. Bone.2009May;44(5):785-794.
[34] Mitsiadis TA, Salmivirta M, Muramatsu T, Muramatsu H, Rauvala H, Lehtonen E, et al.Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associatedwith epithelial-mesenchymal interactions during fetal development and organogenesis [J]. Development.1995Jan;121(1):37-51.
[35] Mikelis C, Papadimitriou E. Heparin-binding protein pleiotrophin: an important player in theangiogenic process [J]. Connect Tissue Res.2008;49(3):149-152.
[36] Perez-Pinera P, Berenson JR, Deuel TF. Pleiotrophin, a multifunctional angiogenic factor:mechanisms and pathways in normal and pathological angiogenesis [J]. Current opinion in hematology.2008May;15(3):210-214.
[37] Choudhuri R, Zhang HT, Donnini S, Ziche M, Bicknell R. An angiogenic role for the neurokinesmidkine and pleiotrophin in tumorigenesis [J]. Cancer Res.1997May1;57(9):1814-1819.
[38] Ezquerra L, Herradon G, Nguyen T, Vogt TF, Bronson R, Silos-Santiago I, et al. Pleiotrophin is amajor regulator of the catecholamine biosynthesis pathway in mouse aorta [J]. Biochem Biophys ResCommun.2004Oct15;323(2):512-517.
[39] Zhang N, Zhong R, Perez-Pinera P, Herradon G, Ezquerra L, Wang ZY, et al. Identification of theangiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch [J].Biochem Biophys Res Commun.2006May5;343(2):653-658.
[40]Takei Y`, Kadomatsu K`, Yuasa K`, et al. Morpholino antisense oligomer targeting human midkine:its application for cancer therapy [J]. International Journal of Cancer.2005`;114:490-497.
[41] Chen S, Bu G, Takei Y, Sakamoto K, Ikematsu S, Muramatsu T, et al. Midkine andLDL-receptor-related protein1contribute to the anchorage-independent cell growth of cancer cells [J].Journal of cell science.2007Nov15;120(Pt22):4009-4015.
[42] Kong Y, Bai PS, Nan KJ, Sun H, Chen NZ, Qi XG. Pleiotrophin is a potential colorectal cancerprognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer [J]. IntJ Colorectal Dis.2012Mar;27(3):287-298.
[43] Weber D, Klomp HJ, Czubayko F, Wellstein A, Juhl H. Pleiotrophin can be rate-limiting forpancreatic cancer cell growth [J]. Cancer Res.2000Sep15;60(18):5284-5288.
[44] Duces A, Karaky R, Martel-Renoir D, Mir L, Hamma-Kourbali Y, Bieche I, et al.16-kDa fragmentof pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development [J]. MolCancer Ther.2008Sep;7(9):2817-2827.
[45] Park TJ, Jeong BR, Tateno C, Kim HS, Ogawa T, Lim IK, et al. Pleiotrophin inhibits transforminggrowth factor beta1-induced apoptosis in hepatoma cell lines [J]. Mol Carcinog.2008Oct;47(10):784-796.
[46] Chang Y, Zuka M, Perez-Pinera P, Astudillo A, Mortimer J, Berenson JR, et al. Secretion ofpleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment[J]. Proc Natl Acad Sci U S A.2007Jun26;104(26):10888-10893.
[47] Souttou B, Juhl H, Hackenbruck J, Rockseisen M, Klomp HJ, Raulais D, et al. Relationshipbetween serum concentrations of the growth factor pleiotrophin and pleiotrophin-positive tumors [J]. JNatl Cancer Inst.1998Oct7;90(19):1468-1473.
[48] Tsirmoula S, Dimas K, Hatziapostolou M, Lamprou M, Ravazoula P, Papadimitriou E.Implications of pleiotrophin in human PC3prostate cancer cell growth in vivo [J]. Cancer Sci.2012Oct;103(10):1826-1832.
[49] Silver K, Desormaux A, Freeman LC, Lillich JD. Expression of pleiotrophin, an importantregulator of cell migration, is inhibited in intestinal epithelial cells by treatment with non-steroidalanti-inflammatory drugs [J]. Growth Factors.2012Aug;30(4):258-266.
[50] Sharifi BG, Zeng Z, Wang L, Song L, Chen H, Qin M, et al. Pleiotrophin inducestransdifferentiation of monocytes into functional endothelial cells [J]. Arterioscler Thromb Vasc Biol.2006Jun;26(6):1273-1280.
[51] Papadimitriou E, Mikelis C, Lampropoulou E, Koutsioumpa M, Theochari K, Tsirmoula S, et al.Roles of pleiotrophin in tumor growth and angiogenesis [J]. Eur Cytokine Netw.2009Dec;20(4):180-190.
[52] Klomp HJ, Zernial O, Flachmann S, Wellstein A, Juhl H. Significance of the expression of thegrowth factor pleiotrophin in pancreatic cancer patients [J]. Clin Cancer Res.2002Mar;8(3):823-827.
[53] Gao SB, Feng ZJ, Xu B, Wu Y, Yin P, Yang Y, et al. Suppression of lung adenocarcinoma throughmenin and polycomb gene-mediated repression of growth factor pleiotrophin [J]. Oncogene.2009Nov19;28(46):4095-4104.
[54] Yu Y, Shi MH, Xu X, Zhang ZL, Hu HC. Analysis of expression profiles of some tumorgrowth-related genes after silencing of pleiotrophin in human small cell lung cancer H446cells[J].Zhonghua Zhong Liu Za Zhi.2010Jun;32(6):405-409.
[55] Yu Y, Shi MH, Xu X, Hu HC. Construction of siRNA lentiviral expressing vector targetingpleiotrophin gene and its impact on growth and apoptosis in H446cells of human small cell lung cancer[J]. Zhonghua Jie He He Hu Xi Za Zhi.2010Apr;33(4):289-294.
[56] Hu YC, Liu ML, Li G, Huo YY, Wu DC. A pleiotrophin-specific siRNA and its effect on PTEN-/-MEF241cells [J]. Ai Zheng.2006Oct;25(10):1210-1215.
[57] Grzelinski M, Urban-Klein B, Martens T, Lamszus K, Bakowsky U, Hobel S, et al. RNAinterference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed smallinterfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts [J]. Hum Gene Ther.2006Jul;17(7):751-766.
[58] Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, et al. Pleiotrophinregulates the expansion and regeneration of hematopoietic stem cells [J]. Nat Med.2010Apr;16(4):475-482.
[59] Li YS, Deuel TF. Pleiotrophin stimulates tyrosine phosphorylation in NIH3T3and NB41A3cells[J]. Biochem Biophys Res Commun.1993Sep15;195(2):1089-1095.
[60] Meng K, Rodriguez-Pena A, Dimitrov T, Chen W, Yamin M, Noda M, et al. Pleiotrophin signalsincreased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalyticactivity of the receptor-type protein tyrosine phosphatase beta/zeta [J]. Proc Natl Acad Sci U S A.2000Mar14;97(6):2603-2608.
[61] Weng T, Liu L. The role of pleiotrophin and beta-catenin in fetal lung development [J].Respiratory research.2010;11:80.
[62] Pariser H, Perez-Pinera P, Ezquerra L, Herradon G, Deuel TF. Pleiotrophin stimulates tyrosinephosphorylation of beta-adducin through inactivation of the transmembrane receptor protein tyrosinephosphatase beta/zeta [J]. Biochem Biophys Res Commun.2005Sep16;335(1):232-239.
[63] Perez-Pinera P, Chang Y, Deuel TF. Pleiotrophin, a multifunctional tumor promoter throughinduction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromalfibroblasts [J]. Cell Cycle.2007Dec1;6(23):2877-2883.
[64] Perez-Pinera P, Zhang W, Chang Y, Vega JA, Deuel TF. Anaplastic lymphoma kinase is activatedthrough the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: analternative mechanism of receptor tyrosine kinase activation [J]. J Biol Chem.2007Sep28;282(39):28683-28690.
[65] Pariser H, Herradon G, Ezquerra L, Perez-Pinera P, Deuel TF. Pleiotrophin regulates serinephosphorylation and the cellular distribution of beta-adducin through activation of protein kinase C [J].Proc Natl Acad Sci U S A.2005Aug30;102(35):12407-12412.
[66] Hida H, Masuda T, Sato T, Kim TS, Misumi S, Nishino H. Pleiotrophin promotes functionalrecovery after neural transplantation in rats [J]. Neuroreport.2007Jan22;18(2):179-183.
[67] Chen H, Gordon MS, Campbell RA, Li M, Wang CS, Lee HJ, et al. Pleiotrophin is highlyexpressed by myeloma cells and promotes myeloma tumor growth [J]. Blood.2007Jul1;110(1):287-295.
[2] Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY. Pleiotrophin: a cytokine with diversefunctions and a novel signaling pathway. Arch Biochem Biophys[J].2002Jan15;397(2):162-71.
[3] Paddock HN, Schultz GS, Baker HV, Varela JC, Beierle EA, Moldawer LL, Mozingo DW.Analysis of gene expression patterns in human postburn hypertrophic scars. J Burn Care Rehabil[J].2003Nov-Dec;24(6):371-7.
[4] Zhao Y, He Q, Niu X.[Expression of alpha1-4integrins in hypertrophic scar fibroblasts][J].Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plasticsurgery.2000;16(1):37-9.
[5] Akaishi S, Ogawa R, Hyakusoku H. Keloid and hypertrophic scar: neurogenic inflammationhypotheses[J]. Medical hypotheses.2008;71(1):32-8.
[6] Ding J, Hori K, Zhang R, Marcoux Y, Honardoust D, Shankowsky HA, et al. Stromal cell-derivedfactor1(SDF-1) and its receptor CXCR4in the formation of postburn hypertrophic scar (HTS)[J].Wound repair and regeneration: official publication of the Wound Healing Society [and] the EuropeanTissue Repair Society.2011;19(5):568-78.
[7] Burd A, Huang L. Hypertrophic response and keloid diathesis: two very different forms of scar[J].Plastic and reconstructive surgery.2005;116(7):150e-7e.
[8] Liu JY, Li SR, Ji SX.[Expression of connective tissue growth factor gene in the hypertrophic scarand keloid tissue][J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waikezazhi=Chinese journal of reparative and reconstructive surgery.2003;17(6):436-8.
[9] Garver RI, Jr., Chan CS, Milner PG. Reciprocal expression of pleiotrophin and midkine in normalversus malignant lung tissues[J]. American journal of respiratory cell and molecular biology.1993;9(5):463-6.
[10] Souttou B, Raulais D, Vigny M. Pleiotrophin induces angiogenesis: involvement of thephosphoinositide-3kinase but not the nitric oxide synthase pathways[J]. Journal of cellular physiology.2001;187(1):59-64.
[11] Deuel TF, Zhang N, Yeh HJ, Silos-Santiago I, Wang ZY. Pleiotrophin: a cytokine with diversefunctions and a novel signaling pathway[J]. Archives of biochemistry and biophysics.2002;397(2):162-71.
[12] Rumsby M, Suggitt F, Haynes L, Hughson E, Kidd D, McNulty S. Substratum of pleiotrophin(HB-GAM) stimulates rat CG-4line oligodendrocytes to adopt a bipolar morphology and disperse:primary O-2A progenitor glial cells disperse similarly on pleiotrophin[J]. Glia.1999;26(4):361-7.
[13] Chung HW, Wen Y, Choi EA, Hao L, Moon HS, Yu HK, et al. Pleiotrophin (PTN) and midkine(MK) mRNA expression in eutopic and ectopic endometrium in advanced stage endometriosis[J].Molecular human reproduction.2002;8(4):350-5.
[14] Sato H, Funahashi M, Kristensen DB, Tateno C, Yoshizato K. Pleiotrophin as a Swiss3T3cell-derived potent mitogen for adult rat hepatocytes[J]. Experimental cell research.1999;246(1):152-64.
[15] Weber D, Klomp HJ, Czubayko F, Wellstein A, Juhl H. Pleiotrophin can be rate-limiting forpancreatic cancer cell growth[J]. Cancer research.2000;60(18):5284-8.
[16] Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, et al. Identification of anaplasticlymphoma kinase as a receptor for the growth factor pleiotrophin[J]. The Journal of biologicalchemistry.2001;276(20):16772-9.
[17] Ochiai K, Muramatsu H, Yamamoto S, Ando H, Muramatsu T. The role of midkine andpleiotrophin in liver regeneration[J]. Liver international: official journal of the InternationalAssociation for the Study of the Liver.2004;24(5):484-91.
[18] Grzelinski M, Bader N, Czubayko F, Aigner A. Ribozyme-targeting reveals the rate-limiting roleof pleiotrophin in glioblastoma[J]. International journal of cancer Journal international du cancer.2005;117(6):942-51.
[19] Feng ZJ, Gao SB, Wu Y, Xu XF, Hua X, Jin GH. Lung cancer cell migration is regulated viarepressing growth factor PTN/RPTP beta/zeta signaling by menin[J]. Oncogene.2010;29(39):5416-26.
[20] Satyamoorthy K, Oka M, Herlyn M. An antisense strategy for inhibition of human melanomagrowth targets the growth factor pleiotrophin[J]. Pigment cell research/sponsored by the EuropeanSociety for Pigment Cell Research and the International Pigment Cell Society.2000;13Suppl8:87-93.
[21] Christman KL, Fang Q, Kim AJ, Sievers RE, Fok HH, Candia AF, et al. Pleiotrophin inducesformation of functional neovasculature in vivo[J]. Biochemical and biophysical researchcommunications.2005;332(4):1146-52.
[22] Mourlevat S, Debeir T, Ferrario JE, Delbe J, Caruelle D, Lejeune O, et al. Pleiotrophin mediatesthe neurotrophic effect of cyclic AMP on dopaminergic neurons: analysis of suppression-subtractedcDNA libraries and confirmation in vitro[J]. Experimental neurology.2005;194(1):243-54.
[23] Taravini IR, Ferrario JE, Delbe J, Ginestet L, Debeir T, Courty J, et al. Immunodetection ofheparin-binding growth associated molecule (pleiotrophin) in striatal interneurons[J]. Brain research.2005;1066(1-2):196-200.
[24] Roger J, Brajeul V, Thomasseau S, Hienola A, Sahel JA, Guillonneau X, et al. Involvement ofPleiotrophin in CNTF-mediated differentiation of the late retinal progenitor cells[J]. Developmentalbiology.2006;298(2):527-39.
[25] Li SR, Liu JY, Ji SX.[Collagen synthesis and expression of connective tissue growth factor in thecultured fibroblasts of human hypertrophic scar][J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2004;20(2):124-7.
[26] Tao L, Liu JY, Li SR, Dai X, Li Z.[Function of STAT1in proliferation and differentiation ofhuman hypertrophic scar fibroblast induced by connective tissue growth factor][J]. Zhonghua yi xue zazhi.2009;89(16):1093-7.
[27] Lang Q, Liu Q, Xu N, Qian KL, Qi JH, Sun YC, et al. The antifibrotic effects of TGF-beta1siRNAon hepatic fibrosis in rats[J]. Biochemical and biophysical research communications.2011;409(3):448-53.
[28] Li Y, Yang K, Mao Q, Zheng X, Kong D, Xie L. Inhibition of TGF-beta receptor I by siRNAsuppresses the motility and invasiveness of T24bladder cancer cells via modulation of integrins andmatrix metalloproteinase[J]. International urology and nephrology.2010;42(2):315-23.
[29] Aarabi S, Longaker MT, Gurtner GC. Hypertrophic scar formation following burns and trauma:new approaches to treatment[J]. PLoS medicine.2007;4(9): e234.
[30] Matsumoto K, Wanaka A, Takatsuji K, Muramatsu H, Muramatsu T, Tohyama M. A novel familyof heparin-binding growth factors, pleiotrophin and midkine, is expressed in the developing rat cerebralcortex[J]. Brain research Developmental brain research.1994;79(2):229-41.
[31] Lai S, Czubayko F, Riegel AT, Wellstein A. Structure of the human heparin-binding growth factorgene pleiotrophin[J]. Biochemical and biophysical research communications.1992;187(2):1113-22.
[32] Vanderwinden JM, Mailleux P, Schiffmann SN, Vanderhaeghen JJ. Cellular distribution of thenew growth factor pleiotrophin (HB-GAM) mRNA in developing and adult rat tissues[J]. Anatomy andembryology.1992;186(4):387-406.
[33] Muramatsu T. Midkine (MK), the product of a retinoic acid responsive gene, and pleiotrophinconstitute a new protein family regulating growth and differentiation[J]. The International journal ofdevelopmental biology.1993;37(1):183-8.
[34] Garver RI, Jr., Radford DM, Donis-Keller H, Wick MR, Milner PG. Midkine and pleiotrophinexpression in normal and malignant breast tissue[J]. Cancer.1994;74(5):1584-90.
[35] Mailleux P, Preud'homme X, Albala N, Vanderwinden JM, Vanderhaeghen JJ.delta-9-Tetrahydrocannabinol regulates gene expression of the growth factor pleiotrophin in theforebrain[J]. Neuroscience letters.1994;175(1-2):25-7.
[36] Mitsiadis TA, Salmivirta M, Muramatsu T, Muramatsu H, Rauvala H, Lehtonen E, et al.Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associatedwith epithelial-mesenchymal interactions during fetal development and organogenesis[J]. Development.1995;121(1):37-51.
[37] Sharifi BG, Zeng Z, Wang L, Song L, Chen H, Qin M, et al. Pleiotrophin inducestransdifferentiation of monocytes into functional endothelial cells[J]. Arteriosclerosis, thrombosis, andvascular biology.2006;26(6):1273-80.
[38] Nakagawara A, Milbrandt J, Muramatsu T, Deuel TF, Zhao H, Cnaan A, et al. Differentialexpression of pleiotrophin and midkine in advanced neuroblastomas[J]. Cancer research.1995;55(8):1792-7.
[39] Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer[J].Cancer letters.2004;204(2):127-43.
[40] Petersen W, Wildemann B, Pufe T, Raschke M, Schmidmaier G. The angiogenic peptidepleiotrophin (PTN/HB-GAM) is expressed in fracture healing: an immunohistochemical study in rats[J].Archives of orthopaedic and trauma surgery.2004;124(9):603-7.
[41] Wu H, Barusevicius A, Babb J, Klein-Szanto A, Godwin A, Elenitsas R, et al. Pleiotrophinexpression correlates with melanocytic tumor progression and metastatic potential[J]. Journal ofcutaneous pathology.2005;32(2):125-30.
[42]Hunter CP. Gene silencing: shrinking the black box of RNAi[J]. Current biology: CB.2000;10(4):R137-40.
[43] Barstead R. Genome-wide RNAi[J]. Current opinion in chemical biology.2001;5(1):63-6.
[44] Ishizuka A, Siomi MC, Siomi H. A Drosophila fragile X protein interacts with components ofRNAi and ribosomal proteins[J]. Genes&development.2002;16(19):2497-508.
[45] Grishok A, Mello CC. RNAi (Nematodes: Caenorhabditis elegans)[J]. Advances in genetics.2002;46:339-60.
[46] Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T. Single-stranded antisense siRNAsguide target RNA cleavage in RNAi[J]. Cell.2002;110(5):563-74.
[47] Fan Y, Xin XY, Chen BL, Ma X. Knockdown of RAB25expression by RNAi inhibits growth ofhuman epithelial ovarian cancer cells in vitro and in vivo[J]. Pathology.2006;38(6):561-7.
[48] Ushida C.[RNA interference (RNAi): gene suppression by dsRNA][J]. Tanpakushitsu kakusankoso Protein, nucleic acid, enzyme.2001;46(10):1381-6.
[49] Carthew RW. Synthesis of dsRNA for RNAi in Drosophila: PCR Template Method[J]. CSHprotocols.2006;2006(3).
[50] Dallas A, Johnston BH. Design and chemical modification of synthetic short shRNAs as potentRNAi triggers[J]. Methods Mol Biol.2013;942:279-90.
[51] Siolas D, Lerner C, Burchard J, Ge W, Linsley PS, Paddison PJ, et al. Synthetic shRNAs as potentRNAi triggers[J]. Nature biotechnology.2005;23(2):227-31.
[52] Zenke K, Kim KH. Novel fugu U6promoter driven shRNA expression vector for efficient vectorbased RNAi in fish cell lines[J]. Biochemical and biophysical research communications.2008;371(3):480-3.
[53] Zhao Y, He Q.[Study on the expression of calreticulin in hypertrophic scar-derived fibroblasts][J].Zhonghua zheng xing shao shang wai ke za zhi=Zhonghua zheng xing shao shang waikf [ie waike]zazhi=Chinese journal of plastic surgery and burns/[Chung-hua cheng hsing shao shang wai k'o tsachih pien1999;15(3):167-9.
[54] Zhang Z, Garron TM, Li XJ, Liu Y, Zhang X, Li YY, et al. Recombinant human decorin inhibitsTGF-beta1-induced contraction of collagen lattice by hypertrophic scar fibroblasts[J]. Burns: journal ofthe International Society for Burn Injuries.2009;35(4):527-37.
[55] Zhang LQ, Laato M, Muona P, Penttinen R, Oikarinen A, Peltonen J. A fibroblast cell line culturedfrom a hypertrophic scar displays selective downregulation of collagen gene expression: barelydetectable messenger RNA levels of the pro alpha1(III) chain of type III collagen[J]. Archives ofdermatological research.1995;287(6):534-8.
[56] Zhao Y, Niu X, Xiao J.[Study on the activity of fibroblast in hypertrophic scar][J]. Zhongguo xiufu chong jian wai ke za zhi=Zhongguo xiufu chongjian waike zazhi=Chinese journal of reparativeand reconstructive surgery.1998;12(2):108-12.
[57] Yang P, Wang AL, Liu DW, Xu S, Gu YH, Huang J, et al.[Effect of transfection of recombinanthuman endothelial nitric oxide synthase gene on hypertrophic scar fibroblasts in vitro][J]. Zhonghuashao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2008;24(4):275-7.
[58] Xiao Z, Zhang F, Lin W, Zhang M, Liu Y. Effect of botulinum toxin type A on transforminggrowth factor beta1in fibroblasts derived from hypertrophic scar: a preliminary report[J]. Aestheticplastic surgery.2010;34(4):424-7.
[59] Tabara H, Grishok A, Mello CC. RNAi in C. elegans: soaking in the genome sequence[J]. Science.1998;282(5388):430-1.
[60] Fire A. Nucleic acid structure and intracellular immunity: some recent ideas from the world ofRNAi[J]. Quarterly reviews of biophysics.2005;38(4):303-9.
[61] Pak J, Maniar JM, Mello CC, Fire A. Protection from Feed-Forward Amplification in an AmplifiedRNAi Mechanism[J]. Cell.2012;151(4):885-99.
[62] Agami R. RNAi and related mechanisms and their potential use for therapy[J]. Current opinion inchemical biology.2002;6(6):829-34.
[63] Bilanges B, Stokoe D. Direct comparison of the specificity of gene silencing using antisenseoligonucleotides and RNAi[J]. The Biochemical journal.2005;388(Pt2):573-83.
[64] Binnie U, Wong K, McAteer S, Masters M. Absence of RNASE III alters the pathway by whichRNAI, the antisense inhibitor of ColE1replication, decays[J]. Microbiology.1999;145(Pt11):3089-100.
[65] Byers HR, Boissel SJ, Tu C, Park HY. RNAi-mediated knockdown of protein kinase C-alphainhibits cell migration in MM-RU human metastatic melanoma cell line[J]. Melanoma research.2010;20(3):171-8.
[66] Caplen NJ, Mousses S. Short interfering RNA (siRNA)-mediated RNA interference (RNAi) inhuman cells[J]. Annals of the New York Academy of Sciences.2003;1002:56-62.
[67] Wang J, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE. Improvement in postburnhypertrophic scar after treatment with IFN-alpha2b is associated with decreased fibrocytes[J]. Journal ofinterferon&cytokine research: the official journal of the International Society for Interferon andCytokine Research.2007;27(11):921-30.
[68] Blondet B, Carpentier G, Lafdil F, Courty J. Pleiotrophin cellular localization in nerve regenerationafter peripheral nerve injury[J]. The journal of histochemistry and cytochemistry: official journal of theHistochemistry Society.2005;53(8):971-7.
[69] Clark DE, Lord EA, Suttie JM. Expression of VEGF and pleiotrophin in deer antler[J]. Theanatomical record Part A, Discoveries in molecular, cellular, and evolutionary biology.2006;288(12):1281-93.
[70] Gonzalez-Gonzalez E, Lopez-Casas PP, del Mazo J. The expression patterns of genes involved inthe RNAi pathways are tissue-dependent and differ in the germ and somatic cells of mouse testis[J].Biochimica et biophysica acta.2008;1779(5):306-11.
[71] Bai H, Palli SR. Functional characterization of bursicon receptor and genome-wide analysis foridentification of genes affected by bursicon receptor RNAi[J]. Developmental biology.2010;344(1):248-58.
[72] Baker N, Alsford S, Horn D. Genome-wide RNAi screens in African trypanosomes identify thenifurtimox activator NTR and the eflornithine transporter AAT6[J]. Molecular and biochemicalparasitology.2011;176(1):55-7.
[73] Kossi J, Vaha-Kreula M, Peltonen J, Risteli J, Laato M. Effect of sucrose on collagen metabolismin keloid, hypertrophic scar, and granulation tissue fibroblast cultures[J]. World journal of surgery.2001;25(2):142-6.
[74] Chu Y, Guo F, Li Y, Li X, Zhou T, Guo Y. A novel truncated TGF-beta receptor II downregulatescollagen synthesis and TGF-beta I secretion of keloid fibroblasts[J]. Connective tissue research.2008;49(2):92-8.
[75] Ju-Lin X, Shao-Hai Q, Tian-Zeng L, Chao-Quan L, Hou-Dong L, Ying-Bin X, et al. Attenuation ofalpha1collagen production with antisense ribonucleic acid in cultured hypertrophic scar fibroblasts[J].Journal of cutaneous medicine and surgery.2009;13(3):129-33.
[76] Krotzsch-Gomez FE, Furuzawa-Carballeda J, Reyes-Marquez R, Quiroz-Hernandez E, Diaz deLeon L. Cytokine expression is downregulated by collagen-polyvinylpyrrolidone in hypertrophicscars[J]. The Journal of investigative dermatology.1998;111(5):828-34.
[77] Kischer CW. Collagen and dermal patterns in the hypertrophic scar[J]. The Anatomical record.1974;179(1):137-45.
[78] Isaac C, Mathor MB, Bariani G, Paggiaro AO, Herson MR, Goldenstein-Schainberg C, et al.Pentoxifylline modifies three-dimensional collagen lattice model contraction and expression of collagentypes I and III by human fibroblasts derived from post-burn hypertrophic scars and from normal skin[J].Burns: journal of the International Society for Burn Injuries.2009;35(5):701-6.
[79] Berthod F, Germain L, Li H, Xu W, Damour O, Auger FA. Collagen fibril network and elasticsystem remodeling in a reconstructed skin transplanted on nude mice[J]. Matrix biology: journal of theInternational Society for Matrix Biology.2001;20(7):463-73.
[80] Callahan LA, Ganios AM, McBurney DL, Dilisio MF, Weiner SD, Horton WE, Jr., et al. ECMproduction of primary human and bovine chondrocytes in hybrid PEG hydrogels containing type Icollagen and hyaluronic acid[J]. Biomacromolecules.2012;13(5):1625-31.
[81] Wang L, Murthy SK, Barabino GA, Carrier RL. Synergic effects of crypt-like topography andECM proteins on intestinal cell behavior in collagen based membranes[J]. Biomaterials.2010;31(29):7586-98.
[82] Ramtani S. Mechanical modelling of cell/ECM and cell/cell interactions during the contraction of afibroblast-populated collagen microsphere: theory and model simulation[J]. Journal of biomechanics.2004;37(11):1709-18.
[83] Colwell AS, Phan TT, Kong W, Longaker MT, Lorenz PH. Hypertrophic scar fibroblasts haveincreased connective tissue growth factor expression after transforming growth factor-betastimulation[J]. Plastic and reconstructive surgery.2005;116(5):1387-90; discussion91-2.
[84] Cao C, Li S, Dai X, Chen Y, Feng Z, Zhao Y, et al. Genistein inhibits proliferation and functionsof hypertrophic scar fibroblasts[J]. Burns: journal of the International Society for Burn Injuries.2009;35(1):89-97.
[85] Cao B, Jiang MC, Lei ZY, Bai SF, Chen H. Effects of PLAB on apoptosis and Smad signalpathway of hypertrophic scar fibroblasts[J]. Journal of Asian natural products research.2008;10(1-2):147-57.
[86] Mi L, Li YY, Lin WH, Li G, Sun JE, Dai LB, et al.[The effect of intergrin-linked kinase on VEGFexpression in fibroblasts from human hypertrophic scar][J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2011;27(4):289-93.
[87] Wang Q, Wu Z.[A study on the detection of apoptosis of hypertrophic scar and its relatedmodulating factors][J]. Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal ofburns.2001;17(1):25-8.
[1] Chvapil M, Koopmann CF, Jr. Scar formation: physiology and pathological states[J].Otolaryngologic clinics of North America.1984;17(2):265-272.
[2] Wu WY, Zhu SZ, Wu RL, Zou CH, Wang ZY, Huang ZX. Expression and significance of Skp2and p27kip1protein in pathological scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxingwaike zazhi=Chinese journal of plastic surgery.2005;21(6):448-451.
[3] Yamada N, Kusumoto M, Maeshima A, Suzuki K, Matsuno Y. Correlation of the solid part onhigh-resolution computed tomography with pathological scar in small lung adenocarcinomas[J].Japanese journal of clinical oncology.2007;37(12):913-917.
[4] Liu Y, Cen Y, Ying T, Xu X. The role of myofibroblast in the development of pathological scar[J].Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waike zazhi=Chinese journal ofreparative and reconstructive surgery.2005;19(1):39-41.
[5] Akaishi S, Ogawa R, Hyakusoku H. Keloid and hypertrophic scar: neurogenic inflammationhypotheses[J]. Medical hypotheses.2008;71(1):32-38.
[6] Burd A, Huang L. Hypertrophic response and keloid diathesis: two very different forms of scar[J].Plastic and reconstructive surgery.2005;116(7):150e-157e.
[7] Jin PS, Chen JJ, Cen Y, Zhang AJ, Tao CB, Li XY. The effect of recombinant HSP47siRNA onthe pathological scar in nude mice: in vivo study[J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2009;25(5):377-380.
[8] Yang L, Scott PG, Dodd C, Medina A, Jiao H, Shankowsky HA, et al. Identification of fibrocytesin postburn hypertrophic scar[J]. Wound repair and regeneration: official publication of the WoundHealing Society [and] the European Tissue Repair Society.2005;13(4):398-404.
[9] Tan J, Peng X, Luo G, Ma B, Cao C, He W, et al. Investigating the role of P311in the hypertrophicscar[J]. PloS one.2010;5(4): e9995.
[10] Dasu MR, Hawkins HK, Barrow RE, Xue H, Herndon DN. Gene expression profiles fromhypertrophic scar fibroblasts before and after IL-6stimulation[J]. The Journal of pathology.2004;202(4):476-485.
[11] Ghahary A, Shen YJ, Nedelec B, Scott PG, Tredget EE. Enhanced expression of mRNA forinsulin-like growth factor-1in post-burn hypertrophic scar tissue and its fibrogenic role by dermalfibroblasts[J]. Molecular and cellular biochemistry.1995;148(1):25-32.
[12] Sidgwick GP, Bayat A. Extracellular matrix molecules implicated in hypertrophic and keloidscarring[J]. Journal of the European Academy of Dermatology and Venereology: JEADV.2012;26(2):141-152.
[13] Leng XF, Wang DC, Huo R, Zhang Q, Xue WJ. Expression and significance of TRAIL receptorsin fibroblasts of hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waikezazhi=Chinese journal of plastic surgery.2005;21(6):444-7.
[14] Cheng YC, Kuo WW, Wu HC, Lai TY, Wu CH, Hwang JM, et al. ZAK induces MMP-2activityvia JNK/p38signals and reduces MMP-9activity by increasing TIMP-1/2expression in H9c2cardiomyoblast cells[J]. Molecular and cellular biochemistry.2009;325(1-2):69-77.
[15] Garner WL, Rittenberg T, Ehrlich HP, Karmiol S, Rodriguez JL, Smith DJ, et al. Hypertrophic scarfibroblasts accelerate collagen gel contraction[J]. Wound repair and regeneration: official publication ofthe Wound Healing Society [and] the European Tissue Repair Society.1995;3(2):185-191.
[16] Kossi J, Laato M. Different metabolism of hexose sugars and sucrose in wound fluid and infibroblast cultures derived from granulation tissue, hypertrophic scar and keloid[J]. Pathobiology:journal of immunopathology, molecular and cellular biology.2000;68(1):29-35.
[17] Guo S, Zhang L, Wang Z, Liu J. Effects of conditioned medium derived from differentkeratinocytes on proliferation and collagen synthesis of hypertrophic scar fibroblasts[J]. Zhonghuazheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2002;18(2):83-85.
[18] Tao L, Liu JY, Li SR, Dai X, Li Z. Function of STAT1in proliferation and differentiation ofhuman hypertrophic scar fibroblast induced by connective tissue growth factor[J]. Zhonghua yi xue zazhi.2009;89(16):1093-1097.
[19] Ghahary A, Shen YJ, Scott PG, Gong Y, Tredget EE. Enhanced expression of mRNA fortransforming growth factor-beta, type I and type III procollagen in human post-burn hypertrophic scartissues[J]. The Journal of laboratory and clinical medicine.1993;122(4):465-473.
[20] Ghahary A, Ghaffari A. Role of keratinocyte-fibroblast cross-talk in development of hypertrophicscar[J]. Wound repair and regeneration: official publication of the Wound Healing Society [and] theEuropean Tissue Repair Society.2007;15Suppl1: S46-53.
[21] Fumagalli M, Musso T, Vermi W, Scutera S, Daniele R, Alotto D, et al. Imbalance between activinA and follistatin drives postburn hypertrophic scar formation in human skin[J]. Experimentaldermatology.2007;16(7):600-610.
[22] Varkey M, Ding J, Tredget EE. Differential collagen-glycosaminoglycan matrix remodeling bysuperficial and deep dermal fibroblasts: potential therapeutic targets for hypertrophic scar[J].Biomaterials.2011;32(30):7581-7591.
[23] van der Veer WM, Bloemen MC, Ulrich MM, Molema G, van Zuijlen PP, Middelkoop E, et al.Potential cellular and molecular causes of hypertrophic scar formation[J]. Burns: journal of theInternational Society for Burn Injuries.2009;35(1):15-29.
[24] Chen L, Wang Z, Li S, Zhao G, Tian M, Sun Z. SFRP2and Slug Contribute to Cellular Resistanceto Apoptosis in Hypertrophic Scars[J]. PloS one.2012;7(12): e50229.
[25] Guan B, Xu S, Bao W. Study on apoptosis of fibroblasts from abnormal scars in media containinglow level of serum and interleukin1beta[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxingwaike zazhi=Chinese journal of plastic surgery.2001;17(5):279-281.
[26] Bao W, Xu S. Mechanism of abnormal scars with treatment of steroid[J]. Zhonghua wai ke za zhi
[Chinese journal of surgery].2000;38(5):378-381.
[27] Ding J, Hori K, Zhang R, Marcoux Y, Honardoust D, Shankowsky HA, et al. Stromal cell-derivedfactor1(SDF-1) and its receptor CXCR4in the formation of postburn hypertrophic scar (HTS)[J].Wound repair and regeneration: official publication of the Wound Healing Society [and] the EuropeanTissue Repair Society.2011;19(5):568-578.
[28] Mi L, Li YY, Lin WH, Li G, Sun JE, Dai LB, et al. The effect of intergrin-linked kinase on VEGFexpression in fibroblasts from human hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2011;27(4):289-293.
[29] Kuhn MA, Moffit MR, Smith PD, Lyle WG, Ko F, Meltzer DD, et al. Silicone sheeting decreasesfibroblast activity and downregulates TGFbeta2in hypertrophic scar model[J]. International journal ofsurgical investigation.2001;2(6):467-474.
[30] Chen W, Fu XB, Sun TZ. Gene expression of stress activated protein kinase and its MAPKs inhypertrophic scar[J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waikezazhi=Chinese journal of reparative and reconstructive surgery.2004;18(1):1-3.
[31] Reid RR, Roy N, Mogford JE, Zimmerman H, Lee C, Mustoe TA. Reduction of hypertrophic scarvia retroviral delivery of a dominant negative TGF-beta receptor II[J]. Journal of plastic, reconstructive&aesthetic surgery: JPRAS.2007;60(1):64-72; discussion3-4.
[32] Schmid P, Itin P, Cherry G, Bi C, Cox DA. Enhanced expression of transforming growthfactor-beta type I and type II receptors in wound granulation tissue and hypertrophic scar[J]. TheAmerican journal of pathology.1998;152(2):485-493.
[33] Dabiri G, Tumbarello DA, Turner CE, Van de Water L. Hic-5promotes the hypertrophic scarmyofibroblast phenotype by regulating the TGF-beta1autocrine loop[J]. The Journal of investigativedermatology.2008;128(10):2518-2525.
[34] Hou XH, Cao B, Liu HQ, Wang YZ, Bai SF, Chen H. Effects of osthole on apoptosis andTGF-beta1of hypertrophic scar fibroblasts[J]. Journal of Asian natural products research.2009;11(7):663-669.
[35] Zunwen L, Shizhen Z, Dewu L, Yungui M, Pu N. Effect of tetrandrine on the TGF-beta-inducedsmad signal transduction pathway in human hypertrophic scar fibroblasts in vitro[J]. Burns: journal ofthe International Society for Burn Injuries.2012;38(3):404-413.
[36] Zhang GY, He B, Liao T, Luan Q, Tao C, Nie CL, et al. Caveolin1inhibits transforming growthfactor-beta1activity via inhibition of Smad signaling by hypertrophic scar derived fibroblasts in vitro[J].Journal of dermatological science.2011;62(2):128-131.
[37] Zhang Z, Finnerty CC, He J, Herndon DN. Smad ubiquitination regulatory factor2expression isenhanced in hypertrophic scar fibroblasts from burned children[J]. Burns: journal of the InternationalSociety for Burn Injuries.2012;38(2):236-246.
[38] Zhang Y, Qiu L, Li MY. Effects of radix astragali on expression of transforming growth factorbeta1and Smad3signal pathway in hypertrophic scar of rabbit[J]. Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2010;26(5):366-370.
[39] Zhang CD, Tian Y, Song L, Zhang CP. The influence of adrenaline on the expression ofTGF-beta1, bFGF and I procollagen for hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2005;21(6):440-444.
[40] Wang R, Ghahary A, Shen Q, Scott PG, Roy K, Tredget EE. Hypertrophic scar tissues andfibroblasts produce more transforming growth factor-beta1mRNA and protein than normal skin andcells[J]. Wound repair and regeneration: official publication of the Wound Healing Society [and] theEuropean Tissue Repair Society.2000;8(2):128-137.
[41] Song B, Lu K, Zhang Y, Guo S, Han Y, Ma F, et al. Angiogenesis in hypertrophic scar of rabbitears and effect of extracellular protein with metalloprotease and thrombospondin1domains onhypertrophic scar[J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufu chongjian waikezazhi=Chinese journal of reparative and reconstructive surgery.2008;22(1):70-74.
[42] Ting-An W, Hong-Xiang Z. PTK-pathways and TGF-beta signaling pathways in schistosomes[J].Journal of basic microbiology.2009;49(1):25-31.
[43] Tredget EE, Wang R, Shen Q, Scott PG, Ghahary A. Transforming growth factor-beta mRNA andprotein in hypertrophic scar tissues and fibroblasts: antagonism by IFN-alpha and IFN-gamma in vitroand in vivo[J]. Journal of interferon&cytokine research: the official journal of the InternationalSociety for Interferon and Cytokine Research.2000;20(2):143-151.
[44] Wang J, Jiao H, Stewart TL, Shankowsky HA, Scott PG, Tredget EE. Improvement in postburnhypertrophic scar after treatment with IFN-alpha2b is associated with decreased fibrocytes[J]. Journal ofinterferon&cytokine research: the official journal of the International Society for Interferon andCytokine Research.2007;27(11):921-930.
[45] Cao C, Li SR, Dai X, Chen YQ, Feng Z, Qin X, et al. The effects of genistein on tyrosine proteinkinase-mitogen activated protein kinase signal transduction pathway in hypertrophic scar fibroblasts[J].Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2008;24(2):118-121.
[46] Acarin L, Gonzalez B, Castellano B. STAT3and NFkappaB activation precedes glial reactivity inthe excitotoxically injured young cortex but not in the corresponding distal thalamic nuclei[J]. Journalof neuropathology and experimental neurology.2000;59(2):151-163.
[47] Shimizu T, Kanai K, Kyo Y, Asano K, Hisamitsu T, Suzaki H. Effect of tranilast on matrixmetalloproteinase production from neutrophils in-vitro[J]. The Journal of pharmacy and pharmacology.2006;58(1):91-99.
[48] Van Tassell BW, Seropian IM, Toldo S, Salloum FN, Smithson L, Varma A, et al. Pharmacologicinhibition of myeloid differentiation factor88(MyD88) prevents left ventricular dilation andhypertrophy after experimental acute myocardial infarction in the mouse[J]. Journal of cardiovascularpharmacology.2010;55(4):385-390.
[49] De Felice B, Ciarmiello LF, Mondola P, Damiano S, Seru R, Argenziano C, et al. Differential p63and p53expression in human keloid fibroblasts and hypertrophic scar fibroblasts[J]. DNA and cellbiology.2007;26(8):541-547.
[50] Oku T, Takigawa M, Fukamizu H, Inoue K, Yamada M. Growth kinetics of fibroblasts derivedfrom normal skin and hypertrophic scar[J]. Acta dermato-venereologica.1987;67(6):526-528.
[51] Song W, Sun G, Guan Z. Comparative study on biological characteristics and ultrastructure of thefibroblasts derived from normal skin, hypertrophic scar and keloidin in vitro culture[J]. Zhonghua zhengxing shao shang wai ke za zhi=Zhonghua zheng xing shao shang waikf [ie waike] zazhi=Chinesejournal of plastic surgery and burns/[Chung-hua cheng hsing shao shang wai k'o tsa chih pien1998;14(6):410-413.
[52] Colwell AS, Phan TT, Kong W, Longaker MT, Lorenz PH. Hypertrophic scar fibroblasts haveincreased connective tissue growth factor expression after transforming growth factor-betastimulation[J]. Plastic and reconstructive surgery.2005;116(5):1387-90; discussion91-92.
[53] Linares HA, Kischer CW, Dobrkovsky M, Larson DL. The histiotypic organization of thehypertrophic scar in humans[J]. The Journal of investigative dermatology.1972;59(4):323-331.
[54] Phan TT, Sun L, Bay BH, Chan SY, Lee ST. Dietary compounds inhibit proliferation andcontraction of keloid and hypertrophic scar-derived fibroblasts in vitro: therapeutic implication forexcessive scarring[J]. The Journal of trauma.2003;54(6):1212-1224.
[55] Peck GL. Hypertrophic scar after cryotherapy and topical tretinoin[J]. Archives of dermatology.1973;108(6):819-822.
[56] Li-Tsang CW, Feng BB, Li KC. Pressure therapy of hypertrophic scar after burns and relatedresearch[J]. Zhonghua shao shang za zhi=Zhonghua shaoshang zazhi=Chinese journal of burns.2010;26(6):411-415.
[57] Harrop AR, Ghahary A, Scott PG, Forsyth N, Uji-Friedland A, Tredget EE. Regulation of collagensynthesis and mRNA expression in normal and hypertrophic scar fibroblasts in vitro byinterferon-gamma[J]. The Journal of surgical research.1995;58(5):471-477.
[58] Ketchum LD, Smith J, Robinson DW, Masters FW. The treatment of hypertrophic scar, keloid andscar contracture by triamcinolone acetonide[J]. Plastic and reconstructive surgery.1966;38(3):209-218.
[59] Saulis AS, Chao JD, Telser A, Mogford JE, Mustoe TA. Silicone occlusive treatment ofhypertrophic scar in the rabbit model[J]. Aesthetic surgery journal/the American Society for AestheticPlastic surgery.2002;22(2):147-153.
[60] Gilman TH. Silicone sheet for treatment and prevention of hypertrophic scar: a new proposal forthe mechanism of efficacy[J]. Wound repair and regeneration: official publication of the WoundHealing Society [and] the European Tissue Repair Society.2003;11(3):235-236.
[61] Lee SJ, Kim JH, Lee SE, Chung WS, Oh SH, Cho SB. Hypertrophic scarring after burn scartreatment with a10,600-nm carbon dioxide fractional laser[J]. Dermatologic surgery: officialpublication for American Society for Dermatologic Surgery [et al].2011;37(8):1168-1172.
[62] Iannello S, Milazzo P, Bordonaro F, Belfiore F. Low-dose enalapril in the treatment of surgicalcutaneous hypertrophic scar and keloid--two case reports and literature review[J]. MedGenMed:Medscape general medicine.2006;8(4):60.
[63] Moulin V, Larochelle S, Langlois C, Thibault I, Lopez-Valle CA, Roy M. Normal skin wound andhypertrophic scar myofibroblasts have differential responses to apoptotic inductors[J]. Journal ofcellular physiology.2004;198(3):350-358.
[64] Gu H, He Q, Lin Z, Liu Q, Zhang X. Effects of microfilaments on the expression of collagenasesand tissue inhibitor of metalloproteinases-1in fibroblasts[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2002;18(3):163-164.
[65] Deten A, Holzl A, Leicht M, Barth W, Zimmer HG. Changes in extracellular matrix and intransforming growth factor beta isoforms after coronary artery ligation in rats[J]. Journal of molecularand cellular cardiology.2001;33(6):1191-1207.
[66] Mahdavian Delavary B, van der Veer WM, van Egmond M, Niessen FB, Beelen RH. Macrophagesin skin injury and repair[J]. Immunobiology.2011;216(7):753-762.
[67] Schultze-Mosgau S, Blaese MA, Grabenbauer G, Wehrhan F, Kopp J, Amann K, et al. Smad-3andSmad-7expression following anti-transforming growth factor beta1(TGFbeta1)-treatment in irradiatedrat tissue[J]. Radiotherapy and oncology: journal of the European Society for Therapeutic Radiologyand Oncology.2004;70(3):249-259.
[68] Ghahary A, Shen YJ, Nedelec B, Wang R, Scott PG, Tredget EE. Collagenase production is lowerin post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-likegrowth factor-1[J]. The Journal of investigative dermatology.1996;106(3):476-481.
[69] Li SR, Liu JY, Ji SX. Collagen synthesis and expression of connective tissue growth factor in thecultured fibroblasts of human hypertrophic scar[J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2004;20(2):124-127.
[70] Guoyou Z, Chenggang Y, Chengyue M, Xuan L, Yan Z, Wei X, et al. Modulation of transforminggrowth factor-beta1production by vector-based RNAi in hypertrophic scar fibroblasts: a therapeuticpotential strategy for hypertrophic scar[J]. Journal of dermatological science.2007;48(1):67-70.
[71] Ha X, Yuan B, Li Y, Lao M, Wu Z. Gene therapy for pathological scar with hepatocyte growthfactor mediated by recombinant adenovirus vector[J]. Science in China Series C, Life sciences/ChineseAcademy of Sciences.2003;46(3):320-327.
[72] Anderson WF, Fletcher JC. Sounding boards. Gene therapy in human beings: when is it ethical tobegin?[J]. The New England journal of medicine.1980;303(22):1293-1297.
[73] Anderson WF, Blaese RM, Culver K. The ADA human gene therapy clinical protocol: Points toConsider response with clinical protocol, July6,1990[J]. Human gene therapy.1990;1(3):331-362.
[74]王健民，韩风来，杨建民，血友病B基因治疔临床研究中华血液学杂志[J]，1994，15；282—285
[75] Diao JS, Zhang X, Ren J, Zeng HF, Liu B, Ma FC, et al. Blocking of Notch signaling decreasedscar formation in rabbit ear hypertrophic scar model[J]. Zhonghua yi xue za zhi.2009;89(16):1088-1092.
[76] Arakawa M, Hatamochi A, Mori Y, Mori K, Ueki H, Moriguchi T. Reduced collagenase geneexpression in fibroblasts from hypertrophic scar tissue[J]. The British journal of dermatology.1996;134(5):863-868.
[77] Qui L, Jin X, Kingston PA, Luo X, Ding X.[Experimental study on BMSCs transfected byendogene inhibiting hypertrophic scar][J]. Zhongguo xiu fu chong jian wai ke za zhi=Zhongguo xiufuchongjian waike zazhi=Chinese journal of reparative and reconstructive surgery.2008;22(2):212-216.
[78] Qi S, Li T, Shan Y. Inhibiting effect of antisense oligodeoxynucleotide of alpha1(I) Precollagengene on hypertrophic scar in an animal model[J]. Zhonghua zheng xing wai ke za zhi=Zhonghuazhengxing waike zazhi=Chinese journal of plastic surgery.2000;16(5):295-297.
[79] Lu F, Gao J, Ogawa R, Hyakusoku H, Ou C. Fas-mediated apoptotic signal transduction in keloidand hypertrophic scar[J]. Plastic and reconstructive surgery.2007;119(6):1714-1721.
[80] Liu YB, Gao JH, Liu XJ, Lu F, Liu HW. The effect of tunicamycin on Fas protein expression andits function in fibroblasts from hypertrophic scar and keloid[J]. Zhonghua zheng xing wai ke za zhi=Zhonghua zhengxing waike zazhi=Chinese journal of plastic surgery.2009;25(3):213-216.
[81] Sun Z, Li S, Cao C, Wu J, Ma B, Tran V. shRNA targeting SFRP2promotes the apoptosis ofhypertrophic scar fibroblast[J]. Molecular and cellular biochemistry.2011;352(1-2):25-33.
[1] Milner PG`, Li YS，Hoffinan RM`, et aL. A novel l7kDa heparin-binding growth factor(HBGF-8)in bovine uterus: purifieationand N-terminal amino amino acid sequence.[J]. Bioehem BioPhys ResCommun. I989`;165:1096-1103
[2] Rauvala H.M18-kd heparin-binding protein of developing brain that is distinct from fibrobIastgrowth factors [J]. EMBO J.1989`;8:2933-2941.
[3] Huber D`, Gautschi-Sova P. Amino-teminal sequences of a novel heparin-binding protein fromhuman`, bovine`, rat`, and chick brain: high interspecies homology [J]. NeuroChem Res.1990`;15:435-439.
[4] Courty J, Dauchel MC, Caruelle D, Perderiset M, Barritault D. Mitogenic properties of a newendothelial cell growth factor related to pleiotrophin [J]. Biochemical and biophysical researchcommunications.1991Oct15;180(1):145-151.
[5] Tezuka K`, Takeshita S`, HakedaY`, et aI. Isolation of mouse and human Cdna clones eneodind aprotein expressed specifically in osteoblast and brain tissues [J]. Biochem BioPhys Res Commun.1990`;173:246-251.
[6] Bohlen P, Kovesdi I. HBNF and MK, members of a novel gene family of heparin-binding proteinswith potential roles in embryogenesis and brain function [J]. Progress in growth factor research.1991;3(2):143-157.
[7] Hampton BS, Marshak DR, Burgess WH. Structural and functional characterization of full-lengthheparin-binding growth associated molecule [J]. Molecular biology of the cell.1992Jan;3(1):85-93.
[8] Li YS, Gurrieri M, Deuel TF. Pleiotrophin gene expression is highly restricted and is regulated byplatelet-derived growth factor [J]. Biochemical and biophysical research communications.1992Apr15;184(1):427-432.
[9] Svensson SL, Pasupuleti M, Walse B, Malmsten M, Morgelin M, Sjogren C, et al. Midkine andpleiotrophin have bactericidal properties: preserved antibacterial activity in a family of heparin-bindinggrowth factors during evolution [J]. J Biol Chem.2010May21;285(21):16105-16115.
[10] Roth TM`, Klett C`, Cowan BD`, et al. Ecpression profile of several genes in human myometriumand uterine leiomyoma [J]. Fertil Steril.2007Mar`;87(3):635-641.
[11] Vanderwinden JM, Mailleux P, Schiffmann SN, Vanderhaeghen JJ. Cellular distribution of thenew growth factor pleiotrophin (HB-GAM) mRNA in developing and adult rat tissues [J]. AnatEmbryol (Berl).1992Sep;186(4):387-406.
[12] Deuel T F`, Zhang N`, Yeh H J`, et al. Pleiotrophin: a cylokine wish diverse functions and a novelsignaling pathway [J]. Arch. Biochem Biophys.2002`;397:162-171.
[13] Fabri L`, Nice E C`, Ward L D`, et al. Characerization of bovine heparin-binding neurotrophicfactor(HBNF)-assignment of disulfide honds [J]. Biochem Int.1992`;28:1-9.
[14] Park T J`, Jeong BR`, Tateno C`, et al. Pleiotrophin inhibits transforming growth factorbetal-induced apoptosis in hepatoma cell lines [J]. Mol Careinog.2008Oct:47(10):784-796.
[15] Jung CG, Hida H, Nakahira K, Ikenaka K, Kim HJ, Nishino H. Pleiotrophin mRNA is highlyexpressed in neural stem (progenitor) cells of mouse ventral mesencephalon and the product promotesproduction of dopaminergic neurons from embryonic stem cell-derived nestin-positive cells [J]. FASEBJ.2004Aug;18(11):1237-1239.
[16] Fukazawa N, Yokoyama S, Eiraku M, Kengaku M, Maeda N. Receptor type protein tyrosinephosphatase zeta-pleiotrophin signaling controls endocytic trafficking of DNER that regulatesneuritogenesis [J]. Mol Cell Biol.2008Jul;28(14):4494-4506.
[17] Soh BS, Song CM, Vallier L, Li P, Choong C, Yeo BH, et al. Pleiotrophin enhances clonal growthand long-term expansion of human embryonic stem cells [J]. Stem Cells.2007Dec;25(12):3029-3037.
[18] Jin L, Jianghai C, Juan L, Hao K. Pleiotrophin and peripheral nerve injury [J]. Neurosurg Rev.2009Oct;32(4):387-933.
[19] Yao J, Ma Q, Wang L, Zhang M. Pleiotrophin expression in human pancreatic cancer and itscorrelation with clinicopathological features, perineural invasion, and prognosis [J]. Dig Dis Sci.2009Apr;54(4):895-901.
[20] Achour A, M'Bika J P, Baudouin F, Caruelle D, Courty J. Pleiotrophin induces expression ofinflammatory cytokines in peripheral blood mononuclear cells [J]. Biochimie.2008Nov-Dec;90(11-12):1791-1795.
[21] Mashour GA, Ratner N, Khan GA, Wang HL, Martuza RL, Kurtz A. The angiogenic factormidkine is aberrantly expressed in NF1-deficient Schwann cells and is a mitogen forneurofibroma-derived cells [J]. Oncogene.2001Jan4;20(1):97-105.
[22] Ezquerra L, Alguacil LF, Nguyen T, Deuel TF, Silos-Santiago I, Herradon G. Different pattern ofpleiotrophin and midkine expression in neuropathic pain: correlation between changes in pleiotrophingene expression and rat strain differences in neuropathic pain [J]. Growth Factors.2008Feb;26(1):44-48.
[23] Kadomatsu K, Muramatsu T. Midkine and pleiotrophin in neural development and cancer [J].Cancer Lett.2004Feb20;204(2):127-143.
[24] Hamma-Kourbali Y, Bernard-Pierrot I, Heroult M, Dalle S, Caruelle D, Milhiet PE, et al.Inhibition of the mitogenic, angiogenic and tumorigenic activities of pleiotrophin by a synthetic peptidecorresponding to its C-thrombospondin repeat-I domain [J]. Journal of cellular physiology.2008Jan;214(1):250-259.
[25] Rosenfield SM, Bowden ET, Cohen-Missner S, Gibby KA, Ory V, Henke RT, et al. Pleiotrophin(PTN) expression and function and in the mouse mammary gland and mammary epithelial cells [J].PLoS One.2012;7(10):e47876.
[26] Weng T, Gao L, Bhaskaran M, Guo Y, Gou D, Narayanaperumal J, et al. Pleiotrophin regulateslung epithelial cell proliferation and differentiation during fetal lung development via beta-catenin andDlk1[J]. J Biol Chem.2009Oct9;284(41):28021-28032.
[27] Neidlinger-Wilke C, Liedert A, Wuertz K, Buser Z, Rinkler C, Kafer W, et al. Mechanicalstimulation alters pleiotrophin and aggrecan expression by human intervertebral disc cells andinfluences their capacity to stimulate endothelial migration [J]. Spine (Phila Pa1976).2009Apr1;34(7):663-669.
[28] Heiss C, Wong ML, Block VI, Lao D, Real WM, Yeghiazarians Y, et al. Pleiotrophin inducesnitric oxide dependent migration of endothelial progenitor cells [J]. J Cell Physiol.2008May;215(2):366-373.
[29] Orr B, Vanpoucke G, Grace OC, Smith L, Anderson RA, Riddick AC, et al. Expression ofpleiotrophin in the prostate is androgen regulated and it functions as an autocrine regulator ofmesenchyme and cancer associated fibroblasts and as a paracrine regulator of epithelia [J]. The Prostate.2011Feb15;71(3):305-317.
[30] Chang Y, Berenson JR, Wang Z, Deuel TF. Dominant negative pleiotrophin induces tetraploidyand aneuploidy in U87MG human glioblastoma cells [J]. Biochem Biophys Res Commun.2006Dec15;351(2):336-339.
[31] Pufe T, Bartscher M, Petersen W, Tillmann B, Mentlein R. Expression of pleiotrophin, anembryonic growth and differentiation factor, in rheumatoid arthritis [J]. Arthritis and rheumatism.2003Mar;48(3):660-667.
[32] Li G, Bunn JR, Mushipe MT, He Q, Chen X. Effects of pleiotrophin (PTN) over-expression onmouse long bone development, fracture healing and bone repair [J]. Calcif Tissue Int.2005Apr;76(4):299-306.
[33] Imai S, Heino TJ, Hienola A, Kurata K, Buki K, Matsusue Y, et al. Osteocyte-derived HB-GAM(pleiotrophin) is associated with bone formation and mechanical loading [J]. Bone.2009May;44(5):785-794.
[34] Mitsiadis TA, Salmivirta M, Muramatsu T, Muramatsu H, Rauvala H, Lehtonen E, et al.Expression of the heparin-binding cytokines, midkine (MK) and HB-GAM (pleiotrophin) is associatedwith epithelial-mesenchymal interactions during fetal development and organogenesis [J]. Development.1995Jan;121(1):37-51.
[35] Mikelis C, Papadimitriou E. Heparin-binding protein pleiotrophin: an important player in theangiogenic process [J]. Connect Tissue Res.2008;49(3):149-152.
[36] Perez-Pinera P, Berenson JR, Deuel TF. Pleiotrophin, a multifunctional angiogenic factor:mechanisms and pathways in normal and pathological angiogenesis [J]. Current opinion in hematology.2008May;15(3):210-214.
[37] Choudhuri R, Zhang HT, Donnini S, Ziche M, Bicknell R. An angiogenic role for the neurokinesmidkine and pleiotrophin in tumorigenesis [J]. Cancer Res.1997May1;57(9):1814-1819.
[38] Ezquerra L, Herradon G, Nguyen T, Vogt TF, Bronson R, Silos-Santiago I, et al. Pleiotrophin is amajor regulator of the catecholamine biosynthesis pathway in mouse aorta [J]. Biochem Biophys ResCommun.2004Oct15;323(2):512-517.
[39] Zhang N, Zhong R, Perez-Pinera P, Herradon G, Ezquerra L, Wang ZY, et al. Identification of theangiogenesis signaling domain in pleiotrophin defines a mechanism of the angiogenic switch [J].Biochem Biophys Res Commun.2006May5;343(2):653-658.
[40]Takei Y`, Kadomatsu K`, Yuasa K`, et al. Morpholino antisense oligomer targeting human midkine:its application for cancer therapy [J]. International Journal of Cancer.2005`;114:490-497.
[41] Chen S, Bu G, Takei Y, Sakamoto K, Ikematsu S, Muramatsu T, et al. Midkine andLDL-receptor-related protein1contribute to the anchorage-independent cell growth of cancer cells [J].Journal of cell science.2007Nov15;120(Pt22):4009-4015.
[42] Kong Y, Bai PS, Nan KJ, Sun H, Chen NZ, Qi XG. Pleiotrophin is a potential colorectal cancerprognostic factor that promotes VEGF expression and induces angiogenesis in colorectal cancer [J]. IntJ Colorectal Dis.2012Mar;27(3):287-298.
[43] Weber D, Klomp HJ, Czubayko F, Wellstein A, Juhl H. Pleiotrophin can be rate-limiting forpancreatic cancer cell growth [J]. Cancer Res.2000Sep15;60(18):5284-5288.
[44] Duces A, Karaky R, Martel-Renoir D, Mir L, Hamma-Kourbali Y, Bieche I, et al.16-kDa fragmentof pleiotrophin acts on endothelial and breast tumor cells and inhibits tumor development [J]. MolCancer Ther.2008Sep;7(9):2817-2827.
[45] Park TJ, Jeong BR, Tateno C, Kim HS, Ogawa T, Lim IK, et al. Pleiotrophin inhibits transforminggrowth factor beta1-induced apoptosis in hepatoma cell lines [J]. Mol Carcinog.2008Oct;47(10):784-796.
[46] Chang Y, Zuka M, Perez-Pinera P, Astudillo A, Mortimer J, Berenson JR, et al. Secretion ofpleiotrophin stimulates breast cancer progression through remodeling of the tumor microenvironment[J]. Proc Natl Acad Sci U S A.2007Jun26;104(26):10888-10893.
[47] Souttou B, Juhl H, Hackenbruck J, Rockseisen M, Klomp HJ, Raulais D, et al. Relationshipbetween serum concentrations of the growth factor pleiotrophin and pleiotrophin-positive tumors [J]. JNatl Cancer Inst.1998Oct7;90(19):1468-1473.
[48] Tsirmoula S, Dimas K, Hatziapostolou M, Lamprou M, Ravazoula P, Papadimitriou E.Implications of pleiotrophin in human PC3prostate cancer cell growth in vivo [J]. Cancer Sci.2012Oct;103(10):1826-1832.
[49] Silver K, Desormaux A, Freeman LC, Lillich JD. Expression of pleiotrophin, an importantregulator of cell migration, is inhibited in intestinal epithelial cells by treatment with non-steroidalanti-inflammatory drugs [J]. Growth Factors.2012Aug;30(4):258-266.
[50] Sharifi BG, Zeng Z, Wang L, Song L, Chen H, Qin M, et al. Pleiotrophin inducestransdifferentiation of monocytes into functional endothelial cells [J]. Arterioscler Thromb Vasc Biol.2006Jun;26(6):1273-1280.
[51] Papadimitriou E, Mikelis C, Lampropoulou E, Koutsioumpa M, Theochari K, Tsirmoula S, et al.Roles of pleiotrophin in tumor growth and angiogenesis [J]. Eur Cytokine Netw.2009Dec;20(4):180-190.
[52] Klomp HJ, Zernial O, Flachmann S, Wellstein A, Juhl H. Significance of the expression of thegrowth factor pleiotrophin in pancreatic cancer patients [J]. Clin Cancer Res.2002Mar;8(3):823-827.
[53] Gao SB, Feng ZJ, Xu B, Wu Y, Yin P, Yang Y, et al. Suppression of lung adenocarcinoma throughmenin and polycomb gene-mediated repression of growth factor pleiotrophin [J]. Oncogene.2009Nov19;28(46):4095-4104.
[54] Yu Y, Shi MH, Xu X, Zhang ZL, Hu HC. Analysis of expression profiles of some tumorgrowth-related genes after silencing of pleiotrophin in human small cell lung cancer H446cells[J].Zhonghua Zhong Liu Za Zhi.2010Jun;32(6):405-409.
[55] Yu Y, Shi MH, Xu X, Hu HC. Construction of siRNA lentiviral expressing vector targetingpleiotrophin gene and its impact on growth and apoptosis in H446cells of human small cell lung cancer[J]. Zhonghua Jie He He Hu Xi Za Zhi.2010Apr;33(4):289-294.
[56] Hu YC, Liu ML, Li G, Huo YY, Wu DC. A pleiotrophin-specific siRNA and its effect on PTEN-/-MEF241cells [J]. Ai Zheng.2006Oct;25(10):1210-1215.
[57] Grzelinski M, Urban-Klein B, Martens T, Lamszus K, Bakowsky U, Hobel S, et al. RNAinterference-mediated gene silencing of pleiotrophin through polyethylenimine-complexed smallinterfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts [J]. Hum Gene Ther.2006Jul;17(7):751-766.
[58] Himburg HA, Muramoto GG, Daher P, Meadows SK, Russell JL, Doan P, et al. Pleiotrophinregulates the expansion and regeneration of hematopoietic stem cells [J]. Nat Med.2010Apr;16(4):475-482.
[59] Li YS, Deuel TF. Pleiotrophin stimulates tyrosine phosphorylation in NIH3T3and NB41A3cells[J]. Biochem Biophys Res Commun.1993Sep15;195(2):1089-1095.
[60] Meng K, Rodriguez-Pena A, Dimitrov T, Chen W, Yamin M, Noda M, et al. Pleiotrophin signalsincreased tyrosine phosphorylation of beta beta-catenin through inactivation of the intrinsic catalyticactivity of the receptor-type protein tyrosine phosphatase beta/zeta [J]. Proc Natl Acad Sci U S A.2000Mar14;97(6):2603-2608.
[61] Weng T, Liu L. The role of pleiotrophin and beta-catenin in fetal lung development [J].Respiratory research.2010;11:80.
[62] Pariser H, Perez-Pinera P, Ezquerra L, Herradon G, Deuel TF. Pleiotrophin stimulates tyrosinephosphorylation of beta-adducin through inactivation of the transmembrane receptor protein tyrosinephosphatase beta/zeta [J]. Biochem Biophys Res Commun.2005Sep16;335(1):232-239.
[63] Perez-Pinera P, Chang Y, Deuel TF. Pleiotrophin, a multifunctional tumor promoter throughinduction of tumor angiogenesis, remodeling of the tumor microenvironment, and activation of stromalfibroblasts [J]. Cell Cycle.2007Dec1;6(23):2877-2883.
[64] Perez-Pinera P, Zhang W, Chang Y, Vega JA, Deuel TF. Anaplastic lymphoma kinase is activatedthrough the pleiotrophin/receptor protein-tyrosine phosphatase beta/zeta signaling pathway: analternative mechanism of receptor tyrosine kinase activation [J]. J Biol Chem.2007Sep28;282(39):28683-28690.
[65] Pariser H, Herradon G, Ezquerra L, Perez-Pinera P, Deuel TF. Pleiotrophin regulates serinephosphorylation and the cellular distribution of beta-adducin through activation of protein kinase C [J].Proc Natl Acad Sci U S A.2005Aug30;102(35):12407-12412.
[66] Hida H, Masuda T, Sato T, Kim TS, Misumi S, Nishino H. Pleiotrophin promotes functionalrecovery after neural transplantation in rats [J]. Neuroreport.2007Jan22;18(2):179-183.
[67] Chen H, Gordon MS, Campbell RA, Li M, Wang CS, Lee HJ, et al. Pleiotrophin is highlyexpressed by myeloma cells and promotes myeloma tumor growth [J]. Blood.2007Jul1;110(1):287-295.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |