人脐带Wharton's Jelly及子宫内膜间充质干细胞免疫调节作用研究
|
摘要
随着医学科学的发展,器官、组织及细胞移植已成为治疗许多疾病的常见而有效的方法。然而,人体内具有非常完善的防御机制,异体移植后,移植物作为一种异物被机体识别,从而动员机体免疫系统针对移植物进行攻击、破坏和清除引起排斥反应。免疫排斥反应对机体具有很大的破坏性,一旦发生排斥反应,外源移植物将会受到损伤,严重时会导致移植器官及组织功能的丧失,危及生命安全。另外,免疫系统疾病也是困扰医疗工作者的一大难题。自身免疫性疾病(autoimmune diseases, AD)是机体免疫系统对自身抗原攻击造成组织器官损伤和功能障碍的一种免疫应答紊乱疾病,具有较高的致残率和致死率,至今尚无有效的治疗方法。
免疫抑制剂的主要作用是使机体降低对外源移植物的排斥反应,以使二者和平共处,因此在器官及组织移植和自身免疫性疾病的临床治疗中起着举足轻重的作用。但是,免疫抑制剂使用所引起的副作用,包括免疫抑制引起的感染、肿瘤发生率增加等给临床治疗提出了巨大的挑战。因此寻找更安全有效的治疗方法具有重要的现实意义。
间充质干细胞(mesenchymal stem cells, MSCs)是一类中胚层来源的具有自我更新能力和多向分化潜能的多能干细胞,是重要的组织工程和细胞治疗的种子细胞。大量研究证明,MSCs还具有低免疫原性及免疫调节作用,可以有效抑制同种异体免疫排斥反应,延长移植物生存时间,提高移植成功率。另外一些研究表明,MSCs在造血干细胞移植(HSCT)导致的移植物抗宿主病(GVHD)以及自身免疫系统疾病方面也同样具有良好的治疗效果。然而,由于种种原因,对于MSCs的研究主要集中于骨髓源间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)。BMSCs在成人骨髓内含量极低且需要创伤途径获取,另外,BMSCs随着年龄增长,其细胞数量和扩增、分化能力明显下降以及其所面临的伦理、法律等众多方面的问题使其应用受到一定限制。因此寻找新的MSCs替代来源,保证MSCs的数量是临床应用的前提。
近年来的研究表明,人脐带Wharton's jelly间充质干细胞(MesenchymalStromal Cells derived from Wharton's jelly cells, WJCs)及人子宫内膜间质干细胞(endometrium Mesenchymal Cells, ERCs)是备受关注的新型种子细胞。与BMSCs相比WJCs及ERCs具有无可比拟的优势,WJCs及ERCs来源广泛,取材方便,可以无创伤获取,不涉及伦理问题,可以成为一种新的MSCs来源,具有良好的应用前景。
本课题组率先在国内成功分离培养WJCs及ERCs,并发现WJCs及ERCs表达的表面标记物和BMSCs,几乎一样,可能具有和BMSCs相似的生物学特性。因此研究WJCs,及ERCs的免疫调节作用具有重要的现实意义,可以为临床应用和基础研究提供理论依据。
本论文共分为二部分,第一部分：WJCs、ERCs的分离、培养及鉴定；第二部分：WJCs、ERCs的免疫调节作用研究。
第一部分：本课题所用胎盘为正常剖宫产的健康产妇志愿捐献,经血由健康志愿者提供。本实验采用组织块贴壁法从人脐带Wharton's jelly中分离WJCs;密度梯度离心法从经血中分离ERCs;倒置显微镜观察细胞形态,流式细胞技术检钡WJCs及ERCs特异性表面标记；CCK-8试剂盒检测各代WJCs及ERCs的增殖活力。结果表明应用组织块贴壁法、密度梯度离心法可以分别从人脐带Wharton's jelly中及经血中成功分离、培养出MSCs;流式结果表明WJCs及ERCs:表达MSCs特异性标记物,低表达HLA-ABC,不表达HLA-DR,具低免疫源性；生长曲线结果表明各代WJCs及ERCs均具有良好的增殖活力。
第二部分：采用原代培养后传至第三代的WJCs及ERCs,将WJCs、ERCs以及其培养上清分别与植物凝集素(PHA)刺激下的小鼠脾淋巴细胞及人外周血淋巴细胞共培养,多功能酶标仪检测’WJCs、ERCs,及其培养上清与PHA刺激下的小鼠脾淋巴细胞及人外周血T淋巴细胞共培养72h后的OD值,观察两种细胞及其培养上清对同源及异源淋巴细胞增殖的影响；另外本实验应用ELISA试剂盒对共培养上清中干扰素-γ(IFN-γ)及人转化生长因子(TGF-β1)表达量变化进行了检测,从细胞因子水平对WJCs,及ERCs的免疫调节作用机制进行了初步探讨。结果发现,WJCs、ERCs及其培养上清对PHA刺激下的小鼠脾淋巴细胞及人外周血淋巴细胞增殖都具有抑制作用,WJCs及ERCs能显著降低人外周血淋巴细胞IFN-γ的分泌。另外WJCs及ERCs可分泌TGF-β1,但同时在人外周血淋巴细胞中亦发现该细胞因子的分泌,且表达量高于WJCs及ERCs与淋巴细胞共培养组,因此TGF-β1可能不是在WJCs及ERCs免疫调节作用中起主要作用的细胞因子。
总之,本研究成功从人脐带Wharton's jelly及经血中分离出MSCs, WJCs及ERCs免疫表型与BMSCs相似,且比BMSCs具有更强的扩增能力可做为一种新的MSCs来源。研究发现,WJCs及ERCs对同源及异源淋巴细胞都具有免疫调节作用,其作用机制可能与细胞间的直接接触及抑制淋巴细胞FN-γ的分泌有关。可以为减少异体移植引起的免疫排斥反应及治疗自身免疫系统疾病提供理论依据。
With the development of medicine science, transplantation of organs, tissues and cells has become the common and effective way to treat many disease. However, human body has very perfect defense mechanism, and exogenous graft can be recognized by the defense system firstly, then the immune system can be activated and cause rejection to attack, destroy and eliminate the graft. Immune rejection has great destructive to the human body. Exogenous graft will be injured when the rejection occured, severely, it will cause transplanted organs and tissues lose function and even made the life endanger. In addition, immune system diseases are also a serious problem which puzzled medical workers. Autoimmune disease is a disease of immune response disorder, which body immune system attacks autoantigen, causes tissue damage and organ dysfunction in diseases with high morbidity and mortality rates, and it has no effective treatment until now.
The primary function of immunosuppressive agents is to reduce the body rejection for foreign objects to make them coexistence peacefully, so it plays an important role in the clinical treatment of organ or tissue transplantition and autoimmune diseases. However, the side effect of immunosuppressive agents, including infection and tumor incidence increased caused by immunosuppression presented such daunting challenges to the clinical treatment. So it has important practical significance to look for a safer and more effective treatment method.
Mesenchymal stem cells are a class of mesodermal pluripotent stem cells which have self-renewal and multilineage differentiation potential that can be used as important seed cells for tissue engineering and cell transplantation. A large number of studies have shown that MSCs also have low immunogenicity and immune regulation, which can effectively inhibit the allogeneic immune rejection, extend the graft survival time and improve the success rate of transplantation. Other studies have shown that MSCs also have a good therapeutic effect in graft-versus-host disease and autoimmune diseases which are caused by hematopoietic stem cell transplantation. However, due to various reasons, the study of MSCs mainly focused on bone marrow mesenchymal stem cells, but bone marrow mesenchymal stem cells which are obtained by the traumatic method also declined in the quantity and quality in ageing people. So it is necessary for clinical application to search new types of stem cells which have a wide range of source and are easy to be collected, especially no ethics issue.
Recent studies have shown that human umbilical cord Wharton s Jelly and menstrual blood-derived mesenchymal cells are a new type of seed cells with a high degree of self-renewal capacity and multi-differentiation potential.Compared with the BMSCs, WJCs and ERCs have lots of advantages. WJCs and ERCs not only have a wider range of source but also are easily to be collected without obvious ethics problems. Additionally, it also has stronger proliferation capability. Therefore, it can become a new source of MSCs and has good application prospects.
Our research group took lead in the successful isolated culture of WJCs and ERCs, and found that the surface marker expression of WJCs and ERCs is almost the same as BMSCs', indicating WJCs and ERCs may have similar biological characteristics to BMSCs. Therefore, studing the immune regulation of WJCs and ERCs has important practical significance for clinical application and basic research.
As followed below, this essay was divided into two parts. PartⅠ:Isolation, culture and identification of WJCs and ERCs, PartⅡ:The immune regulation research of WJCs and ERCs.
PartⅠ:The human umbilical cords used in this subject were supplied by the Department of Obstetrics, First Affiliated Hospital, Zhengzhou University, Peripheral blood obtained from healthy volunteers. WJCs were separated by culture of tissue adherence. ERCs were separated by density gradient centrifugation. WJCs and ERCs morphous was observed with inverted microscope and the flow cytometer was performed to examine the expression of cell surface molecules. Futhermore, the P1, P3, P5 WJCs and ERCs growth activity were tested by CCK-8 kit. The results showed that WJCs can be isolated successfully by tissue culture method from human umbilical cord Wharton's jelly and ERCs can be isolated by density gradient centrifugation from menstrual blood. The result of FCM showed that the WJCs and ERCs express MSCs markers. Low expression of HLA-ABC while HLA-DR was negative, indicating that they only have low immunogenicity. Growth curve results showed that the P1, P3, P5 WJCs and ERCs have good growth vigor.
PartⅡ:We used the P3 WJCs and ERCs which have strong proliferation, put WJCs, ERCs and their culture supernatant co-cultured with the mouse spleen lymphocytes and human peripheral blood lymphocytes simulated by PHA respectively to observe the effect of WJCs, ERCs and their culture supernatant to proliferation of homologous and heterologous lymphocyte. Then, expression of cytokines including human transforming growth factor (TGF-β1)and interferon-y (IFN-y) was aslo evaluated by ELISA detection kit. These experimentations were used to study the immune regulation mechanisms of WJCs and ERCs from the levels of cytokines secretion. The results showed that WJCs, ERCs and their supernatant can inhibite the proliferation of mouse spleen lymphocytes and human peripheral blood lymphocyte induced by PHA. IFN-y secretion of human peripheral blood lymphocytes can suppressed by WJCs and ERCs significantly. In addition, WJCs and ERCs may secrete TGF-β1, but human peripheral blood lymphocytes may secrete this cytokines too and the secretion of TGF-β1 more than WJCs, ERCs and human peripheral blood lymphocytes co-cultured group.
In a word, WJCs and ERCs were isolated successfully from human umbilical cord Wharton's jelly and menstrual blood this study successfully isolated MSCs from Wharton's jelly and menstrual blood respectively, the immunephenotype of WJCs and ERCs is similar to BMSCs, and compared with BMSCs, they have a stronger proliferation capacity, so they can be used as a new kind of MSCs sources. The study found that WJCs and ERCs have a special immune regulation on both homologous and heterologous lymphocytes; the mechanism may be related to direct contact between cells and the secretion of some soluble molecule. It can be providing a theoretical basis to reduce immune rejection caused by allograft and treat autoimmune diseases.
免疫抑制剂的主要作用是使机体降低对外源移植物的排斥反应,以使二者和平共处,因此在器官及组织移植和自身免疫性疾病的临床治疗中起着举足轻重的作用。但是,免疫抑制剂使用所引起的副作用,包括免疫抑制引起的感染、肿瘤发生率增加等给临床治疗提出了巨大的挑战。因此寻找更安全有效的治疗方法具有重要的现实意义。
间充质干细胞(mesenchymal stem cells, MSCs)是一类中胚层来源的具有自我更新能力和多向分化潜能的多能干细胞,是重要的组织工程和细胞治疗的种子细胞。大量研究证明,MSCs还具有低免疫原性及免疫调节作用,可以有效抑制同种异体免疫排斥反应,延长移植物生存时间,提高移植成功率。另外一些研究表明,MSCs在造血干细胞移植(HSCT)导致的移植物抗宿主病(GVHD)以及自身免疫系统疾病方面也同样具有良好的治疗效果。然而,由于种种原因,对于MSCs的研究主要集中于骨髓源间充质干细胞(bone marrow mesenchymal stem cells, BMSCs)。BMSCs在成人骨髓内含量极低且需要创伤途径获取,另外,BMSCs随着年龄增长,其细胞数量和扩增、分化能力明显下降以及其所面临的伦理、法律等众多方面的问题使其应用受到一定限制。因此寻找新的MSCs替代来源,保证MSCs的数量是临床应用的前提。
近年来的研究表明,人脐带Wharton's jelly间充质干细胞(MesenchymalStromal Cells derived from Wharton's jelly cells, WJCs)及人子宫内膜间质干细胞(endometrium Mesenchymal Cells, ERCs)是备受关注的新型种子细胞。与BMSCs相比WJCs及ERCs具有无可比拟的优势,WJCs及ERCs来源广泛,取材方便,可以无创伤获取,不涉及伦理问题,可以成为一种新的MSCs来源,具有良好的应用前景。
本课题组率先在国内成功分离培养WJCs及ERCs,并发现WJCs及ERCs表达的表面标记物和BMSCs,几乎一样,可能具有和BMSCs相似的生物学特性。因此研究WJCs,及ERCs的免疫调节作用具有重要的现实意义,可以为临床应用和基础研究提供理论依据。
本论文共分为二部分,第一部分：WJCs、ERCs的分离、培养及鉴定；第二部分：WJCs、ERCs的免疫调节作用研究。
第一部分：本课题所用胎盘为正常剖宫产的健康产妇志愿捐献,经血由健康志愿者提供。本实验采用组织块贴壁法从人脐带Wharton's jelly中分离WJCs;密度梯度离心法从经血中分离ERCs;倒置显微镜观察细胞形态,流式细胞技术检钡WJCs及ERCs特异性表面标记；CCK-8试剂盒检测各代WJCs及ERCs的增殖活力。结果表明应用组织块贴壁法、密度梯度离心法可以分别从人脐带Wharton's jelly中及经血中成功分离、培养出MSCs;流式结果表明WJCs及ERCs:表达MSCs特异性标记物,低表达HLA-ABC,不表达HLA-DR,具低免疫源性；生长曲线结果表明各代WJCs及ERCs均具有良好的增殖活力。
第二部分：采用原代培养后传至第三代的WJCs及ERCs,将WJCs、ERCs以及其培养上清分别与植物凝集素(PHA)刺激下的小鼠脾淋巴细胞及人外周血淋巴细胞共培养,多功能酶标仪检测’WJCs、ERCs,及其培养上清与PHA刺激下的小鼠脾淋巴细胞及人外周血T淋巴细胞共培养72h后的OD值,观察两种细胞及其培养上清对同源及异源淋巴细胞增殖的影响；另外本实验应用ELISA试剂盒对共培养上清中干扰素-γ(IFN-γ)及人转化生长因子(TGF-β1)表达量变化进行了检测,从细胞因子水平对WJCs,及ERCs的免疫调节作用机制进行了初步探讨。结果发现,WJCs、ERCs及其培养上清对PHA刺激下的小鼠脾淋巴细胞及人外周血淋巴细胞增殖都具有抑制作用,WJCs及ERCs能显著降低人外周血淋巴细胞IFN-γ的分泌。另外WJCs及ERCs可分泌TGF-β1,但同时在人外周血淋巴细胞中亦发现该细胞因子的分泌,且表达量高于WJCs及ERCs与淋巴细胞共培养组,因此TGF-β1可能不是在WJCs及ERCs免疫调节作用中起主要作用的细胞因子。
总之,本研究成功从人脐带Wharton's jelly及经血中分离出MSCs, WJCs及ERCs免疫表型与BMSCs相似,且比BMSCs具有更强的扩增能力可做为一种新的MSCs来源。研究发现,WJCs及ERCs对同源及异源淋巴细胞都具有免疫调节作用,其作用机制可能与细胞间的直接接触及抑制淋巴细胞FN-γ的分泌有关。可以为减少异体移植引起的免疫排斥反应及治疗自身免疫系统疾病提供理论依据。
With the development of medicine science, transplantation of organs, tissues and cells has become the common and effective way to treat many disease. However, human body has very perfect defense mechanism, and exogenous graft can be recognized by the defense system firstly, then the immune system can be activated and cause rejection to attack, destroy and eliminate the graft. Immune rejection has great destructive to the human body. Exogenous graft will be injured when the rejection occured, severely, it will cause transplanted organs and tissues lose function and even made the life endanger. In addition, immune system diseases are also a serious problem which puzzled medical workers. Autoimmune disease is a disease of immune response disorder, which body immune system attacks autoantigen, causes tissue damage and organ dysfunction in diseases with high morbidity and mortality rates, and it has no effective treatment until now.
The primary function of immunosuppressive agents is to reduce the body rejection for foreign objects to make them coexistence peacefully, so it plays an important role in the clinical treatment of organ or tissue transplantition and autoimmune diseases. However, the side effect of immunosuppressive agents, including infection and tumor incidence increased caused by immunosuppression presented such daunting challenges to the clinical treatment. So it has important practical significance to look for a safer and more effective treatment method.
Mesenchymal stem cells are a class of mesodermal pluripotent stem cells which have self-renewal and multilineage differentiation potential that can be used as important seed cells for tissue engineering and cell transplantation. A large number of studies have shown that MSCs also have low immunogenicity and immune regulation, which can effectively inhibit the allogeneic immune rejection, extend the graft survival time and improve the success rate of transplantation. Other studies have shown that MSCs also have a good therapeutic effect in graft-versus-host disease and autoimmune diseases which are caused by hematopoietic stem cell transplantation. However, due to various reasons, the study of MSCs mainly focused on bone marrow mesenchymal stem cells, but bone marrow mesenchymal stem cells which are obtained by the traumatic method also declined in the quantity and quality in ageing people. So it is necessary for clinical application to search new types of stem cells which have a wide range of source and are easy to be collected, especially no ethics issue.
Recent studies have shown that human umbilical cord Wharton s Jelly and menstrual blood-derived mesenchymal cells are a new type of seed cells with a high degree of self-renewal capacity and multi-differentiation potential.Compared with the BMSCs, WJCs and ERCs have lots of advantages. WJCs and ERCs not only have a wider range of source but also are easily to be collected without obvious ethics problems. Additionally, it also has stronger proliferation capability. Therefore, it can become a new source of MSCs and has good application prospects.
Our research group took lead in the successful isolated culture of WJCs and ERCs, and found that the surface marker expression of WJCs and ERCs is almost the same as BMSCs', indicating WJCs and ERCs may have similar biological characteristics to BMSCs. Therefore, studing the immune regulation of WJCs and ERCs has important practical significance for clinical application and basic research.
As followed below, this essay was divided into two parts. PartⅠ:Isolation, culture and identification of WJCs and ERCs, PartⅡ:The immune regulation research of WJCs and ERCs.
PartⅠ:The human umbilical cords used in this subject were supplied by the Department of Obstetrics, First Affiliated Hospital, Zhengzhou University, Peripheral blood obtained from healthy volunteers. WJCs were separated by culture of tissue adherence. ERCs were separated by density gradient centrifugation. WJCs and ERCs morphous was observed with inverted microscope and the flow cytometer was performed to examine the expression of cell surface molecules. Futhermore, the P1, P3, P5 WJCs and ERCs growth activity were tested by CCK-8 kit. The results showed that WJCs can be isolated successfully by tissue culture method from human umbilical cord Wharton's jelly and ERCs can be isolated by density gradient centrifugation from menstrual blood. The result of FCM showed that the WJCs and ERCs express MSCs markers. Low expression of HLA-ABC while HLA-DR was negative, indicating that they only have low immunogenicity. Growth curve results showed that the P1, P3, P5 WJCs and ERCs have good growth vigor.
PartⅡ:We used the P3 WJCs and ERCs which have strong proliferation, put WJCs, ERCs and their culture supernatant co-cultured with the mouse spleen lymphocytes and human peripheral blood lymphocytes simulated by PHA respectively to observe the effect of WJCs, ERCs and their culture supernatant to proliferation of homologous and heterologous lymphocyte. Then, expression of cytokines including human transforming growth factor (TGF-β1)and interferon-y (IFN-y) was aslo evaluated by ELISA detection kit. These experimentations were used to study the immune regulation mechanisms of WJCs and ERCs from the levels of cytokines secretion. The results showed that WJCs, ERCs and their supernatant can inhibite the proliferation of mouse spleen lymphocytes and human peripheral blood lymphocyte induced by PHA. IFN-y secretion of human peripheral blood lymphocytes can suppressed by WJCs and ERCs significantly. In addition, WJCs and ERCs may secrete TGF-β1, but human peripheral blood lymphocytes may secrete this cytokines too and the secretion of TGF-β1 more than WJCs, ERCs and human peripheral blood lymphocytes co-cultured group.
In a word, WJCs and ERCs were isolated successfully from human umbilical cord Wharton's jelly and menstrual blood this study successfully isolated MSCs from Wharton's jelly and menstrual blood respectively, the immunephenotype of WJCs and ERCs is similar to BMSCs, and compared with BMSCs, they have a stronger proliferation capacity, so they can be used as a new kind of MSCs sources. The study found that WJCs and ERCs have a special immune regulation on both homologous and heterologous lymphocytes; the mechanism may be related to direct contact between cells and the secretion of some soluble molecule. It can be providing a theoretical basis to reduce immune rejection caused by allograft and treat autoimmune diseases.
引文
[1]Ming-Yan Chen, Pu-Chang Lie, Zhi-Ling Li, et al. Endothelial differentiation of Wharton's jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells[J], Experimental Hematology.2009,37(5):629-640
[2]Conget P, Minguel JJ. Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow mesenchymal progenytor cells[J]. Experimental Hematol,2000,28 (4):382-390
[3]Muraglia A, Cancedda R, Qrarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model[J]. J Cell Sci,2000, 113(7):1161-1166
[4]Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart [J]. Circulation,2002,105(1):93-98
[5]Woodbury D, Schwarz EJ, Prockop DJ, et al. Adult rat and human bone marrow stromal cells differentiateinte neurons[J]. J Neurosci Res.2000,61(4):364—370
[6]Gary Brooke, Matthew Cooka, et al. Therapeutic applications of mesenchymal stromal cells[J]. Semin Cell Dev Biol.2007,18(6):846-858
[7]Hematti P. Role of mesenchymal stromal cells in solid organ transplantation[J]. Transplant Rev, 2008,22(4):262-273
[8]Bartholomew A, Sturgeon C, Siatskas M, et al.Mesenchymal stem Cells suppress lymphocyte proliferation invitro and prolong skin graft in vivo[J]. Exp Hematol,2002,30(1):42-48
[9]Y anez R, Lamana ML, Garcia-Castro J, et al.Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease[J].Stem Cells,2006,24(11):2582-91
[10]VanLaar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases[J]. Rheumatology (Oxford),2006,45(10):1187-1193
[11]Zvaifler NJ, Marinova-Mutafchieva L, Adams G, et al. Mesenchymal precursor cells in the blood of normal individual[J]. Athritis Res,2000,2(6):477-488
[12]Campagnoli C, Roberts IA, Kumar S, et al. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, Liver, and bone marrow[J]. Blood,2001,98 (8):2396-402
[13]Zuk PA,Zhu M,Mizunon H,et al. Multilineage cells from human adipose tissue: implication for cell-based therapies[J]. Tissue Eng,2001,7 (2):211-28
[14]Warejcka DJ, Harvey R, Taylor BJ, et al. A population of cells isolated from rat heart capable of differentiating into several mesodermal phenotype[J]. J Surg Res,1996,62 (2):233-42
[15]Williams JT, Southerland SS, Souza J, et al. Cells isolated from human skeletal muscle capable of differentiating into multiple mesodermal phenotype[J]. Am Surg,1999,65 (1):22
[16]Young HE, Steele TA, Bray RA, et al. Human reserve pluripotent stem cells are present in the connective tissue of skeletal muscle and dermis derived f rom fetal, adult, and geriatric donors[J]. Anat Rec,2001,263 (1):51
[17]Troyer DL, Weiss ML, et al.Concise Review:Wharton's jelly-derived cells are a primitive stromal cell population [J].Stem Cells.2008,26(3):591-599
[18]Wang M, Yang Y, Yang D, et al. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro[J]. Immunology,2009,126(2),220-232
[19]Peng HQ, Levitin-Smith M, Rochelson B, et al. Umbilical cord stricture and overcoiling are common causes of fetal demise [J]. Pediatr Dev Pathol,2006,9(1):14-19
[20]Trevisanuto D, Doglioni N, Zanardo V et al. Overcoiling of the umbilical cord[J]. J Pediatr 2007,150(1):112
[21]Toren A, Nagler A, Amariglio N, et al. Successful human umbilical cord blood stem cell transplantation with conditioning in severe combined immune deficiency[J]. Bone Marrow Transplant,1999,23(4):405-408
[22]Sarugaser R, Lickorish D, Baksh D, et al. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors[J]. Stem Cells,2005,23(2):220-229
[23]Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells:candidate MSC-like cells from umbilical cord[J]. Stem Cells 2003,21(1):105-110
[24]薛美思.脐带间充质干细胞在细胞治疗中的研究进展[J].中国美容医学,2008,17(9)：1405-07
[25]Musina RA, Belyavski AV, Tarusova OV, et al. Endometrial mesenchymal stem cells isolated from the menstrual blood [J]. Bulletin of Experimental Biology and Medicine,2008,145(4): 539-543
[26]Mitchell KE, Weiss ML, Mitchell BM, et al. Matrix cells from Wharton's jelly form neurons and glia [J]. Stem Cells,2003,21(1):50-60
[27]Karahuseyinoglu S, Cinar O, Kilic E, et al. Biology of the stem cells in human umbilical cord stroma:in situ and in vitro surveys[J]. Stem Cells,2007,25(2):319-331
[28]Lu LL, Liu YJ, Yang SG et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials[J]. Haematologica,2006,91(8):1017-1026
[29]Weiss ML, Medicetty S, Bledsoe AR et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease[J]. Stem Cells,2006,24(3):781-792
[30]Fu YS, Shih YT, Cheng YC et al. Transformation of human umbilical mesenchymal cells into neurons in vitro [J]. J Biomed Sci,2004,11(5):652-660
[31]Wang HS, Hung SC, Peng ST et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord [J]. Stem Cells,2004,22(7):1330-37
[32]Weiss ML, Anderson C, Medicetty S, et al. Immune Properties of Human Umbilical Cord Wharton's Jelly-Derived Cells[J]. Stem Cells.2008,26(11):2865-74
[33]Le Blanc K L, Tammik L, SundbergB, et al.Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex [J]. Scand J Immunol,2003,57(1):11-20
[34]ZhangJ, LiY, ChenJ, et al. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice [J].Exp Neurol,2005,195(1):16-26
[35]Djouad F, Fritz V, Apparailly F,et al.Reversal of the Immunosuppressive Properties of Mesenchymal Stem Cells by Tumor Necrosis Factor alpha Collagen-induced Althritis [J]. Arthritis Rheum,2005,52(5):1595-03
[36]Karussis D, Kassis I, Basan GS, et al.Immununomodulation and neuroprotection With mesenchymal bone marrow stem cells(MSCs):Aproposed treatment for multiple Sclerosis and other neuroimmunological/neurodegenerative diseases [J].J Neurol Sci,2008, 265(1-2):131-135
[37]朱雅姝,赵春华.间充质干细胞的免疫调节能力—临床治疗的希望[J].生命科学.2009,39(8)：727-735
[38]NicolaMD, Carlo-Stella C, Magni M, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing t-cell anergy [J]. Blood,2002,99(11):3838-43.
[39]Nasef A, Chapel A, Mazurier C,et al. Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells[J].Gene expression,2007,13(4-5):217-26
[40]Wu Tao,BaiI Hai,Wang Jing chang,et al,Preliminary study on biological properties of adult human bone marrow-derived mesenchymal stem cells[J]. The Chinese-German Journal of Clinical oncology,2006,5:285-290
[41]KramperaM, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigenspecific T cells to their cognate peptide[J]. Blood, 2003,101(9):3722-29
[42]Bian Li, Guo ZK, Wang HX, et al. In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells [J]. in vivo,2009, 23(1):21-27.
[43]Bommireddy R, Saxena V, Ormsby I, et al.TGF-betal regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes [J]. J Immunol, 2003,170(9):4612-22.
[44]Xu G, Zhang Y,Zhang L, et al. The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells [J]. Biochem Biophys Res Commun,2007,361(3):745-750
[45]TseWT, Pendleton JD, BeyerWM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation[J].Transplantation,2003,75(3): 389-397
[46]Reddy P. Pathophysiology of acute graft-versus-host disease [J]. Hematol Oncol,2003,21(4): 149-161
[47]Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions[J]. Blood,2006,107(1):367-372
[48]Asari S, Itakura S, Ferreri K, et al. Mesenchymal stem cells suppress B-cell terminal differentiation [J]. Exp Hematol,2009,37(5):604-15
[49]Sotiropoulou P A, Perez S A, Gritzapis A D, et al. Interactions between human mesenchymal stem cells and natural killer cells [J]. Stem Cells,2006,24(1):74-85
[50]Spaggiari G M, Capobianco A, Abdelrazik H, et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2 [J]. Blood,2008,111(3):1327-33
[1]Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells:in vitro cultivation and transplantation in diffusion chambers [J]. Cell Tissue Kinet,1987, 20(3):263-272
[2]Erices A, Conget P, Minguell. Mesenchymal progenitor cells in human umbilical cord blood [J]. Br J Haematol,2000,109(1):235-242
[3]In't Anker PS, Scherjon SA, Kleijburg-vander Keur C, et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta[J]. Stem Cells,2004,22(7):1338-45
[4]Musina RA, Belyavski AV, Tarusova OV et al. Endometrial mesenchymal stem cells isolated from the Menstrual Blood[J]. Bulletin of Experimental Biology and Medicine,2008, 145(4):539-543
[5]Pittenger MF, Mackay AM, Jaiswal SC, et al. Multilineage potential of mesenchymal stem cell[J]. Science,1999,284 (5411):143-147
[6]Karahuseyinoglu S, Cinar O, Kilic E et al. Biology of the stem cells in human umbilical cord stroma:in situ and in vitro surveys [J]. Stem Cells,2007,25 (2):319-331
[7]Lu LL, Liu YJ, Yang SG et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials[J]. Haematologica,2006,91 (8):1017-26
[8]Weiss ML, Medicetty S, Bledsoe AR et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease[J]. Stem Cells,2006,24 (3):781-92
[9]Fu YS, Shih YT, Cheng YC et al. Transformation of human umbilical mesenchymal cells into neurons in vitro [J]. J Biomed Sci,2004,11(5):652-60
[10]Wang HS, Hung SC, Peng ST et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord[J]. Stem Cells,2004,22 (7):1330-37
[11]Ming-Yan Chen, Pu-Chang Lie, Zhi-Ling Li, et al. Endothelial differentiation of Wharton's jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells[J], Experimental Hematology,2009,37 (5):629-40
[12]Conget P, Minguel JJ. Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow mesenchymal progenytor cells [J]. Experimental Hematol,2000,28 (4):382-90
[13]Muraglia A, Cancedda R, Qrarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model[J]. J Cell Sci,2000, 113(7):1161-66
[14]Lou J, Xu F, Merkel K, et al. Gene therapy:adenovirus-mediated human bone morphogenetic protein-2 gene transfer induces mesenchymal prongitor cell proliferation and differentiation in vitro and bone formation in vivo [J]. J Orthop Res,1999,17(1):43-50
[15]Mbalaviele G, Jaiwal N, Meng A. et al. Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors [J]. Endocrinology,1999,140(8):3736-43
[16]Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart [J]. Circulation,2002,105(1):93-98
[17]Woodbury D, Schwarz EJ, Prockop DJ, et al. Adult rat and human bone marrow stromal cells differentiateinte neurons[J]. J Neurosci Res.2000,61(4):364-70
[18]Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bonemarrow cell transp lantation in chronic coronary artery disease: the IACT study[J]. J Am Coll Cardiol,2005,46 (9):1651-58
[19]Chen SL, FangWW, Qian J, et al. Improvement of cardiac function after transplantation of autologous bone marrow mesenchymal stem cells in patients with acute myocardial infarction[J].ChinMed J,2004,117 (10):1443-48
[20]Son BR, Marquez-Curtis LA, Kucia M. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-metaxes and involve smatrix metalloproteinases[J]. Stem Cells, 2006,24 (5):1254-64
[21]Wynn RF, Hart CA, Corradi-Perini C. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow[J]. Blood,2004,104 (9):2643-45
[22]Li Y, Yu X, Lin S, et al. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells [J]. Biochem Biophys Res Commun,2007,356 (3):780-84.
[23]Herrera MB, Bussolati B, Bruno S, et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury[J]. Kidney Int,2007,72 (4):389-90
[24]Le-Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor)and CD38 on phytohaemag-glutinin activatde lymphocytes[J]. Scand J Immunol,2004,60(3):307-15
[25]Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific Tcells to their cognate peptide [J]. Blood, 2003,101(9):3722-29
[26]Puissant B, Barreau C, Bourin P, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells:comparison with bone marrow mesenchymal stem cells[J]. Br J Haematol,2005,129(1):118-29
[27]Chang C J, Yen M L, Chen Y C, et al. Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma [J]. Stem Cells,2006,24(11):2466-77.
[28]栾希英,张光波,胡玉敏,等.人骨髓MSC对PHA活化T细胞周期以及表型和细胞因子分泌的影响[J].细胞与分子免疫学杂志,2007,3(5)：402-405
[29]Wang JW, L iu YB, Xu B, et al.The study on i mmunomodulati on of donor mesenchymal stem cells on discordant liver xenotransplantation[J]. Zhonghua Wai Ke Za Zhi,2005,43(19): 1254-58
[30]Magatti M, De Munari S.Vertua E, et al. Human amnion mesenchyme harbors cells with allogeneic T-cell suppression and stimulation capabilities[J]. Stem Cells,2008,26(l):182-92
[31]Meisel R,Zibert A,Laryea M,et al.Human bone marrow stromal cells inhibit allogeneic T-cell responses by indole amine 2,3-dioxy-genase-mediated tryptophan degradation[J]. Blood, 2004,103(12):4619-21
[32]Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions[J]. Blood,2006,107(1):367-72
[33]Asari S, Itakura S, Ferreri K, et al. Mesenchymal stem cells suppress B-cell terminal differentiation[J]. Exp Hematol,2009,37(5):604-15
[34]Krampera M,Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells [J].Stem Cells,2006,24(2):386-98
[35]Spaggiari GM, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions:evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation[J]. Blood,2006,107(4):1484-90
[36]Sotiropoulou P A, Perez S A, Gritzapis A D, et al. Interactions between human mesenchymal stem cells and natural killer cells[J]. Stem Cells,2006,24(1):74-85
[37]Spaggiari G M, Capobianco A, Abdelrazik H, et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood [J],2008,111(3):1327-33
[38]English K, Barry F P, Mahon B P. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation[J]. Immunol Lett,2008,115(1):50-58
[39]Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2 dependent regulatory dendritic cell population[J].Blood,2009,113(1):46-57
[40]Chen L, Zhang W, Yue H, et al. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells[J]. Stem Cells Dev,2007,16(5): 719—731
[41]黄鑫,韩晓燕,洪雅贞等.骨髓间充质干细胞的免疫学研究进展[J].生命科学2009,21(5)：702-705
[42]Jiang X, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells[J]. blood,2005,105(10):4120-26
[43]Nauta A, Kruisselbrink A, Lurvink E, et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells [J]. J Immunol,2006, 177 (4):2080-87
[44]Zhang W, Ge W, Li C, et al. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells[J]. Stem Cells Dev,2004,13(3): 263-71
[45]Aggarwal S, Pittenger ME Human mesenchymal stem cells modulate allogeneic immune cell responses [J]. Blood,2005,105(4):1815-22
[46]Selmani Z, Naji A, Gaiffe E, et al. HLA-G is a crucial immunosuppressive molecule secreted by adult human mesenchymal stem cells[J]. Transplantation,2009,87(9 Suppl):S62—S66
[47]NicolaMD, Carlo-Stella C, Magni M,et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing t-cell anergy[J]. Blood,2002,99(11):3838-43
[48]TseWT, Pendleton JD, BeyerWM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplntation[J]. Transplantation,2003,75(3): 389-97
[49]申娜,陈乃耀,郑丽坤.骨髓间充质干细胞的免疫调节活性[J].第二军医大学学报,2009,30(6)：717-21
[50]Xu G,Zhang Y, Zhang L,et al. The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells[J]. Biochem Biophys Res Commun,2007,361 (3):745-50
[51]Nasef A, Chapel A, Mazurier C,et al. Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells[J].Gene expression,2007,13(4-5):217-26
[52]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature,2006,441(7090):235-38
[53]Huber S, Schrader J, Fritz G, et al. P38 MAP kinase signaling is required for the conversion of CD4+CD25-T cells into iTreg[J]. PLoS one,2008,3(10):e3302
[54]Dazzi F, Horwood N J. Potential of mesenchymal stem cell therapy[J]. Curr Opin Oncol, 2007,19(6):650-55
[55]Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation,2006,81(10):1390-97
[56]Lazarus H, Curtin P, Devine S, et al. Role of mesenchymal stem cells in allogeneic transplantation:early phase I clinical results[J]. Blood,2000,96:392a
[57]Fang B, Song YP, Liao LM, et al. Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells[J]. Bone Marrow Transplant,2006,38(5):389-90
[58]ZhangW, Qin C, Zhou Z M. Mesenchymal stem cells modulate immune responses combined with cyclosporine in a rat renal transplantation model [J]. Transplantation Proceedings,2007, 39 (10):3404-08
[59]Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model[J]. Transplantation,2006,81 (1):1589-95
[60]Zhou HP, Yi DH, Yu S Q, et al. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft [J]. Transplantation Proceedings,2006,38 (9):3046-51
[61]Wan Chidan, Cheng Rui, Wang Hongbo, et al. Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model [J]. Hepatobiliary & Pancreatic Diseases Internati onal.2008,7 (1):29-33
[62]李明,蔡德鸿,张桦,等.间充质干细胞联合骨髓细胞输注诱导胰岛移植免疫耐受的研 究[J].解放军医学杂志,2008,33(3)：269-72
[63]Bartholomew A, Sturgeon C, SiatskasM, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo [J]. Experimental Hematology, 2002,30 (1):42-48
[64]Petit F, Minns AB, Nazzal JA, et al. Prolongation of skin allograft survival after neonatal injection of donor bone marrow and epidermal cells [J]. Plastic and Reconstructive Surgery, 2004,113(1):270-76
[65]Ikehara S. New strategies for BMT, organ transplantation, and regeneration therapy [J]. Hematology,2003,8(2):77-81
[66]Deng W, Han Q, Liao L, et al. Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice[J]. DNA Cell Biol,2005,24(7): 458-63
[67]Augello A, Tasso R, Negrini SM, et a 1. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum,2007,56(4):1175-86
[68]Djouad F, Fritz V, Apparailly F, et al. Reversal of the Immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor-a in collagen-induced arthritis [J]. Arthritis Rheum,2005,52(5):1595-03
[69]朱雅姝,赵春华.间充质干细胞的免疫调节能力—临床治疗的希望[J].生命科学.2009,39(8)：727-35
[70]Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007,61(3):219-27.
[71]Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy [J]. B lood,2005,106(5):1755-61
[72]Gordon D, Pavlovska G, G lover CP, et al. Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration[J]. Neurosci Lett,2008,448(1):71-73
[73]Cipriani P, Guiducci S, M iniati I, et a 1. Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells:new insight into the pathogenesis of systemic sclerosis[J].Arthritis Rheum,2007,56(6):1994-04
[2]Conget P, Minguel JJ. Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow mesenchymal progenytor cells[J]. Experimental Hematol,2000,28 (4):382-390
[3]Muraglia A, Cancedda R, Qrarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model[J]. J Cell Sci,2000, 113(7):1161-1166
[4]Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart [J]. Circulation,2002,105(1):93-98
[5]Woodbury D, Schwarz EJ, Prockop DJ, et al. Adult rat and human bone marrow stromal cells differentiateinte neurons[J]. J Neurosci Res.2000,61(4):364—370
[6]Gary Brooke, Matthew Cooka, et al. Therapeutic applications of mesenchymal stromal cells[J]. Semin Cell Dev Biol.2007,18(6):846-858
[7]Hematti P. Role of mesenchymal stromal cells in solid organ transplantation[J]. Transplant Rev, 2008,22(4):262-273
[8]Bartholomew A, Sturgeon C, Siatskas M, et al.Mesenchymal stem Cells suppress lymphocyte proliferation invitro and prolong skin graft in vivo[J]. Exp Hematol,2002,30(1):42-48
[9]Y anez R, Lamana ML, Garcia-Castro J, et al.Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease[J].Stem Cells,2006,24(11):2582-91
[10]VanLaar JM, Tyndall A. Adult stem cells in the treatment of autoimmune diseases[J]. Rheumatology (Oxford),2006,45(10):1187-1193
[11]Zvaifler NJ, Marinova-Mutafchieva L, Adams G, et al. Mesenchymal precursor cells in the blood of normal individual[J]. Athritis Res,2000,2(6):477-488
[12]Campagnoli C, Roberts IA, Kumar S, et al. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, Liver, and bone marrow[J]. Blood,2001,98 (8):2396-402
[13]Zuk PA,Zhu M,Mizunon H,et al. Multilineage cells from human adipose tissue: implication for cell-based therapies[J]. Tissue Eng,2001,7 (2):211-28
[14]Warejcka DJ, Harvey R, Taylor BJ, et al. A population of cells isolated from rat heart capable of differentiating into several mesodermal phenotype[J]. J Surg Res,1996,62 (2):233-42
[15]Williams JT, Southerland SS, Souza J, et al. Cells isolated from human skeletal muscle capable of differentiating into multiple mesodermal phenotype[J]. Am Surg,1999,65 (1):22
[16]Young HE, Steele TA, Bray RA, et al. Human reserve pluripotent stem cells are present in the connective tissue of skeletal muscle and dermis derived f rom fetal, adult, and geriatric donors[J]. Anat Rec,2001,263 (1):51
[17]Troyer DL, Weiss ML, et al.Concise Review:Wharton's jelly-derived cells are a primitive stromal cell population [J].Stem Cells.2008,26(3):591-599
[18]Wang M, Yang Y, Yang D, et al. The immunomodulatory activity of human umbilical cord blood-derived mesenchymal stem cells in vitro[J]. Immunology,2009,126(2),220-232
[19]Peng HQ, Levitin-Smith M, Rochelson B, et al. Umbilical cord stricture and overcoiling are common causes of fetal demise [J]. Pediatr Dev Pathol,2006,9(1):14-19
[20]Trevisanuto D, Doglioni N, Zanardo V et al. Overcoiling of the umbilical cord[J]. J Pediatr 2007,150(1):112
[21]Toren A, Nagler A, Amariglio N, et al. Successful human umbilical cord blood stem cell transplantation with conditioning in severe combined immune deficiency[J]. Bone Marrow Transplant,1999,23(4):405-408
[22]Sarugaser R, Lickorish D, Baksh D, et al. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors[J]. Stem Cells,2005,23(2):220-229
[23]Romanov YA, Svintsitskaya VA, Smirnov VN. Searching for alternative sources of postnatal human mesenchymal stem cells:candidate MSC-like cells from umbilical cord[J]. Stem Cells 2003,21(1):105-110
[24]薛美思.脐带间充质干细胞在细胞治疗中的研究进展[J].中国美容医学,2008,17(9)：1405-07
[25]Musina RA, Belyavski AV, Tarusova OV, et al. Endometrial mesenchymal stem cells isolated from the menstrual blood [J]. Bulletin of Experimental Biology and Medicine,2008,145(4): 539-543
[26]Mitchell KE, Weiss ML, Mitchell BM, et al. Matrix cells from Wharton's jelly form neurons and glia [J]. Stem Cells,2003,21(1):50-60
[27]Karahuseyinoglu S, Cinar O, Kilic E, et al. Biology of the stem cells in human umbilical cord stroma:in situ and in vitro surveys[J]. Stem Cells,2007,25(2):319-331
[28]Lu LL, Liu YJ, Yang SG et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials[J]. Haematologica,2006,91(8):1017-1026
[29]Weiss ML, Medicetty S, Bledsoe AR et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease[J]. Stem Cells,2006,24(3):781-792
[30]Fu YS, Shih YT, Cheng YC et al. Transformation of human umbilical mesenchymal cells into neurons in vitro [J]. J Biomed Sci,2004,11(5):652-660
[31]Wang HS, Hung SC, Peng ST et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord [J]. Stem Cells,2004,22(7):1330-37
[32]Weiss ML, Anderson C, Medicetty S, et al. Immune Properties of Human Umbilical Cord Wharton's Jelly-Derived Cells[J]. Stem Cells.2008,26(11):2865-74
[33]Le Blanc K L, Tammik L, SundbergB, et al.Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex [J]. Scand J Immunol,2003,57(1):11-20
[34]ZhangJ, LiY, ChenJ, et al. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice [J].Exp Neurol,2005,195(1):16-26
[35]Djouad F, Fritz V, Apparailly F,et al.Reversal of the Immunosuppressive Properties of Mesenchymal Stem Cells by Tumor Necrosis Factor alpha Collagen-induced Althritis [J]. Arthritis Rheum,2005,52(5):1595-03
[36]Karussis D, Kassis I, Basan GS, et al.Immununomodulation and neuroprotection With mesenchymal bone marrow stem cells(MSCs):Aproposed treatment for multiple Sclerosis and other neuroimmunological/neurodegenerative diseases [J].J Neurol Sci,2008, 265(1-2):131-135
[37]朱雅姝,赵春华.间充质干细胞的免疫调节能力—临床治疗的希望[J].生命科学.2009,39(8)：727-735
[38]NicolaMD, Carlo-Stella C, Magni M, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing t-cell anergy [J]. Blood,2002,99(11):3838-43.
[39]Nasef A, Chapel A, Mazurier C,et al. Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells[J].Gene expression,2007,13(4-5):217-26
[40]Wu Tao,BaiI Hai,Wang Jing chang,et al,Preliminary study on biological properties of adult human bone marrow-derived mesenchymal stem cells[J]. The Chinese-German Journal of Clinical oncology,2006,5:285-290
[41]KramperaM, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigenspecific T cells to their cognate peptide[J]. Blood, 2003,101(9):3722-29
[42]Bian Li, Guo ZK, Wang HX, et al. In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells [J]. in vivo,2009, 23(1):21-27.
[43]Bommireddy R, Saxena V, Ormsby I, et al.TGF-betal regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes [J]. J Immunol, 2003,170(9):4612-22.
[44]Xu G, Zhang Y,Zhang L, et al. The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells [J]. Biochem Biophys Res Commun,2007,361(3):745-750
[45]TseWT, Pendleton JD, BeyerWM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation[J].Transplantation,2003,75(3): 389-397
[46]Reddy P. Pathophysiology of acute graft-versus-host disease [J]. Hematol Oncol,2003,21(4): 149-161
[47]Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions[J]. Blood,2006,107(1):367-372
[48]Asari S, Itakura S, Ferreri K, et al. Mesenchymal stem cells suppress B-cell terminal differentiation [J]. Exp Hematol,2009,37(5):604-15
[49]Sotiropoulou P A, Perez S A, Gritzapis A D, et al. Interactions between human mesenchymal stem cells and natural killer cells [J]. Stem Cells,2006,24(1):74-85
[50]Spaggiari G M, Capobianco A, Abdelrazik H, et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2 [J]. Blood,2008,111(3):1327-33
[1]Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells:in vitro cultivation and transplantation in diffusion chambers [J]. Cell Tissue Kinet,1987, 20(3):263-272
[2]Erices A, Conget P, Minguell. Mesenchymal progenitor cells in human umbilical cord blood [J]. Br J Haematol,2000,109(1):235-242
[3]In't Anker PS, Scherjon SA, Kleijburg-vander Keur C, et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta[J]. Stem Cells,2004,22(7):1338-45
[4]Musina RA, Belyavski AV, Tarusova OV et al. Endometrial mesenchymal stem cells isolated from the Menstrual Blood[J]. Bulletin of Experimental Biology and Medicine,2008, 145(4):539-543
[5]Pittenger MF, Mackay AM, Jaiswal SC, et al. Multilineage potential of mesenchymal stem cell[J]. Science,1999,284 (5411):143-147
[6]Karahuseyinoglu S, Cinar O, Kilic E et al. Biology of the stem cells in human umbilical cord stroma:in situ and in vitro surveys [J]. Stem Cells,2007,25 (2):319-331
[7]Lu LL, Liu YJ, Yang SG et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials[J]. Haematologica,2006,91 (8):1017-26
[8]Weiss ML, Medicetty S, Bledsoe AR et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease[J]. Stem Cells,2006,24 (3):781-92
[9]Fu YS, Shih YT, Cheng YC et al. Transformation of human umbilical mesenchymal cells into neurons in vitro [J]. J Biomed Sci,2004,11(5):652-60
[10]Wang HS, Hung SC, Peng ST et al. Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord[J]. Stem Cells,2004,22 (7):1330-37
[11]Ming-Yan Chen, Pu-Chang Lie, Zhi-Ling Li, et al. Endothelial differentiation of Wharton's jelly-derived mesenchymal stem cells in comparison with bone marrow-derived mesenchymal stem cells[J], Experimental Hematology,2009,37 (5):629-40
[12]Conget P, Minguel JJ. Adenoviral-mediated gene transfer into ex vivo expanded human bone marrow mesenchymal progenytor cells [J]. Experimental Hematol,2000,28 (4):382-90
[13]Muraglia A, Cancedda R, Qrarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model[J]. J Cell Sci,2000, 113(7):1161-66
[14]Lou J, Xu F, Merkel K, et al. Gene therapy:adenovirus-mediated human bone morphogenetic protein-2 gene transfer induces mesenchymal prongitor cell proliferation and differentiation in vitro and bone formation in vivo [J]. J Orthop Res,1999,17(1):43-50
[15]Mbalaviele G, Jaiwal N, Meng A. et al. Human mesenchymal stem cells promote human osteoclast differentiation from CD34+ bone marrow hematopoietic progenitors [J]. Endocrinology,1999,140(8):3736-43
[16]Toma C, Pittenger MF, Cahill KS, et al. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart [J]. Circulation,2002,105(1):93-98
[17]Woodbury D, Schwarz EJ, Prockop DJ, et al. Adult rat and human bone marrow stromal cells differentiateinte neurons[J]. J Neurosci Res.2000,61(4):364-70
[18]Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bonemarrow cell transp lantation in chronic coronary artery disease: the IACT study[J]. J Am Coll Cardiol,2005,46 (9):1651-58
[19]Chen SL, FangWW, Qian J, et al. Improvement of cardiac function after transplantation of autologous bone marrow mesenchymal stem cells in patients with acute myocardial infarction[J].ChinMed J,2004,117 (10):1443-48
[20]Son BR, Marquez-Curtis LA, Kucia M. Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-metaxes and involve smatrix metalloproteinases[J]. Stem Cells, 2006,24 (5):1254-64
[21]Wynn RF, Hart CA, Corradi-Perini C. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow[J]. Blood,2004,104 (9):2643-45
[22]Li Y, Yu X, Lin S, et al. Insulin-like growth factor 1 enhances the migratory capacity of mesenchymal stem cells [J]. Biochem Biophys Res Commun,2007,356 (3):780-84.
[23]Herrera MB, Bussolati B, Bruno S, et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury[J]. Kidney Int,2007,72 (4):389-90
[24]Le-Blanc K, Rasmusson I, Gotherstrom C, et al. Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor)and CD38 on phytohaemag-glutinin activatde lymphocytes[J]. Scand J Immunol,2004,60(3):307-15
[25]Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific Tcells to their cognate peptide [J]. Blood, 2003,101(9):3722-29
[26]Puissant B, Barreau C, Bourin P, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells:comparison with bone marrow mesenchymal stem cells[J]. Br J Haematol,2005,129(1):118-29
[27]Chang C J, Yen M L, Chen Y C, et al. Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma [J]. Stem Cells,2006,24(11):2466-77.
[28]栾希英,张光波,胡玉敏,等.人骨髓MSC对PHA活化T细胞周期以及表型和细胞因子分泌的影响[J].细胞与分子免疫学杂志,2007,3(5)：402-405
[29]Wang JW, L iu YB, Xu B, et al.The study on i mmunomodulati on of donor mesenchymal stem cells on discordant liver xenotransplantation[J]. Zhonghua Wai Ke Za Zhi,2005,43(19): 1254-58
[30]Magatti M, De Munari S.Vertua E, et al. Human amnion mesenchyme harbors cells with allogeneic T-cell suppression and stimulation capabilities[J]. Stem Cells,2008,26(l):182-92
[31]Meisel R,Zibert A,Laryea M,et al.Human bone marrow stromal cells inhibit allogeneic T-cell responses by indole amine 2,3-dioxy-genase-mediated tryptophan degradation[J]. Blood, 2004,103(12):4619-21
[32]Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions[J]. Blood,2006,107(1):367-72
[33]Asari S, Itakura S, Ferreri K, et al. Mesenchymal stem cells suppress B-cell terminal differentiation[J]. Exp Hematol,2009,37(5):604-15
[34]Krampera M,Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells [J].Stem Cells,2006,24(2):386-98
[35]Spaggiari GM, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions:evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation[J]. Blood,2006,107(4):1484-90
[36]Sotiropoulou P A, Perez S A, Gritzapis A D, et al. Interactions between human mesenchymal stem cells and natural killer cells[J]. Stem Cells,2006,24(1):74-85
[37]Spaggiari G M, Capobianco A, Abdelrazik H, et al. Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood [J],2008,111(3):1327-33
[38]English K, Barry F P, Mahon B P. Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation[J]. Immunol Lett,2008,115(1):50-58
[39]Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2 dependent regulatory dendritic cell population[J].Blood,2009,113(1):46-57
[40]Chen L, Zhang W, Yue H, et al. Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells[J]. Stem Cells Dev,2007,16(5): 719—731
[41]黄鑫,韩晓燕,洪雅贞等.骨髓间充质干细胞的免疫学研究进展[J].生命科学2009,21(5)：702-705
[42]Jiang X, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells[J]. blood,2005,105(10):4120-26
[43]Nauta A, Kruisselbrink A, Lurvink E, et al. Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells [J]. J Immunol,2006, 177 (4):2080-87
[44]Zhang W, Ge W, Li C, et al. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells[J]. Stem Cells Dev,2004,13(3): 263-71
[45]Aggarwal S, Pittenger ME Human mesenchymal stem cells modulate allogeneic immune cell responses [J]. Blood,2005,105(4):1815-22
[46]Selmani Z, Naji A, Gaiffe E, et al. HLA-G is a crucial immunosuppressive molecule secreted by adult human mesenchymal stem cells[J]. Transplantation,2009,87(9 Suppl):S62—S66
[47]NicolaMD, Carlo-Stella C, Magni M,et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing t-cell anergy[J]. Blood,2002,99(11):3838-43
[48]TseWT, Pendleton JD, BeyerWM, et al. Suppression of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplntation[J]. Transplantation,2003,75(3): 389-97
[49]申娜,陈乃耀,郑丽坤.骨髓间充质干细胞的免疫调节活性[J].第二军医大学学报,2009,30(6)：717-21
[50]Xu G,Zhang Y, Zhang L,et al. The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells[J]. Biochem Biophys Res Commun,2007,361 (3):745-50
[51]Nasef A, Chapel A, Mazurier C,et al. Identification of IL-10 and TGF-beta transcripts involved in the inhibition of T-lymphocyte proliferation during cell contact with human mesenchymal stem cells[J].Gene expression,2007,13(4-5):217-26
[52]Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature,2006,441(7090):235-38
[53]Huber S, Schrader J, Fritz G, et al. P38 MAP kinase signaling is required for the conversion of CD4+CD25-T cells into iTreg[J]. PLoS one,2008,3(10):e3302
[54]Dazzi F, Horwood N J. Potential of mesenchymal stem cell therapy[J]. Curr Opin Oncol, 2007,19(6):650-55
[55]Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease[J]. Transplantation,2006,81(10):1390-97
[56]Lazarus H, Curtin P, Devine S, et al. Role of mesenchymal stem cells in allogeneic transplantation:early phase I clinical results[J]. Blood,2000,96:392a
[57]Fang B, Song YP, Liao LM, et al. Treatment of severe therapy-resistant acute graft-versus-host disease with human adipose tissue-derived mesenchymal stem cells[J]. Bone Marrow Transplant,2006,38(5):389-90
[58]ZhangW, Qin C, Zhou Z M. Mesenchymal stem cells modulate immune responses combined with cyclosporine in a rat renal transplantation model [J]. Transplantation Proceedings,2007, 39 (10):3404-08
[59]Inoue S, Popp FC, Koehl GE, et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model[J]. Transplantation,2006,81 (1):1589-95
[60]Zhou HP, Yi DH, Yu S Q, et al. Administration of donor-derived mesenchymal stem cells can prolong the survival of rat cardiac allograft [J]. Transplantation Proceedings,2006,38 (9):3046-51
[61]Wan Chidan, Cheng Rui, Wang Hongbo, et al. Immunomodulatory effects of mesenchymal stem cells derived from adipose tissues in a rat orthotopic liver transplantation model [J]. Hepatobiliary & Pancreatic Diseases Internati onal.2008,7 (1):29-33
[62]李明,蔡德鸿,张桦,等.间充质干细胞联合骨髓细胞输注诱导胰岛移植免疫耐受的研 究[J].解放军医学杂志,2008,33(3)：269-72
[63]Bartholomew A, Sturgeon C, SiatskasM, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo [J]. Experimental Hematology, 2002,30 (1):42-48
[64]Petit F, Minns AB, Nazzal JA, et al. Prolongation of skin allograft survival after neonatal injection of donor bone marrow and epidermal cells [J]. Plastic and Reconstructive Surgery, 2004,113(1):270-76
[65]Ikehara S. New strategies for BMT, organ transplantation, and regeneration therapy [J]. Hematology,2003,8(2):77-81
[66]Deng W, Han Q, Liao L, et al. Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice[J]. DNA Cell Biol,2005,24(7): 458-63
[67]Augello A, Tasso R, Negrini SM, et a 1. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis[J]. Arthritis Rheum,2007,56(4):1175-86
[68]Djouad F, Fritz V, Apparailly F, et al. Reversal of the Immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor-a in collagen-induced arthritis [J]. Arthritis Rheum,2005,52(5):1595-03
[69]朱雅姝,赵春华.间充质干细胞的免疫调节能力—临床治疗的希望[J].生命科学.2009,39(8)：727-35
[70]Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis[J]. Ann Neurol, 2007,61(3):219-27.
[71]Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy [J]. B lood,2005,106(5):1755-61
[72]Gordon D, Pavlovska G, G lover CP, et al. Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration[J]. Neurosci Lett,2008,448(1):71-73
[73]Cipriani P, Guiducci S, M iniati I, et a 1. Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells:new insight into the pathogenesis of systemic sclerosis[J].Arthritis Rheum,2007,56(6):1994-04