低血清浓度培养的间充质干细胞特性及其对人Th细胞的免疫调节作用
|
摘要
背景:间充质干细胞(multipotent mesenchymal stem cells,MSC)是一种存在于多种组织中的具有自我更新和多向分化能力的多能干细胞。MSC具有易于分离和扩增、多向分化、低免疫原性和免疫调节的特性,这些特性使它们成为组织工程和再生医学的理想种子细胞。细胞治疗中的一个重要问题是MSC替代来源的的可获得性,而细胞治疗的成功的决定性因素则是MSC的生物学特性。对MSC生物学特性的理解有利于充分的利用MSC的治疗潜能,因此,MSC生物学特性的研究越来越引起人们的兴趣。到目前为止,大多数的治疗性应用是以成体骨髓来源的MSC为研究对象,但是成体骨髓MSC存在骨髓体积有限,获取标本时需进行侵袭性操作以及MSC的绝对数量和分化能力会随着年龄增加而下降等不足。这就需要研究人员寻找替代的MSC细胞来源,同时,研制良好的细胞培养试剂为MSC的生长和扩增提供适合的环境,从而满足临床治疗和研究方面的需求。
目的:本研究旨在鉴定低血清浓度完全培养基培养的MSC的一般特性如形态、核型、增殖动力学、表型特点和分化潜能等生物学性状,从而提供一种MSC的培养试剂并为MSC作为组织工程的种子细胞提供理论基础。
方法:①应用贴壁培养的方法从胎儿的骨髓和肺组织以及脐带中分离获得单个细胞,在低血清完全培养基中培养,除去非贴壁的细胞、通过体外传代培养使细胞纯化。②测定培养的MSC的核型和生长曲线。③应用流式细胞仪对培养的MSC进行细胞周期分析。④运用流式细胞技术检测MSC的免疫表型和胚胎干细胞的全能标志物。⑤在诱导体系中定向诱导MSC向脂肪细胞、成骨细胞和软骨细胞分化,利用油红0、茜素红和阿尔新蓝染色观测脂滴形成、钙盐沉积和酸性粘多糖合成情况;利用流式细胞仪检测系分化特异性标志物过氧化物酶体增生物激活受体-γ(PPAR-γ)、骨钙蛋白(osteocalcin)和Ⅱ型胶原的表达。⑥采用两步诱导方案使骨髓和肺组织来源的MSC体外诱导分化为神经细胞,利用激光共聚焦显微镜检测诱导细胞中的神经细胞标志物微管相关蛋白2(microtubule- associated protein2,MAP2)、Nestin和神经胶质酸性蛋白(glial fibrillary acidic protein,GFAP)的表达。⑦采用两步诱导方法使肺组织来源的MSC体外诱导分化为肝细胞,利用RT-PCR方法检测诱导细胞中的肝细胞标志物如甲胎蛋白(αFP)、白蛋白(albumin)和细胞角蛋白18(cytokeratin18,CK18)的表达;利用糖原染色和培养上清中白蛋白的分泌水平对诱导后细胞进行功能性检测。
结果:①低血清浓度完全培养基培养的MSC贴壁生长和呈长梭形,细胞生长速度快,细胞融合时出现漩涡状外观。②MSC具有正常核型以及典型的“S”型生长曲线。③细胞周期表明大多数细胞处于G0/G1期,少部分的细胞处于活跃增殖期。④MSC高表达间充质细胞标志物如CD13,CD29,CD44,CD90,CD49e,CD105,CD166和HLA-Ⅰ,而不表达造血细胞和内皮细胞的标志物,如CD31、CD34、CD11b、CD45、CD117,CD133和HLA-Ⅱ。更重要的是,表达胚胎干细胞标志物Oct4,Nanog,Sox2和SSEA-4,其中传代到第25代(P25)的肺组织来源的MSC仍可保持免疫表型和胚胎干细胞标志物表达的稳定。⑤MSC经诱导后,油红0、茜素红和阿尔新蓝染色均为阳性,且高表达系分化特异性标志物,说明其能够分化为脂肪细胞、骨细胞和软骨细胞,其中肺组织来源的MSC能保持其三系分化能力到P25。⑥神经细胞标志物在诱导细胞中的表达水平显著高于其在对照细胞中的水平。⑦与对照细胞相比,肝细胞标志物在诱导细胞中的表达上调;诱导后细胞具有储存糖原和分泌白蛋白的功能。
结论:①低血清浓度完全培养基是一种很好的培养MSC的细胞试剂。②利用该培养基培养的MSC具有较强增殖能力,可满足组织工程种子细胞的需要。③利用该培养基培养的MSC可在体外定向分化为脂肪组织、骨组织和软骨组织,而且肺组织来源的MSC能够将这种多系分化潜能保持到P25,从而为进一步构建组织工程化骨或软骨提供了充足的细胞来源。④利用该培养基培养的MSC表达胚胎干细胞的标志物,而且能在体外分化为中胚层以外的细胞如外胚层的神经细胞和/或内胚层的肝细胞。⑤利用该培养基培养的MSC具有良好的生物学特性,可作为组织工程和再生医学的优秀种子细胞。
背景:间充质干细胞(multipotent mesenchymal stem cells,MSC)是能分化为中胚层组织的多能干细胞,它可以从机体的各种组织中分离得到。MSC还因其对免疫细胞的免疫调节作用而备受关注,该调节作用能调节多种免疫效应功能。最近,一个新的CD4+T细胞亚类被命名为Th17细胞,它特异性地优先表达IL-17。Th17细胞被认为是自身免疫性疾病和变态反应性疾病发展过程和宿主对抗病原体过程中的重要效应细胞。虽然MSC免疫调节功能的准确机制还不是很清楚,但是MSC已被用于多种临床试验,旨在降低免疫介导的疾病的负担。
目的:研究胎儿骨髓间充质干细胞(FBM-MSC)对人T细胞的免疫调节作用。
方法:我们在存在或不存在FBM-MSC的情况下培养PBMC和CD4+T细胞,PBMC或CD4+T细胞与FBM-MSC的共培养被称为共培养细胞。除非特别说明,培养基均包含PHA和rIL-2。我们采用实时定量PCR,ELISA和流式细胞分析等方法检测:①正常人外周血单个核细胞(PBMC)和CD4+T细胞及其与FBM-MSC共培养中IL17的表达水平,观察FBM-MSC对Th17细胞的调节作用;②添加外源性的IL-6,IL-6中和抗体,转化生长因子-β1(TGF-β1)后IL17表达水平的改变,观察IL-6通路在FBM-MSC调节IL17中的作用;③正常人PBMC和CD4+T细胞及其与FBM-MSC共培养中IL-1和IL-23在FBM-MSC调节IL17中的作用;④PBMC和CD4+T细胞及其与FBM-MSC共培养中IFN-γ的表达水平,研究FBM-MSC对Th1细胞的调节作用;⑤PBMC及其与FBM-MSC共培养中Foxp3的表达水平,初步研究FBM-MSC对Treg的调节作用。
结果:实时定量PCR,ELISA和流式细胞分析等结果表明:①在含有或不含有PHA和rIL-2刺激的情况下,IL-17在PBMC和CD4+T细胞中的分子和细胞表达水平均显著低于其在共培养中的水平(p＜0.05);②添加外源性的IL-6能增加IL-17的表达水平,而添加外源性的IL-6中和抗体则会显著的降低IL-17的表达水平,添加外源性的TGFβ1会导致IL-17表达水平的降低;③IL-1在CD4+T细胞培养上清中的浓度低于其在共培养中的浓度(p＜0.05),而IL-23在PBMC中的转录水平与其在共培养中的水平无明显差异(p＞0.05),IL-23在CD4+T细胞中的蛋白分泌水平与其在共培养中的水平亦无明显差异(p＞0.05);④Th1细胞产生的IFN-γ在PBMC和CD4+T细胞中的mRNA和蛋白表达水平显著低于其在共培养中的水平(p＜0.05);⑤Foxp3在PBMC中的mRNA表达水平低于其在共培养中的水平(p＜0.05)。
结论:FBM-MSC对人Th17细胞具有正性调节作用。IL-6是该调节作用的机制之一,IL-1亦可能是其中的一个机制,而IL-23似乎在我们研究的调节作用中不发挥作用。另外,FBM-MSC对人Th1细胞具有抑制作用并且能抑制Th1细胞产生IFN-γ,而对Treg细胞具有促进作用。
Background:Multipotent mesenchymal stem cells(MSC),isolated from many tissues,are multipotent stem cells with the capacity for self-renewal and multilineage differentiation.Their ease of isolation and expansion,their multipotency,their low immunogenicity and immune-modulatory properties present them as an ideal stem cell candidate for tissue engineering and regenerative medicine.An important issue in cellular therapeutics is the availability of alternative MSC sources,while key to the success of cell therapy is the biological properties of MSC.Understanding the biological properties of MSC will be beneficial for fully utilizing the therapeutic potential of MSC,therefore,there has been an increased interest in understanding the biology of MSC due to their potential use in cell-based therapy.To date,most therapeutic applications are based on adult bone marrow(ABM) MSC,but ABM MSC have many drawbacks,including the limited volume,the invasive procedures of their harvest,and the age-dependent decline in the absolute number and differential capacity.This has prompted researchers to look for alternative sources of MSC and suitable culture medium for MSC so as to meet the requirement of clinics and research.
Objective:This study aims at identificating the biological properties of MSC cultured with low serum by evaluating their morphous,karyotype, growth kinetics,immunophenotype and differentiation potential during in vitro expansion so as to supply the rationale for their therapeutic potential for tissue engineering.
Methods:①Cells were isolated from fetal bone marrow and lung as well as umbilical cord by adherent culture,cultured in the culture medium containing DMEM/DF12 as well as 2%fetal bovine serum,and purified by passaging in vitro.②The karyotype and growth curve of MSC were detected.③Cell cycle was assayed by flow cytometry.④The immunophenotype and the pluripotent marker expression were obtained by flow cytometry analysis.⑤MSC were induced for adipocytes,osteoblasts and chondrocytes in the induction media.Oil red 0,alizarin red and alcian blue staining was performed to examine lipid droplet,mineralization and acid mucopolysaccharide,respectively.The expression of lineage-specific markers such as PPAR-γ,osteocalcin and collagenⅡwas evaluated by flow cytometry analysis.⑥MSC from fetal bone marrow and lung could differentiate into neural cells by two-step introduction and the expression of neural markers including MAP2,Nestin and GFAP in differentiated cells were confirmed by confocal microscopy.⑦The two-step procedure was performed for hepatocyte introduction.The mRNA expression of hepatic specific markers such asαFP,albumin and cytokeratin 18(CK18) was examined by RT-PCR.Hepatocyte function was assessed by detecting glycogen by periodic acid schiff(PAS) staining and dosing albumin in culture supernatants.
Results:①MSC cultured with low serum had adherent and spindle-shaped characterizations,grow rapidly,and reached confluence with a whirl pool-like appearance.②They maintained a normal karyotype and displayed the growth curve of 'S' type.③Most cells were in the G0/G1 phases and only a small proportion of cells actively proliferated as revealed by cell cycles analysis.④They highly expressed mesenchymal markers including CD13, CD29,CD44,CD49e,CD90,CD105,CD166,HLA classⅠ,and did not express hematopoietic and endothelial markers such as CD31,CD34,CD11b,CD45,CD117, CD133 and HLA classⅡ.Importantly,MSC could even express pluripotent markers of embryonic stem cells such as Oct4,Nanog,Sox2 and SSEA-4.The expression levels of all markers in MSC from fetal lung were remained stable through 25 passages.⑤The induced MSC showed positive staining of oil red 0,alizarin red and alcian blue and high expression of lineage-specific markers.The data confirmed their potentials to differentiate directedly into adipocytes,osteoblasts and chondrocytes;moreover,MSC from fetal lung (P25) possessed the similar differentiation potentials.⑥The expression levels of neural markers in the differentiated cells were significantly higher than those in control cells.⑦Compared with control cells,the expression of hepatocyte markers was upregulated in the induced cells that also demonstrated the capability of storing glycogen and secreting albumin.
Conclusion:①Culture medium with low serum is good culture reagent for MSC.②MSC cultured in the medium show great proliferation potential and suffice the demand of seed cells for tissue engineering.③They are able to differentiate into adipocytes,osteoblasts and chondrocytes and MSC from fetal lung maintain the ability up to 25 passages,which make it possible to supply enough cells for tissue engineering of bone or cartilage.④MSC express pluripotent markers of embryonic stem cells and differentiat directedly towards extramensenchymal lineages such as neuroectoderm cells and hepatocytes of endoderm.⑤The biological properties of MSC are favourable,and MSC have emerged as excellent seed cells for tissue engineering and regenerative medicine.
Background:Multipotent mesenchymal stem cells(MSC) are multipotent stem cells that can differentiate into tissues of mesodermal origin and can be isolated from various tissues.MSC have also been noted to have profound immunomodulatory effects on immune cells,leading to the modulation of several effector functions.Recently,a new CD4+ T-cell subset has been designated as Th17 cells that preferentially produce IL-17.Th17 cells have been widely accepted as important effector cells in the development of autoimmune and allergic diseases and host defenses against a group of pathogens.Whereas the exact mechanisms underlying the immunomodulatory functions of MSC remain largely unknown,these cells have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease.
Objective:This article aimed to investigate the immunoregulatory effects of fetal bone marrow-derived MSC on human T lymphocytes,especially Th17 cells,so as to broaden our understanding of the immunomodulatory properties of MSC and provide insights as to their potential for clinical use as a cell-based therapy for immune-mediated disorders.
Methods:We cultured PBMC and CD4+ T cells with or without FBM-MSC,and we named the coculture of PBMC or CD4+ T cells with FBM-MSC as coculture cells.The culture media included PHA and rIL-2,if not specifically mentioned.We used qRT-PCR,ELISA and flow cytometry analyses to compare①the expression levels of IL-17 bewteen PBMC as well as CD4+ T cells and their coculture cells in the absence or presence of PHA and rIL-2;②the change of IL-17 expression when supplemented with additional IL-6,IL-6 neutralizing antibody and TGF-β1;③the expression levels of IL-1 and IL-23 between PBMC as well as CD4+ T cells and their coculture cells;④the expression of IFN-γbetween PBMC as well as CD4+ T cells and their coculture cells;⑤the mRNA expression of Foxp3 between PBMC and its coculture cell.
Results:qRT-PCR,ELISA and flow cytometry data showed①that the molecular and cell expression levels of IL-17 in PBMC and CD4+ T cells were lower than those in their coculture cells with or without PHA and rIL-2,respectively(p<0.05);②that the addition of IL-6 increased the expression of IL-17(p<0.05),while the addition of IL-6 neutralizing antibody and TGF-β1 decreased the expression of IL-17(p<0.05);③that the increased concentration of IL-1 in the supernant of CD4+ T cells than that in the supernant of their coculture cells(p<0.05),and that no significant difference of IL-23 expression was found between PBMC as well as CD4+ T cells and their coculture cells(p>0.05);④that the expression levels of IFN-γproduced by Th1 cells in PBMC and CD4+ T cells were lower than those in their coculture cells(p<0.05);⑤that the mRNA expression of Foxp3 in PBMC was lower than that in their coculture cells(p<0.05).
Conclusion:Our data demonstrated for the first time that FBM-MSC could positively regulated human Th17 cells.The mechanisms underlying the regulation might include IL-6 as well as IL-1,whereas IL-23 seemed not to involve in the investigated regulation.In addition,FBM-MSC might exert a negative role in IFN-γproducing Th1 cells,but maybe promote Treg.
目的:本研究旨在鉴定低血清浓度完全培养基培养的MSC的一般特性如形态、核型、增殖动力学、表型特点和分化潜能等生物学性状,从而提供一种MSC的培养试剂并为MSC作为组织工程的种子细胞提供理论基础。
方法:①应用贴壁培养的方法从胎儿的骨髓和肺组织以及脐带中分离获得单个细胞,在低血清完全培养基中培养,除去非贴壁的细胞、通过体外传代培养使细胞纯化。②测定培养的MSC的核型和生长曲线。③应用流式细胞仪对培养的MSC进行细胞周期分析。④运用流式细胞技术检测MSC的免疫表型和胚胎干细胞的全能标志物。⑤在诱导体系中定向诱导MSC向脂肪细胞、成骨细胞和软骨细胞分化,利用油红0、茜素红和阿尔新蓝染色观测脂滴形成、钙盐沉积和酸性粘多糖合成情况;利用流式细胞仪检测系分化特异性标志物过氧化物酶体增生物激活受体-γ(PPAR-γ)、骨钙蛋白(osteocalcin)和Ⅱ型胶原的表达。⑥采用两步诱导方案使骨髓和肺组织来源的MSC体外诱导分化为神经细胞,利用激光共聚焦显微镜检测诱导细胞中的神经细胞标志物微管相关蛋白2(microtubule- associated protein2,MAP2)、Nestin和神经胶质酸性蛋白(glial fibrillary acidic protein,GFAP)的表达。⑦采用两步诱导方法使肺组织来源的MSC体外诱导分化为肝细胞,利用RT-PCR方法检测诱导细胞中的肝细胞标志物如甲胎蛋白(αFP)、白蛋白(albumin)和细胞角蛋白18(cytokeratin18,CK18)的表达;利用糖原染色和培养上清中白蛋白的分泌水平对诱导后细胞进行功能性检测。
结果:①低血清浓度完全培养基培养的MSC贴壁生长和呈长梭形,细胞生长速度快,细胞融合时出现漩涡状外观。②MSC具有正常核型以及典型的“S”型生长曲线。③细胞周期表明大多数细胞处于G0/G1期,少部分的细胞处于活跃增殖期。④MSC高表达间充质细胞标志物如CD13,CD29,CD44,CD90,CD49e,CD105,CD166和HLA-Ⅰ,而不表达造血细胞和内皮细胞的标志物,如CD31、CD34、CD11b、CD45、CD117,CD133和HLA-Ⅱ。更重要的是,表达胚胎干细胞标志物Oct4,Nanog,Sox2和SSEA-4,其中传代到第25代(P25)的肺组织来源的MSC仍可保持免疫表型和胚胎干细胞标志物表达的稳定。⑤MSC经诱导后,油红0、茜素红和阿尔新蓝染色均为阳性,且高表达系分化特异性标志物,说明其能够分化为脂肪细胞、骨细胞和软骨细胞,其中肺组织来源的MSC能保持其三系分化能力到P25。⑥神经细胞标志物在诱导细胞中的表达水平显著高于其在对照细胞中的水平。⑦与对照细胞相比,肝细胞标志物在诱导细胞中的表达上调;诱导后细胞具有储存糖原和分泌白蛋白的功能。
结论:①低血清浓度完全培养基是一种很好的培养MSC的细胞试剂。②利用该培养基培养的MSC具有较强增殖能力,可满足组织工程种子细胞的需要。③利用该培养基培养的MSC可在体外定向分化为脂肪组织、骨组织和软骨组织,而且肺组织来源的MSC能够将这种多系分化潜能保持到P25,从而为进一步构建组织工程化骨或软骨提供了充足的细胞来源。④利用该培养基培养的MSC表达胚胎干细胞的标志物,而且能在体外分化为中胚层以外的细胞如外胚层的神经细胞和/或内胚层的肝细胞。⑤利用该培养基培养的MSC具有良好的生物学特性,可作为组织工程和再生医学的优秀种子细胞。
背景:间充质干细胞(multipotent mesenchymal stem cells,MSC)是能分化为中胚层组织的多能干细胞,它可以从机体的各种组织中分离得到。MSC还因其对免疫细胞的免疫调节作用而备受关注,该调节作用能调节多种免疫效应功能。最近,一个新的CD4+T细胞亚类被命名为Th17细胞,它特异性地优先表达IL-17。Th17细胞被认为是自身免疫性疾病和变态反应性疾病发展过程和宿主对抗病原体过程中的重要效应细胞。虽然MSC免疫调节功能的准确机制还不是很清楚,但是MSC已被用于多种临床试验,旨在降低免疫介导的疾病的负担。
目的:研究胎儿骨髓间充质干细胞(FBM-MSC)对人T细胞的免疫调节作用。
方法:我们在存在或不存在FBM-MSC的情况下培养PBMC和CD4+T细胞,PBMC或CD4+T细胞与FBM-MSC的共培养被称为共培养细胞。除非特别说明,培养基均包含PHA和rIL-2。我们采用实时定量PCR,ELISA和流式细胞分析等方法检测:①正常人外周血单个核细胞(PBMC)和CD4+T细胞及其与FBM-MSC共培养中IL17的表达水平,观察FBM-MSC对Th17细胞的调节作用;②添加外源性的IL-6,IL-6中和抗体,转化生长因子-β1(TGF-β1)后IL17表达水平的改变,观察IL-6通路在FBM-MSC调节IL17中的作用;③正常人PBMC和CD4+T细胞及其与FBM-MSC共培养中IL-1和IL-23在FBM-MSC调节IL17中的作用;④PBMC和CD4+T细胞及其与FBM-MSC共培养中IFN-γ的表达水平,研究FBM-MSC对Th1细胞的调节作用;⑤PBMC及其与FBM-MSC共培养中Foxp3的表达水平,初步研究FBM-MSC对Treg的调节作用。
结果:实时定量PCR,ELISA和流式细胞分析等结果表明:①在含有或不含有PHA和rIL-2刺激的情况下,IL-17在PBMC和CD4+T细胞中的分子和细胞表达水平均显著低于其在共培养中的水平(p＜0.05);②添加外源性的IL-6能增加IL-17的表达水平,而添加外源性的IL-6中和抗体则会显著的降低IL-17的表达水平,添加外源性的TGFβ1会导致IL-17表达水平的降低;③IL-1在CD4+T细胞培养上清中的浓度低于其在共培养中的浓度(p＜0.05),而IL-23在PBMC中的转录水平与其在共培养中的水平无明显差异(p＞0.05),IL-23在CD4+T细胞中的蛋白分泌水平与其在共培养中的水平亦无明显差异(p＞0.05);④Th1细胞产生的IFN-γ在PBMC和CD4+T细胞中的mRNA和蛋白表达水平显著低于其在共培养中的水平(p＜0.05);⑤Foxp3在PBMC中的mRNA表达水平低于其在共培养中的水平(p＜0.05)。
结论:FBM-MSC对人Th17细胞具有正性调节作用。IL-6是该调节作用的机制之一,IL-1亦可能是其中的一个机制,而IL-23似乎在我们研究的调节作用中不发挥作用。另外,FBM-MSC对人Th1细胞具有抑制作用并且能抑制Th1细胞产生IFN-γ,而对Treg细胞具有促进作用。
Background:Multipotent mesenchymal stem cells(MSC),isolated from many tissues,are multipotent stem cells with the capacity for self-renewal and multilineage differentiation.Their ease of isolation and expansion,their multipotency,their low immunogenicity and immune-modulatory properties present them as an ideal stem cell candidate for tissue engineering and regenerative medicine.An important issue in cellular therapeutics is the availability of alternative MSC sources,while key to the success of cell therapy is the biological properties of MSC.Understanding the biological properties of MSC will be beneficial for fully utilizing the therapeutic potential of MSC,therefore,there has been an increased interest in understanding the biology of MSC due to their potential use in cell-based therapy.To date,most therapeutic applications are based on adult bone marrow(ABM) MSC,but ABM MSC have many drawbacks,including the limited volume,the invasive procedures of their harvest,and the age-dependent decline in the absolute number and differential capacity.This has prompted researchers to look for alternative sources of MSC and suitable culture medium for MSC so as to meet the requirement of clinics and research.
Objective:This study aims at identificating the biological properties of MSC cultured with low serum by evaluating their morphous,karyotype, growth kinetics,immunophenotype and differentiation potential during in vitro expansion so as to supply the rationale for their therapeutic potential for tissue engineering.
Methods:①Cells were isolated from fetal bone marrow and lung as well as umbilical cord by adherent culture,cultured in the culture medium containing DMEM/DF12 as well as 2%fetal bovine serum,and purified by passaging in vitro.②The karyotype and growth curve of MSC were detected.③Cell cycle was assayed by flow cytometry.④The immunophenotype and the pluripotent marker expression were obtained by flow cytometry analysis.⑤MSC were induced for adipocytes,osteoblasts and chondrocytes in the induction media.Oil red 0,alizarin red and alcian blue staining was performed to examine lipid droplet,mineralization and acid mucopolysaccharide,respectively.The expression of lineage-specific markers such as PPAR-γ,osteocalcin and collagenⅡwas evaluated by flow cytometry analysis.⑥MSC from fetal bone marrow and lung could differentiate into neural cells by two-step introduction and the expression of neural markers including MAP2,Nestin and GFAP in differentiated cells were confirmed by confocal microscopy.⑦The two-step procedure was performed for hepatocyte introduction.The mRNA expression of hepatic specific markers such asαFP,albumin and cytokeratin 18(CK18) was examined by RT-PCR.Hepatocyte function was assessed by detecting glycogen by periodic acid schiff(PAS) staining and dosing albumin in culture supernatants.
Results:①MSC cultured with low serum had adherent and spindle-shaped characterizations,grow rapidly,and reached confluence with a whirl pool-like appearance.②They maintained a normal karyotype and displayed the growth curve of 'S' type.③Most cells were in the G0/G1 phases and only a small proportion of cells actively proliferated as revealed by cell cycles analysis.④They highly expressed mesenchymal markers including CD13, CD29,CD44,CD49e,CD90,CD105,CD166,HLA classⅠ,and did not express hematopoietic and endothelial markers such as CD31,CD34,CD11b,CD45,CD117, CD133 and HLA classⅡ.Importantly,MSC could even express pluripotent markers of embryonic stem cells such as Oct4,Nanog,Sox2 and SSEA-4.The expression levels of all markers in MSC from fetal lung were remained stable through 25 passages.⑤The induced MSC showed positive staining of oil red 0,alizarin red and alcian blue and high expression of lineage-specific markers.The data confirmed their potentials to differentiate directedly into adipocytes,osteoblasts and chondrocytes;moreover,MSC from fetal lung (P25) possessed the similar differentiation potentials.⑥The expression levels of neural markers in the differentiated cells were significantly higher than those in control cells.⑦Compared with control cells,the expression of hepatocyte markers was upregulated in the induced cells that also demonstrated the capability of storing glycogen and secreting albumin.
Conclusion:①Culture medium with low serum is good culture reagent for MSC.②MSC cultured in the medium show great proliferation potential and suffice the demand of seed cells for tissue engineering.③They are able to differentiate into adipocytes,osteoblasts and chondrocytes and MSC from fetal lung maintain the ability up to 25 passages,which make it possible to supply enough cells for tissue engineering of bone or cartilage.④MSC express pluripotent markers of embryonic stem cells and differentiat directedly towards extramensenchymal lineages such as neuroectoderm cells and hepatocytes of endoderm.⑤The biological properties of MSC are favourable,and MSC have emerged as excellent seed cells for tissue engineering and regenerative medicine.
Background:Multipotent mesenchymal stem cells(MSC) are multipotent stem cells that can differentiate into tissues of mesodermal origin and can be isolated from various tissues.MSC have also been noted to have profound immunomodulatory effects on immune cells,leading to the modulation of several effector functions.Recently,a new CD4+ T-cell subset has been designated as Th17 cells that preferentially produce IL-17.Th17 cells have been widely accepted as important effector cells in the development of autoimmune and allergic diseases and host defenses against a group of pathogens.Whereas the exact mechanisms underlying the immunomodulatory functions of MSC remain largely unknown,these cells have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease.
Objective:This article aimed to investigate the immunoregulatory effects of fetal bone marrow-derived MSC on human T lymphocytes,especially Th17 cells,so as to broaden our understanding of the immunomodulatory properties of MSC and provide insights as to their potential for clinical use as a cell-based therapy for immune-mediated disorders.
Methods:We cultured PBMC and CD4+ T cells with or without FBM-MSC,and we named the coculture of PBMC or CD4+ T cells with FBM-MSC as coculture cells.The culture media included PHA and rIL-2,if not specifically mentioned.We used qRT-PCR,ELISA and flow cytometry analyses to compare①the expression levels of IL-17 bewteen PBMC as well as CD4+ T cells and their coculture cells in the absence or presence of PHA and rIL-2;②the change of IL-17 expression when supplemented with additional IL-6,IL-6 neutralizing antibody and TGF-β1;③the expression levels of IL-1 and IL-23 between PBMC as well as CD4+ T cells and their coculture cells;④the expression of IFN-γbetween PBMC as well as CD4+ T cells and their coculture cells;⑤the mRNA expression of Foxp3 between PBMC and its coculture cell.
Results:qRT-PCR,ELISA and flow cytometry data showed①that the molecular and cell expression levels of IL-17 in PBMC and CD4+ T cells were lower than those in their coculture cells with or without PHA and rIL-2,respectively(p<0.05);②that the addition of IL-6 increased the expression of IL-17(p<0.05),while the addition of IL-6 neutralizing antibody and TGF-β1 decreased the expression of IL-17(p<0.05);③that the increased concentration of IL-1 in the supernant of CD4+ T cells than that in the supernant of their coculture cells(p<0.05),and that no significant difference of IL-23 expression was found between PBMC as well as CD4+ T cells and their coculture cells(p>0.05);④that the expression levels of IFN-γproduced by Th1 cells in PBMC and CD4+ T cells were lower than those in their coculture cells(p<0.05);⑤that the mRNA expression of Foxp3 in PBMC was lower than that in their coculture cells(p<0.05).
Conclusion:Our data demonstrated for the first time that FBM-MSC could positively regulated human Th17 cells.The mechanisms underlying the regulation might include IL-6 as well as IL-1,whereas IL-23 seemed not to involve in the investigated regulation.In addition,FBM-MSC might exert a negative role in IFN-γproducing Th1 cells,but maybe promote Treg.
引文
1.Jethva R,Otsuru S,Dominici M,Horwitz EM.Cell therapy for disorders of bone.Cytotherapy 11:3-17,2009
2.Kogler,G,Sensken,S,Airey,J.A,Trapp,T,Mtlschen,M,Feldhahn,N,Liedtke,S,Sorg RV,Fischer J,Rosenbaum C,Greschat S,Knipper A,Bender J,Degistirici 0,Gao J,Caplan AI,Colletti EJ,Almeida-Porada G,Mtlller HW,Zanjani E,Wernet P.A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential.J Exp Med 200:123-135,2004
3.Ramos GA,Hare JM.Cardiac cell-based therapy:cell types and mechanisms of actions.Cell Transplant 16:951-961,2007
4.Torrente Y,Polli E.Mesenchymal stem cell transplantation for neurodegenerative diseases.Cell Transplant 17:1103-1113,2008
5.Valtieri M,Sorrentino A.The mesenchymal stromal cell contribution to homeostasis.J Cell Physiol 217:296-300,2008
6.Fox JM,Chamberlain G,Ashton BA,Middleton J.Recent advances into the understanding of mesenchymal stem cell trafficking.Br J Haematol 137:491-502,2007
7.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood 110:3499-3506,2007
8.Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krausc D,Deans R,Keating A,Prockop D,Horwitz E.Minimal criteria for defining multipotent mesenchymal stromal cells.The International Society for Cellular Therapy position statement.Cytotherapy 8:315-317,2006
9.Arthur A,Zannettino A,Gronthos S.The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair.J Cell Physiol 218:237-245,2009
10.Bilic G,Zeisberger SM,Mallik AS,Zimmermann R,Zisch AH.Comparative characterization of cultured human termiamnion epithelial and mesenchymal stromal cells for application in cell therapy.Cell Transplant 17:955-968,2008
ll.Campagnoli C,Roberts IA,Kumar S,Bennett PR,Bellantuono I,Fisk NM.Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood,liver,and bone marrow.Blood 98:2396-2402, 2001
12.Ferrero I,Mazzini L,Rustichelli D,Gunetti M,Mareschi K,Testa L,Nasuelli N,Oggioni GD,Fagioli F.Bone marrow mesenchymal stem cells from healthy donors and sporadic amyotrophic lateral sclerosis patients.Cell Transplant 17:255-266,2008
13.Gronthos S,Brahim J,Li W,Fisher LW,Cherman N,Boyde A,DenBesten P,Robey PG,Shi S.Stem cell properties of human dental pulp stem cells.J Dent Res 81:531-535,2002
14.Lee JK,Lee MK,Jin HJ,Kim DS,Yang YS,Oh W,Yang SE,Park TS,Lee SY,Kim BS,Jeun SS.Efficient intracytoplasmic labeling of human umbilical cord blood mesenchymal stromal cells with ferumoxides.Cell Transplant 16:849-857,2007
15.Peng L,Jia Z,Yin X,Zhang X,Liu Y,Chen P,Ma K,Zhou C.Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow,Cartilage and Adipose Tissue.Stem Cells Dev 17:761-773,2008
16.Prusa AR,Marton E,Rosner M,Bernaschek G,Hengstschlager M.Oct-4-expressing cells in human amniotic fluid:A new source for stem cell research? Hum Reprod 18:U89-U93,2003
17.Tateishi K,Ando W,Higuchi C,Hart DA,Hashimoto J,Nakata K,Yoshikawa H,Nakamura N.Comparison of human serum with fetal bovine serum for expansion and differentiation of human synovial MSC:potential feasibility for clinical applications.Cell Transplant 17:549-557,2008
18.Yen BL,Huang HI,Chien CC,Jui HY,Ko BS,Yao M,Shun CT,Yen ML,Lee MC,Chen YC.Isolation of multipotent cells from human term placenta.Stem Cells 23:3-9,2005
19.Wagner W,Wein F,Seckinger A,Frankhauser M,Wirkner U,Krause U,Blake J,Schwager C,Eckstein V,Ansorge W,Ho A.D.Comparative characteristics of mesenchymal stem cells from human bone marrow,adipose tissue,and umbilical cord blood.Exp Hematol 33:1402-1416,2005
20.Le Blanc K.Immunomodulatory effects of fetal and adult mesenchymal stem cells.Cytotherapy 5:485-489,2003
21.Guillot PV,Gotherstrom C,Chan J,Kurata H,Fisk NM.Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.Stem Cells 25:646-654,2007
22.Gonzalez R,Maki CB,Pacchiarotti J,Csontos S,Pham JK,Slepko N,Patel A,Silva F.Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells.Biochem Biophys Res Commun 362:491-497,2007
23.Wang XY,Lan Y,He WY,Zhang L,Yao HY,Hou CM,Tong Y,Liu YL,Yang G,Liu XD,Yang X,Liu B,Mao N.Identification of mesenchymal stem cells in aorta-gonad-mesonephros and yolk sac of human embryos.Blood 111:2436-2443,2008
24.Bieback K,Kern S,Kltlter H,Eichler H.Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood.Stem Cells 22:625-634,2004
25.Guo H,Fang B,Liao L,Zhao Z,Liu J,Chen H,Hsu SH,Cui Q,Zhao RC.Hemangioblastic characteristics of fetal bone marrow-derived Flkl(+)CD31(-)CD34(-)cells.Exp Hematol 31:650-658,2003.
26.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
27.Yen ML,Chienm CC,Chiu IM,Huang HI,Chen YC,Hu HI,Yen BL.Multilineage differentiation and characterization of the human fetal osteoblastic 1.19 cell line:a possible in vitro model of human mesenchymal progenitors.Stem Cells 25:125-131,2007
28.in't Anker PS,Noor WA,Scherjon SA,Klei jburg-van der KeurC,Kruisselbrink AB,van Bezooijen RL,Beekhuizen W,Willemze R,Kanhai HH,Fibbe WE.Mesenchymal stem cells in human second-trimester bone marrow,liver,lung,and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential.Haematologica 88:845-852,2003
29.O'Donoghue K,Fisk NM.Fetal stem cells.Best Pract Res Clin Obstet Gynaecol 18:853-875,2004
30.Fan CG,Tang FW,Zhang QJ,Lu SH,Liu HY,Zhao ZM,Liu B,Han ZB,Han ZC.Characterization and neural differentiation of fetal lung mesenchymal stem cells.Cell Transplant 14:311-321,2005
31.Ho AD,Wagner W,Franke W.Heterogeneity of mesenchymal stromal cell preparations.Cytotherapy 10:320-330,2008
32.Mitchell KE,Weiss ML,Mitchell BM,Martin P,Davis D,Morales L,Helwig B,Beerenstrauch M,Abou-Easa K,Hildreth T,Troyer D,Medicetty S.Matrix cells from Wharton's jelly form neurons and glia.Stem Cells 21:50-60,2003
33.Banfi A,Muraglia A,Dozin B,Mastrogiacomo M,Cancedda R,Quarto R.Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stroma cells:Implication for their use in cell therapy.Exp Hematol 28:707-715,2000
34.Battula VL,Bareiss PM,Treml S,Conrad S,Albert I,Hojak S,Abele H,Schewe B,Just L,Skutella T,Btlhring HJ.Human placenta and bone marrow derived MSC cultured in serum-free,b-FGF-containing medium express cell surface frizzled-9 and SSEA-4 and give rise to multilineage differentiation.Differentiation 75:279-291,2007
35.Takahashi K,Yamanaka S.Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell 126:663-676,2006
1.Horwitz EM,Le Blanc K,Dominici M,Mueller I,Slaper-Cortenbach I,Marini FC,Deans RJ,Krause DS,Keating A.the International Society for Cellular Therapy.Clarification of the nomenclature for MSC:The International Society for Cellular Therapy position statement.Cytotherapy 7:393-395,2005
2.Nakahara H,Bruder SP,Haynesworth SE,Holecek JJ,Baber MA,Goldberg VM,Caplan AI.Bone and cartilage formation in diffusion chambers by subcultured cells derived from the periosteum.Bone 11:181-188,1990
3.Gronthos S,Mankani M,Brahim J,Robey PG,Shi S.Postnatal human dental pulp stem cells (DPSCs)in vitro and in vivo.Proc Natl Acad Sci USA 97:13625-13630,2000
4.Romanov YA,Svintsitskaya VA,Smirnov VN.Searching for alternative sources of postnatal human mesenchymal stem cells:Candidate MSC-like cells from umbilical cord.Stem Cells 21:105-110,2003
5.Seo BM,MiuraM,Gronthos S,Bartold PM,Batouli S,Brahim J,Young M,Robey PG,Wang CY,Shi S.Investigation of multipotent postnatal stem cells from human periodontal ligament.Lancet 364:149-155,2004
6.Pountos I,Giannoudis PV.Biology of mesenchymal stem cells.Injury 36:S8-S12,2005
7.Bi Y,Ehirchiou D,Kilts TM,Inkson CA,Embree MC,Sonoyama W,Li L,Leet AI,Seo BM,Zhang L,Shi S,Young MF.Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.Nat Med 13:1219-1227,2007
8.Zannettino AC,Paton S,Arthur A,Khor F,Itescu S,Gimble JM,Gronthos S.Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo.J Cell Physiol 214:413-421,2008
9.Guillot PV,Gotherstrom C,Chan J,Kurata H,Fisk NM.Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.Stem Cells 25:646-654,2007
10.Gonzalez R,Maki CB,Pacchiarotti J,Csontos S,Pham JK,Slepko N,Patel A,Silva F.Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells.Biochem Biophys Res Commun 362:491-497,2007
ll.Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krause D,Deans R,Keating A,Prockop D,Horwitz E.Minimal criteria for defining multipotent mesenchymal stromal cells.The International Society for Cellular Therapy position statement.Cytotherapy 8:315-317,2006
12.Keating,A.Mesenchymal stromal cells.Curr Opin Hematol 13:419-425,2006
13.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood 110:3499-3506,2007
14.Abdi R,Fiorina P,Adra CN,Atkinson M,Sayegh MH.Immunomodulation by mesenchymal stem cells:a potential therapeutic strategy for type 1 diabetes.Diabetes 57:1759-1767,2008
15.Krampera M,Glennie S,Dyson J,Scott D,Laylor R,Simpson E,Dazzi F.' Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.Blood 101:3722-3729,2003
16.Di Nicola M,Carlo-Stella C,Magni M,Milanesi M,Longoni PD,Matteucci P,Grisanti S,Gianni AM.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.Blood 99:3838-3843,2002
17.Rasmusson I,Ringd6n 0,Sundberg B,Le Blanc K.Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms.Exp Cell Res 305:33-41,2005
18.Sato K,Ozaki K,Oh I,Meguro A,Hatanaka K,Nagai T,Muroi K,Ozawa K.Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells.Blood 109:228-234,2007
19.Le Blanc K,Rasmusson I,Sundberg B,Gotherstrom C,Hassan M,Uzunel M,Ringd6n 0.Treatment of severe graft versus-host disease with third party haploidentical mesenchymal stem cells.Lancet 363:1439-1441,2004
20.Ringd6n 0,Uzunel M,Rasmusson I,Remberger M,Sundberg B,Lonnies H,Marschall HU,Dlugosz A,Szakos A,Hassan Z,Omazic B,Aschan J,Barkholt L,Le Blanc K.Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.Transplantation 81:1390-1397,2006
21.Mosmann TR,Coffman RL.TH1 and TH2 cells:different patterns of lymphokine secretion lead to different functional properties.Annu Rev Immunol 7:145-173,1989
22.Mosmann TR,Sad S.The expanding universe of T-cell subsets:Th1,Th2and more.Immunol Today 17:138-146,1996
23.Rouvier E,Luciani MF,Mattei MG,Denizot F,Golstein P.CTLA-8,cloned from an activated T cell,bearing AU-rich messenger RNA instability sequences,and homologous to a herpesvirus saimiri gene.J Immunol 150:5445-5456,1993
24.Yao Z,Painter SL,Fanslow WC,Ulrich D,Macduff BM,Spriggs MK,Armitage RJ.Human IL-17:a novel cytokine derived from T cells.J Immunol 155:5483-5486,1995
25.Yao Z,Timour M,Painter S,Fanslow W,Spriggs M.Complete nucleotide sequence of the mouse CTLA8 gene.Gene 168:223-225,1996
26.Fossiez F,Djossou O,Chomarat P,Flores-Romo L,Ait-Yahia S,Maat C,Pin JJ,Garrone P,Garcia E,Saeland S,Blanchard D,Gaillard C,Das Mahapatra B,Rouvier E,Golstein P,Banchereau J,Lebecque S.T cell interleukin-17induces stromal cells to produce proinflammatory and hematopoietic cytokines.J Exp Med 183:2593-2603,1996
27.Romani L.Cell mediated immunity to fungi:a reassessment.Med Mycol 1-15,2008 Mar 12
28.Steinman L.A brief history of T(H)17,the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.Nat Med13:139-145,2007
29.Bronte V.Th17 and cancer:friends or foes? Blood 112:214,2008
30.Langowski JL,Kastelein RA,Oft M.Swords into plowshares:IL-23repurposes tumor immune surveillance.Trends Immunol 28:207-212,2007节 1.08 31.Iwakura Y,Nakae S,Saijo S,Ishigame H.The roles of IL-17A in inflammatory immune responses and host defense against pathogens.Immunol Rev 226:57-79,2008
32.McGeachy MJ,Bak-Jensen KS,Chert Y,Taro CM,Blumenschein W,McClanahan T,Cua DJ.TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.Nat Immunol 8:1390-1397,2007
33.Filaci G,Fravega M,Fenoglio D,Rizzi M,Negrini S,Viggiani R,Indiveri F.Non-antigen specific CD8+T suppressor lymphocytes.Clin Exp Med4:86-92,2004
34.Hegde S,Pahne J,Smola-Hess S.Novel immunosuppressive properties of interleukin-6 in dendritic cells:Inhibition of NF-kappaB binding activity and CCR7 expression.FASEB J 18:1439-1441,2004
35.Fan CG,Tang FW,Zhang QJ,Lu SH,Liu HY,Zhao ZM,Liu B,Han ZB,Han ZC.Characterization and neural differentiation of fetal lung mesenchymal stem cells.Cell Transplant 14:311-321,2005
36.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
37.Krampera M,Cosmi L,Angeli R,Pasini A,Liotta F,Andreini A,Santarlasci V,et al.,Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.Stem Cells 24:386-398,2006
38.Amadi-Obi A,Yu CR,Liu X,Mahdi RM,Clarke GL,Nussenblatt RB,Gery I,Lee YS,Egwuagu CE.TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1.Nat Med 13:711-718,2007
39.Bettelli E,Carrier Y,GaoW,KornT,Strom TB,OukkaM,Weiner HL,Kuchroo VK.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature 441:235-238,2006
40.Veldhoen M,Hocking RJ,Atkins CJ,Locksley RM,Stockinger B.TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity 24:179-189,2006
41.Acosta-Rodriguez EV,Napolitani G,Lanzavecchia A,Sallusto F.Interleukins lbeta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.Nat Immunol 8:942-949,2007
44.Chen Z,Tato CM,Muul L,Laurence A,O'Shea JJ.Distinct regulation of IL-17 in human helper T lymphocytes.Arthritis Rheum 56:2936-2946,2007
45.Wilson NJ,Boniface K,Chan JR,McKenzie BS,Blumenschein WM,Mattson JD,Basham B,Smith K,Chen T,Morel F,Lecron JC,Kastelein RA,Cua DJ,McClanahan TK,Bowman EP,de Waal Malefyt R.Development,cytokine profile and function of human interleukin 17-producing helper T cells.Nat Immunol 8:950-957,2007
46.Fontenot JD,Rasmussen JP,Williams LM,Dooley JL,Farr AG,Rudensky AY.Regulatory T cell lineage specification by the forkhead transcription factor FoxP3.Immunity 22:329-341,2005
47.Sakaguchi S.Naturally arising CD4 regulatory T cells for immunologic selftolerance and negative control of immune responses.Annu Rev Immunol 22:531-562,2004
48.Aggarwal S,Pittenger MF.Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood 105:1815-1822,2005
49.Meisel R,Zibert A,Laryea M,G(o|)bel U,D(a|)ubener W,Dilloo D.Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenasemediated tryptophan degradation.Blood 103:4619-4621,2004
50.Glennie S,Soeiro I,Dyson PJ,Lam EW,Dazzi F.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 105:2821-2827,2005
51.Dong C.TH17 cells in development:an updated viewof their molecular identity and genetic programming.Nat Rev Immunol 8:337-348,2008
52.McGeachy MJ,Cua DJ.Th17 cell differentiation:the long and winding road.Immunity 28:445-453,2008
53.Zhou L,Ivanov Ⅱ,Spolski R,Min R,Shenderov K,Egawa T,Levy DE,Leonard WJ,Littman DR.IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Nat Immunol 8:967-974,2007
54.Veldhoen M,Hocking RJ,Atkins CJ,Locksley RM,Stockinger B.TGFb in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity 4:179-189,2006
55.Matusevicius D,Kivis(a|)kk P,He B,Kostulas N,Ozenci V,Fredrikson S,Link H.Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.Mult Scler 5:101-104,1999
56.Lind(?)n A,Hoshino H,Laan M.Airway neutrophils and interleukin-17.Eur Respir J 15:973-977,2000
57.Wong CK,Ho CY,Li EK,Lam CW.Elevation of proinflammatory cytokine (IL-18,IL-17,IL-12) and Th2 cytokine(IL-4) concentrations in patients with systemic lupus erythema- tosus.Lupus 9:589-593,2000
58.Laan M,Lotvall J,Chung KF,Linden A.IL-17-induced cytokine release in human bronchial epithelial cells in vitro:role of mitogen-activated protein(MAP) kinases.Br J Pharmacol 133:200-206,2001
59.Hwang sg,Kim JY,Kim KW,Park MK,Moon Y,Kim WU,Kim HY.IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kB- and PI3- kinase/Akt-dependent pathways.Arthritis Res Ther 6:R120-R128,2004
60.Schwandner R,Yamaguchi K,Cao Z.Requirement of tumor necrosis factor receptor-associated factor(TRAF)6 in interleukin 17 signal transduction.J Exp Med 191:1233-1240,2000
61.Shen F,Hu Z,Goswami J,Gaffen SL.Identification of common transcriptional regulatory elements in interleukin-17 target genes.J Biol Chem 281:24138-24148,2006
62.Uccelli A,Moretta L,Pistoia V.Uesenchymal stem cells in health and disease.Nat Rev Immunol 8:726-36,2008
63.Aggarwal S,Pittenger MF.Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood 105:1815-1822,2005
64.Di Ianni M,Del Papa B,De Ioanni M,Moretti L,Bonifacio E,Cecchini D,Sportoletti P,Falzetti F,Tabilio A.Mesenchymal cells recruit and regulate T regulatory cells.Exp Hematol 36:309-318,2008
1.Prockop DJ.Marrow stromal cells as stem cells for nonhematopoietic tissues.Science 276:71-74,1997
2.Dennis JE,AIC.Stem Cells Handbook.Totowa,NJ,Human Press,2004
3.Friedenstein AJ,Piatetzky S Ⅱ,Petrakova KV.Osteogenesis in transplants of bone marrow cells.J Embryol Exp Morphol 16:381-390,1966
4.Friedenstein AJ,Petrakova KV,Kurolesova AI,Frolova GP.Heterotopic of bone marrow:analysis of precursor cells for osteogenic and hematopoietic tissues.Transplantation 6:230-247,1968
5.Owen M.Marrow stromal stem cells.J Cell Sci Suppl 10:63-76,1988
6.Friedenstein AJ,Chailakhyan RK,Latsinik NV,Panasyuk AF,Keiliss-Borok IV.Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues.Cloning in vitro and retransplantation in vivo.Transplantation 17:331-340,1974
7.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
8.Kopen GC,Prockop DJ,Phinney DG.Marrow stromal cells migrate throughout forebrain and cerebellum,and they differentiate into astrocytes after injection into neonatal mouse brains.Proc Natl Acad Sci USA 96:10711-10716,1999
9.Dennis JE,Charbord P.Origin and differentiation of human and murine stroma.Stem Cells 20:205-214,2002
10.Takashima Y,Era T,Nakao K,Kondo S,Kasuga M,Smith AG,Nishikawa S.Neuroepithelial cells supply an initial transient wave of MSC differentiation.Cell 129:1377-1388,2007
11.Phinney DG,Hill K,Michelson C,DuTreil M,Hughes C,Humphries S,Wilkinson R,Baddoo M,Bayly E.Biological activities encoded by the murine mesenchymal stem cell transcriptome provide a basis for their developmental potential and broad therapeutic efficacy.Stem Cells 24:186-198,2006
12.Pedemonte E,Benvenuto F,Casazza S,Mancardi G,Oksenberg JR,Uccelli A,Baranzini SE.The molecular signature of therapeutic mesenchymal stem cells exposes the architecture of the hematopoietic stem cell niche synapse.BMC Genomics 8:65,2007
13.Phinney DG,Prockop D J.Mesenchymal stem/multi-potent stromal cells (MSCs):the state of transdifferentiation and modes of tissue repair —current views.Stem Cells 25:2896-2902,2007
14.Pedemonte E,Benvenuto F,Casazza S,Mancardi G,Oksenberg JR,Uccelli A,Baranzini SE.Repair of large bone defects with the use of autologous bone marrow stromal cells.N Engl J Med 344:385-386,2001
15.Caplan AI.Mesenchymal stem cells.J Orthop Res 9:641-650,1991
16.Horwitz EM,Le Blanc K,Dominici M,Mueller I,Slaper-Cortenbach I,Marini FC,Deans RJ,Krause DS,Keating A.Clarification of the nomenclature for MSC:The International Society for Cellular Therapy position statement.Cytotherapy 7:393-395,2005
17.Pittenger MF,Martin BJ.Mesenchymal stem cells and their potential as cardiac therapeutics.Circ Res 95:9-20,2004
18.Sacchetti B,Funari A,Michienzi S,Di Cesare S,Piersanti S,Saggio I,Tagliafico E,Ferrari S,Robey PG,Riminucci M,Bianco P.Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.Cell 131:324-336,2007
19.Fibbe WE.Mesenchymal stem cells:a potential source for skeletal repair.Ann Rheum Dis 61(Suppl.2):ii29-ii31,2002
20.da Silva Meirelles L,Chagastelles PC,Nardi NB.Mesenchymal stem cells reside in virtually all post-natal organs and tissues.J Cell Sci 119:2204-2213,2006
21.Keyser KA,Beagles KE,Kiem HP.Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation.Cell Transplant 16:555-562,2007
22.Sugiyama T,Kohara H,Noda M,Nagasawa T.Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches.Immunity 25:977-988,2006
23.Chamberlain G,Fox J,Ashton B,Middleton J.Concise review:mesenchymal stem cells:their phenotype,differentiation capacity,immunological features,and potential for homing.Stem Cells 25:2739-2749,2007
24.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
25.Tyndall A,Walker UA,Cope A,Dazzi F,De Bari C,Fibbe W,Guiducci S,Jones S,Jorgensen C,Le Blanc K,Luyten F,McGonagle D,Martin I,Bocelli-Tyndall C,Pennesi G,Pistoia V,Pitzalis C,Uccelli A,Wulffraat N,Feldmann M.Immunomodulatory properties of mesenchymal stem cells:a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division,London,UK,31 October 2005.Arthritis Res Ther9:301,2007
26.Schofield R.The relationship between the spleen colony-forming cell and the haemopoietic stem cell.Blood Cells 4:7-25,1978
27.Bocelli-Tyndall C,Barbero A,Candrian C,Ceredig R,Tyndall A,Martin I.Human articular chondrocytes suppress in vitro proliferation of anti-CD3 activated peripheral blood mononuclear cells.J Cell Physiol 209:732-734,2006
28.Jones S,Horwood N,Cope A,Dazzi F.The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells.J.Immunol.179:2824-2831,2007
29.Haniffa MA,Wang XN,Holtick U,Rae M,Isaacs JD,Dickinson AM,Hilkens CM,Collin MP.Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells.J.Immunol.179:1595-1604,2007
30.Parsonage G,Filer AD,Haworth O,Nash GB,Rainger GE,Salmon M,Buckley CD.A stromal address code defined by fibroblasts.Trends Immunol 26:150-156,2005
31.Bartholomew A,Sturgeon C,Siatskas M,Ferrer K,Mcintosh K,Patil S,Hardy W,Devine S,Ucker D,Deans R,Moseley A,Hoffman R.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol 30:42-48,2002
32.Le Blanc K,Tammik L,Sundberg B,Haynesworth SE,Ringden O.Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex.Scand J Immunol 57:11-20,2003
33.Krampera M,Glennie S,Dyson J,Scott D,Laylor R,Simpson E,Dazzi F.Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.Blood 101:3722-3729,2003
34.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood 110:3499-3506,2007
35.Meisel R,Zibert A,Laryea M,Gobel U,Daubener W,Dilloo D.Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation.Blood 103:4619-4621,2004
36.Sato K,Ozaki K,Oh I,Meguro A,Hatanaka K,Nagai T,Muroi K,Ozawa K.Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells.Blood 109:228-234,2007
37.Chabannes D,Hill M,Merieau E,Rossignol J,Brion R,SoulillouJP,Anegon I,Cuturi MC.A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells.Blood 110:3691-3694,2007
38.Ryan JM,Barry FP,Murphy JM,Mahon BP.Mesenchymal stem cells avoid allogeneic 'rejection.J Inflamm (Lond)2:8,2005
39.Nauta AJ,Kruisselbrink AB,Lurvink E,Willemze R,Fibbe WE.Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells.J Immunol 177:2080-2087,2006
40.Jiang XX,Zhang Y,Liu B,Zhang SX,Wu Y,Yu XD,Mao N.Human mesenchymal stem cells inhibit differentiation and function of monocytederived dendritic cells.Blood 105:4120-4126,2005
41.Ramasamy R,Fazekasova H,Lam EW,Soeiro I,Lombardi G,Dazzi F.Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle.Transplantation 83:71-76,2007
42.Aggarwal S,Pittenger MF.Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood 105:1815-1822,2005
43.Beyth S,Borovsky Z,Mevorach D,Liebergall M,Gazit Z,Asian H,Galun E,Rachmilewitz J.Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness.Blood 105:2214-2219,2005
44.Maccario R,Podesta M,Moretta A,Cometa A,Comoli P,Montagna D,Daudt L,Ibatici A,Piaggio G,Pozzi S,Frassoni F,Locatelli F.Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype.Haematologica 90:516-525,2005
45.Moretta A.Natural killer cells and dendritic cells:rendezvous in abused tissues.Nature Rev Immunol 2:957-964,2002
46.Moretta A,Bottino C,Vitale M,Pende D,Biassoni R,Mingari MC,Moretta L.Receptors for HLA class-I molecules in human natural killer cells.Annu Rev Immunol 14:619-648,1996
47.Moretta A,Bottino C,Vitale M,Pende D,Cantoni C,Mingari MC,Biassoni R,Moretta L.Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.Annu Rev Immuno 19:197-223,2001
48.Spaggiari GM,Capobianco A,Becchetti S,Mingari MC,Moretta L.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.Blood 107:1484-1490,2006
49.Spaggiari GM,Capobianco A,Abdelrazik H,Becchetti F,Mingari MC,Moretta L.Mesenchymal stem cells inhibit natural killer-cell proliferation,cytotoxicity,and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2.Blood 111:1327-1333,2008
50.Sotiropoulou PA,Perez SA,Gritzapis AD,Baxevanis CN,Papamichail M.Interactions between human mesenchymal stem cells and natural killer cells.Stem Cells 24:74-85,2006
51.Selmani Z,Naji A,Zidi I,Favier B,Gaiffe E,Obert L,Borg C,Saas P,Tiberghien P,Rouas-Freiss N,Carosella ED,Deschaseaux F.Human leukocyte antigen~G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highF0XP3+ regulatory T cells.Stem Cells 2§:2\2-222,2008
52.Rasmusson I,Ringden 0,Sundberg B,Le Blanc K.Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes,but not activated cytotoxic T lymphocytes or natural killer cells.Transplantation 76:1208-1213,2003
53.Krampera M,Cosmi L,Angeli R,Pasini A,LiottaF,Andreini A,Santarlasci V,Mazzinghi B,Pizzolo G,Vinante F,Romagnani P,Maggi E,Romagnani S,Annunziato F.Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.Stem Cells 24:386-398,2006
54.Poggi A,Prevosto C,Massaro AM,Negrini S,Urbani S,Pierri I,Saccardi R,Gobbi M,Zocchi MR.Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering:role of NKp30 and NKG2D receptors.J Immunol 175:6352-6360,2005
55.Raffaghello L,Bianchi G,Bertolotto M,Montecucco F,Busca A,Dallegri F,Ottonello L,Pistoia V.Human mesenchymal stem cells inhibit neutrophil apoptosis:a model for neutrophil preservation in the bone marrow niche.Stem Cells 26:151-162,2008
56.Fadeel B,Ahlin A,Henter JI,Orrenius S,Hampton MB.Involvement of caspases in neutrophil apoptosis:regulation by reactive oxygen species.Blood 92:4808-4818,1998
57.Craddock CG,Jr Perry S,Ventzke LE,Lawrence JS.Evaluation of marrow granulocytic reserves in normal and disease states.Blood 15:840-855,1960
58.Di Nicola M,Carlo-Stella C,Magni M,Milanesi M,Longoni PD,Matteucci P,Grisanti S,Gianni AM.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.Blood 99:3838-3843,2002
59.Tse WT,Pendleton JD,Beyer WM,Egalka MC,Guinan EC.Suppression of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation.Transplantation 75:389-397,2003
60.Rasmusson I,Ringden 0,Sundberg B,Le Blanc K.Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms.Exp Cell Res 305:33-41,2005
61.Glennie S,Soeiro I,Dyson PJ,Lam EW,Dazzi F.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 105:2821-2827,2005
62.Ren G,Zhang L,Zhao X,Xu G,Zhang Y,Roberts AI,Zhao RC,Shi Y.Mesenchymal stem-cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.Cell Stew Cell 2:141-150,2008
63.Benvenuto F,Ferrari S,Gerdoni E,Gualandi F,Frassoni F,Pistoia V,Mancardi G,Uccelli A.Human mesenchymal stem cells promote survival of T cells in a quiescent state.Stem Cells 25:1753-1760,2007
64.Augello A,Tasso R,Negrini SM,Amateis A,Indiveri F,Cancedda R,Pennesi G.Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway.Eur J Immunol 35:1482-1490,2005
65.Rasmusson I,Uhlin M,Le Blanc K,Levitsky V.Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes.J Leukocyte Biol 82:887-893,2007
66.Morandi F,Raffaghello L,Bianchi G,Meloni F,Salis A,Millo E,Ferrone S,Barnaba V,Pistoia V.Immunogenicity of human mesenchymal stem cells in HLA-class-I-restricted T-cell responses against viral or tumor-associated antigens.Stem Cells 26:1275-1287,2008
67.Pevsner-Fischer M,Morad V,Cohen-Sfady M,Rousso-Noori L,Zanin-Zhorov A,Cohen S,Cohen IR,Zipori D.Toll-like receptors and their ligands control mesenchymal stem cell functions.Blood 109:1422-1422,2007
68.Tomchuck SL,Zwezdaryk KJ,Coffelt SB,Waterman RS,Danka ES,Scandurro AB.Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses.Stem Cells 26:99-107,2008
69.Hwa ChoH,Bae YC,Jung JS.Role of Toll-like receptors on human adipose-derived stromal cells.Stem Cells 24:2744-2752,2006
70.Liotta F,Angeli R,Cosmi L,Fill L,Manuelli C,Frosali F,Mazzinghi B,Maggi L,Pasini A,Lisi V,Santarlasci V,Consoloni L,Angelottr ML,Romagnani P,Parronchi P,Krampera M,Maggi E,Romagnani S,Annunziato F.Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling.Stem Cells 26:279-289,2008
71.Svensson M,Kaye PM.Stromal-cell regulation of dendritic-cell differentiation and function.Trends Immunol 27:580-587,2006
72.Traggiai E,Volpi S,Schena F,Gattorno M,Ferlito F,Moretta L,Martini A.Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients.Stem Cells 26:562-569,2008
73.Corcione A,Benvenuto F,Ferretti E,Giunti D,Cappiello V,Cazzanti F,Risso M,Gualandi F,Mancardi GL,Pistoia V,Uccelli A.Human mesenchymal stem cells modulate B-cell functions.Blood 107:367-372,2006
74.Rasmusson I,Le Blanc K,Sundberg B,Ringden 0.Mesenchymal stem cells stimulate antibody secretion in human B cells.Scand J Immunol 65:336-343,2007
75.Gerdoni E,GalloB,Casazza S,Musio S,Bonanni I,Pedemonte E,Mantegazza R,Frassoni F,Mancardi G,Pedotti R,Uccelli A.Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis.Ann Neurol 61:219-227,2007
76.Deng W,Han Q,Liao L,You S,Deng H,Zhao RC.Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice.DNA Cell Biol 24:458-463,2005
77.Stagg J,Pommey S,Eliopoulos N,Galipeau J.Interferon-y-stimulated marrow stromal cells:a new type of nonhematopoietic antigen-presenting cell.Blood 107:2570-2577,2006
78.Chan JL,Tang KC,Patel AP,Bonilla LM,Pierobon N,Ponzio NM,Rameshwar P.Antigen presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-y.Blood 107:4817-4824,2006
79.Feuerer M,Beckhove P,Garbi N,Mahnke Y,Limmer A,Hommel M,Hammerling GJ,Kyewski B,Hamann A,Umansky V,Schirrmacher V.Bone marrow as a priming site for T-cell responses to blood-borne antigen.Nature Med 9:1151-1157,2003
80.Fox JM,Chamberlain G,Ashton BA,M'iddleton J.Recent advances into the understanding of mesenchymal stem cell trafficking.Br J Haematol 137:491-502,2007
81.Nauta AJ,Westerhuis G,Kruisselbrink AB,Lurvink EG,Willemze R,Fibbe WE.Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting.Blood 108:2114-2120,2006
82.Le Blanc K,Tammik C,Rosendahl K,Zetterberg E,Ringden O.HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol 31:890-896,2003
83.Klyushnenkova E,Mosca JD,Zernetkina V,Majumdar MK,Beggs KJ,Simonetti DW,Deans RJ,Mcintosh KR.T cell responses to allogeneic human mesenchymal stem cells:immunogenicity,tolerance,and suppression.J Biomed Sci 12:47-57,2005
84.Le Blanc K,Ringden 0.Immunomodulation by mesenchymal stem cells and clinical experience.J In tern Med 262:509-525,2007
85.Morigi M,Imberti B,Zoja C,Corna D,Tomasoni S,Abbate M,Rottoli D,Angioletti S,Benigni A,Perico N,Alison M,Remuzzi G.Mesenchymal stem cells are renotropic,helping to repair the kidney and improve function in acute renal failure.J Am Soc Nephrol 15:1794-1804,2004
86.Duffield JS,Park KM,Hsiao LL,Kelley VR,Scadden DT,Ichimura T,Bonventre JV.Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells.J Clin Invest 115:1743-1755,2005
87.Lee RH,Seo MJ,Reger RL,Spees JL,Pulin AA,Olson SD,Prockop DJ.Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice.Proc Natl Acad Sci USA 103:17438-17443,2006
88.Zappia E,Casazza S,Pedemonte E,Benvenuto F,Bonanni I,Gerdoni E,Giunti D,Ceravolo A,Cazzanti F,Frassoni F,Mancardi G,Uccelli A.Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy.Blood 106:1755-1761,2005
89.Augello A,Tasso R,Negrini SM,Cancedda R,Pennesi G.Cell Therapy Using Allogeneic Bone Marrow Mesenchymal Stem Cells Prevents Tissue Damage in Collagen-Induced Arthritis.Arthritis & Rheumatism 56:1175-1186,2007
90.Itakura S,Asari S,Rawson J,Ito T,Todorov I,Liu CP,Sasaki N,Kandeel F,Mullen Y.Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat.Am J Transplant 7:336-346,2007
91.Le Blanc K,Rasmusson I,Sundberg B,Gotherstrom C,Hassan M,Uzunel M,Ringden O.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lancet 363:1439-1441,2004
92.Ringden 0,Uzunel M,Rasmusson I,Remberger M,Sundberg B,Lonnies H,Marschall HU,Dlugosz A,Szakos A,Hassan Z,Omazic B,Aschan J,Barkholt L,Le Blanc K.Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.Transplantation 81:1390-1397,2006
93.Yanez R,Lamana ML,Garcia-Castro J,Colmenero I,Ramirez M,Bueren JA.Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease.Stem Cells Dev 24:2582-2591,2006
94.Sudres M,Norol F,Trenado A,Gregoire S,Charlotte F,Levacher B,Lataillade JJ,Bourin P,Holy X,Vernant JP,Klatzmann D,Cohen JL.Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice.J Immunol 176:7761-7767,2006
95.Inoue S,Popp FC,Koehl GE,Piso P,Schlitt HJ,Geissler EK,Dahlke MH.Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant mode1.Transplantation 81:1589-1595,2006
96.Ryan JM,Barry F,Murphy JM,Mahon BP.Interferon-y does not break,but promotes the immunosuppressive capacity of adult human mesenchymal stem cells.Clin Exp Immunol 149:353-363,2007
97.Kogler G,Radke TF,Lefort A,Sensken S,Fischer J,Sorg RV,Wernet P.Cytokine production and hematopoiesis supporting activity of cord bloodderived unrestricted somatic stem cells.Exp Hematol 33:573-583,2005
98.Djouad F,Charbonnier LM,Bouffi C,Louis-Plence P,Bony C,Apparailly F,Cantos C,Jorgensen C,Noel D.Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism.Stem Cells 25:2025-2032,2007
99.Almeida-Porada G,Porada CD,Tran N,Zanjani ED.Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation.Blood95:3620-3627,2000
100.Pereira RF,Halford KW,0'Hara MD,Leeper DB,Sokolov BP,Pollard MD,Bagasra 0,Prockop DJ.Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone,cartilage,and lung in irradiated mice.Proc Natl Acad Sci USA 92:4857-4861,1995
101.Eliopoulos N,Stagg J,Lejeune L,Pommey S,Galipeau J.Allogeneic marrow stromal cells are immune rejected by MHC class I-and class Ⅱ-mismatched recipient mice.Blood 106:4057-4065,2005
102.Murphy JM,Dixon K,Beck S,Fabian D,Feldman A,Barry F.Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis.Arthritis Rheum 46:704-713,2002
103.Papadaki HA,Tsagournisakis M,Mastorodemos V,Pontikoglou C,Damianaki A,Pyrovolaki K,Stamatopoulos K,Fassas A,Plaitakis A,Eliopoulos GD.Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis.Bone Marrow Transplant 36:1053-1063,2005
104.Kastrinaki MC,Sidiropoulos P,Roche S,Ringe J,Lehmann S,Kritikos H,Vlahava VM,Delorme B,Eliopoulos GD,Jorgensen C,Charbord P,H(a|¨)upl T, Boumpas DT,Papadaki HA.Functional,molecular and proteomic characterization of bone marrow mesenchymal stem cells in rheumatoid arthritis.Ann Rheum Dis 67:741-749,2008
105.Bacigalupo A,Valle M,Podesta M,Pitto A,Zocchi E,De Flora A,Pozzi S,Luchetti S,Frassoni F,Van Lint MT,Piaggio G.T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia.Exp Hematol 33:819-827,2005
106.Arnulf B,Lecourt S,Soulier J,Ternaux B,Lacassagne MN,Crinquette A,Dessoly J,Sciaini AK,Benbunan M,Chomienne C,Fermand JP,Marolleau JP,Larghero J.Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma.Leukemia 21:158-163,2007
107.Devine SM,Cobbs C,Jennings M,Bartholomew A,Hoffman R.Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into non-human primates.Blood 101:2999-3001,2003
108.Li Y,Chen J,Chen XG,Wang L,Gautam SC,Xu YX,Katakowski M,Zhang LJ,LuM,Janakiraman N,ChoppM.Human marrow stromal cell therapy for stroke in rat:neurotrophins and functional recovery.Neurology 59:514-523,2002
109.RUsterB,Gottig S,Ludwig RJ,Bistrian R,Müller S,Seifried E,Gille J,Henschler R.Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells.Blood 108:3938-3944,2006
110.Sordi V,Malosio ML,Marchesi F,Mercalli A,Melzi R,Giordano T,Belmonte N,Ferrari G,Leone BE,Bertuzzi F,Zerbini G,AllavenaP,Bonifacio E,Piemonti L.Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets.Blood 106:419-427,2005
111.Son BR,Marquez-Curtis LA,Kucia M,Wysoczynski M,Turner AR,Ratajczak J,Ratajczak MZ,Janowska-Wieczorek A.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~Met axes and involves matrix metalloproteinases.Stem Cells 24:1254-1264,2006
112.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol 28:219-226,2007
113.Munoz JR,Stoutenger BR,Robinson AP,Spees JL,Prockop DJ.Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice.Proc.Natl Acad.Sci.USA 102:18171-18176,2005
114.Rivera FJ,Couillard-Despres S,Pedre X,Ploetz S,Caioni M,Lois C,Bogdahn U,Aigner L Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells.Stem Cells 24:2209-2219,2006
115.Urbdn VS,Kiss J,Kovdcs J,G6cza E,Vas V,Monostori E,Uher F.Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes.Stem Cells 26:244-253,2008
116.Togel F,Hu Z,Weiss K,Isaac J,Lange C,Westenfelder C.Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.Am J Physiol Renal Physiol 289:F31-F42,2005
117.Ortiz LA,Dutreil M,Fattman C,Pandey AC,Torres G,Go K,Phinney DG.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc.Natl Acad.Sci.USA 104:11002-11007,2007
118.Mirotsou M,Zhang Z,Deb A,Zhang L,Gnecchi M,Noiseux N,Mu H,Pachori A,Dzau V.Secreted frizzled related protein 2 (Sfrp2)is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair.Proc Natl Acad Sci USA 104:1643-1648,2007
119.Ramasamy R,Lam EW,Soeiro I,Tisato V,Bonnet D,Dazzi F.Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells:impact on in vivo tumor growth.Leukemia 21:304-310,2007
120.Djouad F,Plence P,Bony C,Tropel P,Apparailly F,Sany J,No(e|¨)l D,Jorgensen C.Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals.Blood 102:3837-3844,2003
121.Ame-Thomas P,Maby-El Hajjami H,Monvoisin C,Jean R,Monnier D,Caulet-MaugendreS,Guillaudeux T,Lamy T,Fest T,Tarte K.Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth:role of stromal cells in follicular lymphoma pathogenesis.Blood 109:693-702,2007
122.Khakoo AY,Pati S,Anderson SA,Reid W,Elshal MF,Rovira Ⅱ,Nguyen AT,Malide D,Combs CA,Hall G,Zhang J,Raff eld M,Rogers TB,Stetler-Stevenson W,Frank JA,Reitz M,Finkel T.Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 203:1235-1247,2006
123.Karnoub AE,Dash AB,Vo AP,Sullivan A,Brooks MW,Bell GW,Richardson AL,Polyak K,Tubo R,Weinberg RA.Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.Nature 449:557-563,2007
124.Liotta LA,Kohn EC.The microenvironment of the tumour-host interface.Nature 411:375-379,2001
125.Horwitz EM,Prockop DJ,Fitzpatrick LA,Koo WW,Gordon PL,Neel M,Sussman M,Orchard P,Marx JC,Pyeritz RE,Brenner MK.Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta.Nature Med 5:309-313,1999
126.Koc ON,Gerson SL,Cooper BW,Dyhouse SM,Haynesworth SE,Caplan AI,Lazarus HM.Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving highdose chemotherapy.J Clin Oncol 18:307-316,2000
127.Ning H,Yang F,Jiang M,Hu L,Feng K,Zhang J,Yu Z,Li B,Xu C,Li Y,Wang J,Hu J,Lou X,Chen H.The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients:outcome of a pilot clinical study.Leukemia 22:593-599,2008
128.Ball LM,Bernardo ME,Roelofs H,Lankester A,Cometa A,Egeler RM,Locatelli F,Fibbe WE.Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation.Blood 110:2764-2767,2007
129.Okamoto R,Yajima T,Yamazaki M,Kanai T,Mukai M,Okamoto S,Ikeda Y,Hibi T,Inazawa J,Watanabe M.Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract.Nature Med 8:1011-1017,2002
130.Mazzini L,Mareschi K,Ferrero I,Vassallo E,Oliveri G,Boccaletti R,Testa L,Livigni S,Fagioli F.Autologous mesenchymal stem cells:clinical applications in amyotrophic lateral sclerosis.Neurol Res 28:523-526,2006
131.Koc ON,Day J,Nieder M,Gerson SL,Lazarus HM,Krivit W.Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD)and Hurler syndrome (MPS-IH).Bone Marrow Transplant 30:215-222,2002
132.Numaguchi Y,Sone T,Okumura K,Ishii M,Morita Y,Kubota R,Yokouchi K,Imai H,Harada M,Osanai H,Kondo T,Murohara T.The impact of the capability of circulating progenitor cell to differentiate on myocardial salvage in patients with primary acute myocardial infarction.Circulation 114:1114-1119,2006
133.Tolar J,Nauta AJ,Osborn MJ,Panoskaltsis Mortari A,McElmurry RT,Bell S,XiaL,Zhou N,Riddle M,SchroederTM,Westendorf J J,Mclvor RS,Hogendoorn PC,Szuhai K,Oseth L,Hirsch B,Yant SR,Kay MA,Peister A,Prockop DJ,Fibbe WE,Blazar BR.Sarcoma derived from cultured mesenchymal stem cells.Stem Cells 25:371-379,2007
134.Breitbach M,Bostani T,Roell W,Xia Y,Dewald 0,Nygren JM,Fries JW,Tiemann K,Bohlen H,Hescheler J,Welz A,Bloch W,Jacobsen SE,Fleischmann BK.Potential risks of bone marrow cell transplantation into infarcted hearts.Blood 110:1362-1369,2007
135.Atsma DE,Fibbe WE,Rabelink TJ.Opportunities and challenges for mesenchymal stem cell-mediated heart repair.Curr Opin Lipidol 18:645-649,2007
136.Wilson A,TrumppA.Bone-marrow haematopoietic-stem-cell niches.Nature Rev Immunol 6:93-106,2006
137.Kiel MJ,Morrison SJ.Uncertainty in the niches that maintain haematopoietic stem cells.Nature Rev Immunol 8:290-301,2008
138.Stier S,Ko Y,Forkert R,Lutz C,Neuhaus T,Grünewald E,Cheng T,Dombkowski D,Calvi LM,Rittling SR,Scadden DT.Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size.J Exp Med 201:1781-1791,2005
139.Arai F,Hirao A,Ohmura M,Sato H,Matsuoka S,Takubo K,Ito K,Koh GY,Suda T.Tie2/angiopoietin-l signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.Cell 118:149-161,2004
140.Martino G,Pluchino S.The therapeutic potential of neural stem cells.Nature Rev Neurosci 7:395-406,2006
141.Duncan AW,Rattis FM,DiMascio LN,Congdon KL,Pazianos G,Zhao C,Yoon K,Cook JM,Willert K,Gaiano N,Reya T.Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance.Nature Immunol 6:314-322, 2005
142.Rubio D,Garcia-Castro J,Martin MC,de la Fuente R,Cigudosa JC,Lloyd AC,Bernad A.Spontaneous human adult stem cell transformation.Cancer Res 65:3035-3039,2005
143.Bernardo ME,Zaffaroni N,Novara F,Cometa AM,Avanzini MA,Moretta A,Montagna D,Maccario R,Villa R,Daidone MG,Zuffardi O,Locatelli F.Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms.Cancer Res 67:9142-9149,2007
2.Kogler,G,Sensken,S,Airey,J.A,Trapp,T,Mtlschen,M,Feldhahn,N,Liedtke,S,Sorg RV,Fischer J,Rosenbaum C,Greschat S,Knipper A,Bender J,Degistirici 0,Gao J,Caplan AI,Colletti EJ,Almeida-Porada G,Mtlller HW,Zanjani E,Wernet P.A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential.J Exp Med 200:123-135,2004
3.Ramos GA,Hare JM.Cardiac cell-based therapy:cell types and mechanisms of actions.Cell Transplant 16:951-961,2007
4.Torrente Y,Polli E.Mesenchymal stem cell transplantation for neurodegenerative diseases.Cell Transplant 17:1103-1113,2008
5.Valtieri M,Sorrentino A.The mesenchymal stromal cell contribution to homeostasis.J Cell Physiol 217:296-300,2008
6.Fox JM,Chamberlain G,Ashton BA,Middleton J.Recent advances into the understanding of mesenchymal stem cell trafficking.Br J Haematol 137:491-502,2007
7.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood 110:3499-3506,2007
8.Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krausc D,Deans R,Keating A,Prockop D,Horwitz E.Minimal criteria for defining multipotent mesenchymal stromal cells.The International Society for Cellular Therapy position statement.Cytotherapy 8:315-317,2006
9.Arthur A,Zannettino A,Gronthos S.The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair.J Cell Physiol 218:237-245,2009
10.Bilic G,Zeisberger SM,Mallik AS,Zimmermann R,Zisch AH.Comparative characterization of cultured human termiamnion epithelial and mesenchymal stromal cells for application in cell therapy.Cell Transplant 17:955-968,2008
ll.Campagnoli C,Roberts IA,Kumar S,Bennett PR,Bellantuono I,Fisk NM.Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood,liver,and bone marrow.Blood 98:2396-2402, 2001
12.Ferrero I,Mazzini L,Rustichelli D,Gunetti M,Mareschi K,Testa L,Nasuelli N,Oggioni GD,Fagioli F.Bone marrow mesenchymal stem cells from healthy donors and sporadic amyotrophic lateral sclerosis patients.Cell Transplant 17:255-266,2008
13.Gronthos S,Brahim J,Li W,Fisher LW,Cherman N,Boyde A,DenBesten P,Robey PG,Shi S.Stem cell properties of human dental pulp stem cells.J Dent Res 81:531-535,2002
14.Lee JK,Lee MK,Jin HJ,Kim DS,Yang YS,Oh W,Yang SE,Park TS,Lee SY,Kim BS,Jeun SS.Efficient intracytoplasmic labeling of human umbilical cord blood mesenchymal stromal cells with ferumoxides.Cell Transplant 16:849-857,2007
15.Peng L,Jia Z,Yin X,Zhang X,Liu Y,Chen P,Ma K,Zhou C.Comparative Analysis of Mesenchymal Stem Cells from Bone Marrow,Cartilage and Adipose Tissue.Stem Cells Dev 17:761-773,2008
16.Prusa AR,Marton E,Rosner M,Bernaschek G,Hengstschlager M.Oct-4-expressing cells in human amniotic fluid:A new source for stem cell research? Hum Reprod 18:U89-U93,2003
17.Tateishi K,Ando W,Higuchi C,Hart DA,Hashimoto J,Nakata K,Yoshikawa H,Nakamura N.Comparison of human serum with fetal bovine serum for expansion and differentiation of human synovial MSC:potential feasibility for clinical applications.Cell Transplant 17:549-557,2008
18.Yen BL,Huang HI,Chien CC,Jui HY,Ko BS,Yao M,Shun CT,Yen ML,Lee MC,Chen YC.Isolation of multipotent cells from human term placenta.Stem Cells 23:3-9,2005
19.Wagner W,Wein F,Seckinger A,Frankhauser M,Wirkner U,Krause U,Blake J,Schwager C,Eckstein V,Ansorge W,Ho A.D.Comparative characteristics of mesenchymal stem cells from human bone marrow,adipose tissue,and umbilical cord blood.Exp Hematol 33:1402-1416,2005
20.Le Blanc K.Immunomodulatory effects of fetal and adult mesenchymal stem cells.Cytotherapy 5:485-489,2003
21.Guillot PV,Gotherstrom C,Chan J,Kurata H,Fisk NM.Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.Stem Cells 25:646-654,2007
22.Gonzalez R,Maki CB,Pacchiarotti J,Csontos S,Pham JK,Slepko N,Patel A,Silva F.Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells.Biochem Biophys Res Commun 362:491-497,2007
23.Wang XY,Lan Y,He WY,Zhang L,Yao HY,Hou CM,Tong Y,Liu YL,Yang G,Liu XD,Yang X,Liu B,Mao N.Identification of mesenchymal stem cells in aorta-gonad-mesonephros and yolk sac of human embryos.Blood 111:2436-2443,2008
24.Bieback K,Kern S,Kltlter H,Eichler H.Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood.Stem Cells 22:625-634,2004
25.Guo H,Fang B,Liao L,Zhao Z,Liu J,Chen H,Hsu SH,Cui Q,Zhao RC.Hemangioblastic characteristics of fetal bone marrow-derived Flkl(+)CD31(-)CD34(-)cells.Exp Hematol 31:650-658,2003.
26.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
27.Yen ML,Chienm CC,Chiu IM,Huang HI,Chen YC,Hu HI,Yen BL.Multilineage differentiation and characterization of the human fetal osteoblastic 1.19 cell line:a possible in vitro model of human mesenchymal progenitors.Stem Cells 25:125-131,2007
28.in't Anker PS,Noor WA,Scherjon SA,Klei jburg-van der KeurC,Kruisselbrink AB,van Bezooijen RL,Beekhuizen W,Willemze R,Kanhai HH,Fibbe WE.Mesenchymal stem cells in human second-trimester bone marrow,liver,lung,and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential.Haematologica 88:845-852,2003
29.O'Donoghue K,Fisk NM.Fetal stem cells.Best Pract Res Clin Obstet Gynaecol 18:853-875,2004
30.Fan CG,Tang FW,Zhang QJ,Lu SH,Liu HY,Zhao ZM,Liu B,Han ZB,Han ZC.Characterization and neural differentiation of fetal lung mesenchymal stem cells.Cell Transplant 14:311-321,2005
31.Ho AD,Wagner W,Franke W.Heterogeneity of mesenchymal stromal cell preparations.Cytotherapy 10:320-330,2008
32.Mitchell KE,Weiss ML,Mitchell BM,Martin P,Davis D,Morales L,Helwig B,Beerenstrauch M,Abou-Easa K,Hildreth T,Troyer D,Medicetty S.Matrix cells from Wharton's jelly form neurons and glia.Stem Cells 21:50-60,2003
33.Banfi A,Muraglia A,Dozin B,Mastrogiacomo M,Cancedda R,Quarto R.Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stroma cells:Implication for their use in cell therapy.Exp Hematol 28:707-715,2000
34.Battula VL,Bareiss PM,Treml S,Conrad S,Albert I,Hojak S,Abele H,Schewe B,Just L,Skutella T,Btlhring HJ.Human placenta and bone marrow derived MSC cultured in serum-free,b-FGF-containing medium express cell surface frizzled-9 and SSEA-4 and give rise to multilineage differentiation.Differentiation 75:279-291,2007
35.Takahashi K,Yamanaka S.Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell 126:663-676,2006
1.Horwitz EM,Le Blanc K,Dominici M,Mueller I,Slaper-Cortenbach I,Marini FC,Deans RJ,Krause DS,Keating A.the International Society for Cellular Therapy.Clarification of the nomenclature for MSC:The International Society for Cellular Therapy position statement.Cytotherapy 7:393-395,2005
2.Nakahara H,Bruder SP,Haynesworth SE,Holecek JJ,Baber MA,Goldberg VM,Caplan AI.Bone and cartilage formation in diffusion chambers by subcultured cells derived from the periosteum.Bone 11:181-188,1990
3.Gronthos S,Mankani M,Brahim J,Robey PG,Shi S.Postnatal human dental pulp stem cells (DPSCs)in vitro and in vivo.Proc Natl Acad Sci USA 97:13625-13630,2000
4.Romanov YA,Svintsitskaya VA,Smirnov VN.Searching for alternative sources of postnatal human mesenchymal stem cells:Candidate MSC-like cells from umbilical cord.Stem Cells 21:105-110,2003
5.Seo BM,MiuraM,Gronthos S,Bartold PM,Batouli S,Brahim J,Young M,Robey PG,Wang CY,Shi S.Investigation of multipotent postnatal stem cells from human periodontal ligament.Lancet 364:149-155,2004
6.Pountos I,Giannoudis PV.Biology of mesenchymal stem cells.Injury 36:S8-S12,2005
7.Bi Y,Ehirchiou D,Kilts TM,Inkson CA,Embree MC,Sonoyama W,Li L,Leet AI,Seo BM,Zhang L,Shi S,Young MF.Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche.Nat Med 13:1219-1227,2007
8.Zannettino AC,Paton S,Arthur A,Khor F,Itescu S,Gimble JM,Gronthos S.Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo.J Cell Physiol 214:413-421,2008
9.Guillot PV,Gotherstrom C,Chan J,Kurata H,Fisk NM.Human first-trimester fetal MSC express pluripotency markers and grow faster and have longer telomeres than adult MSC.Stem Cells 25:646-654,2007
10.Gonzalez R,Maki CB,Pacchiarotti J,Csontos S,Pham JK,Slepko N,Patel A,Silva F.Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells.Biochem Biophys Res Commun 362:491-497,2007
ll.Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krause D,Deans R,Keating A,Prockop D,Horwitz E.Minimal criteria for defining multipotent mesenchymal stromal cells.The International Society for Cellular Therapy position statement.Cytotherapy 8:315-317,2006
12.Keating,A.Mesenchymal stromal cells.Curr Opin Hematol 13:419-425,2006
13.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood 110:3499-3506,2007
14.Abdi R,Fiorina P,Adra CN,Atkinson M,Sayegh MH.Immunomodulation by mesenchymal stem cells:a potential therapeutic strategy for type 1 diabetes.Diabetes 57:1759-1767,2008
15.Krampera M,Glennie S,Dyson J,Scott D,Laylor R,Simpson E,Dazzi F.' Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.Blood 101:3722-3729,2003
16.Di Nicola M,Carlo-Stella C,Magni M,Milanesi M,Longoni PD,Matteucci P,Grisanti S,Gianni AM.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.Blood 99:3838-3843,2002
17.Rasmusson I,Ringd6n 0,Sundberg B,Le Blanc K.Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms.Exp Cell Res 305:33-41,2005
18.Sato K,Ozaki K,Oh I,Meguro A,Hatanaka K,Nagai T,Muroi K,Ozawa K.Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells.Blood 109:228-234,2007
19.Le Blanc K,Rasmusson I,Sundberg B,Gotherstrom C,Hassan M,Uzunel M,Ringd6n 0.Treatment of severe graft versus-host disease with third party haploidentical mesenchymal stem cells.Lancet 363:1439-1441,2004
20.Ringd6n 0,Uzunel M,Rasmusson I,Remberger M,Sundberg B,Lonnies H,Marschall HU,Dlugosz A,Szakos A,Hassan Z,Omazic B,Aschan J,Barkholt L,Le Blanc K.Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.Transplantation 81:1390-1397,2006
21.Mosmann TR,Coffman RL.TH1 and TH2 cells:different patterns of lymphokine secretion lead to different functional properties.Annu Rev Immunol 7:145-173,1989
22.Mosmann TR,Sad S.The expanding universe of T-cell subsets:Th1,Th2and more.Immunol Today 17:138-146,1996
23.Rouvier E,Luciani MF,Mattei MG,Denizot F,Golstein P.CTLA-8,cloned from an activated T cell,bearing AU-rich messenger RNA instability sequences,and homologous to a herpesvirus saimiri gene.J Immunol 150:5445-5456,1993
24.Yao Z,Painter SL,Fanslow WC,Ulrich D,Macduff BM,Spriggs MK,Armitage RJ.Human IL-17:a novel cytokine derived from T cells.J Immunol 155:5483-5486,1995
25.Yao Z,Timour M,Painter S,Fanslow W,Spriggs M.Complete nucleotide sequence of the mouse CTLA8 gene.Gene 168:223-225,1996
26.Fossiez F,Djossou O,Chomarat P,Flores-Romo L,Ait-Yahia S,Maat C,Pin JJ,Garrone P,Garcia E,Saeland S,Blanchard D,Gaillard C,Das Mahapatra B,Rouvier E,Golstein P,Banchereau J,Lebecque S.T cell interleukin-17induces stromal cells to produce proinflammatory and hematopoietic cytokines.J Exp Med 183:2593-2603,1996
27.Romani L.Cell mediated immunity to fungi:a reassessment.Med Mycol 1-15,2008 Mar 12
28.Steinman L.A brief history of T(H)17,the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.Nat Med13:139-145,2007
29.Bronte V.Th17 and cancer:friends or foes? Blood 112:214,2008
30.Langowski JL,Kastelein RA,Oft M.Swords into plowshares:IL-23repurposes tumor immune surveillance.Trends Immunol 28:207-212,2007节 1.08 31.Iwakura Y,Nakae S,Saijo S,Ishigame H.The roles of IL-17A in inflammatory immune responses and host defense against pathogens.Immunol Rev 226:57-79,2008
32.McGeachy MJ,Bak-Jensen KS,Chert Y,Taro CM,Blumenschein W,McClanahan T,Cua DJ.TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.Nat Immunol 8:1390-1397,2007
33.Filaci G,Fravega M,Fenoglio D,Rizzi M,Negrini S,Viggiani R,Indiveri F.Non-antigen specific CD8+T suppressor lymphocytes.Clin Exp Med4:86-92,2004
34.Hegde S,Pahne J,Smola-Hess S.Novel immunosuppressive properties of interleukin-6 in dendritic cells:Inhibition of NF-kappaB binding activity and CCR7 expression.FASEB J 18:1439-1441,2004
35.Fan CG,Tang FW,Zhang QJ,Lu SH,Liu HY,Zhao ZM,Liu B,Han ZB,Han ZC.Characterization and neural differentiation of fetal lung mesenchymal stem cells.Cell Transplant 14:311-321,2005
36.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
37.Krampera M,Cosmi L,Angeli R,Pasini A,Liotta F,Andreini A,Santarlasci V,et al.,Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.Stem Cells 24:386-398,2006
38.Amadi-Obi A,Yu CR,Liu X,Mahdi RM,Clarke GL,Nussenblatt RB,Gery I,Lee YS,Egwuagu CE.TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1.Nat Med 13:711-718,2007
39.Bettelli E,Carrier Y,GaoW,KornT,Strom TB,OukkaM,Weiner HL,Kuchroo VK.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature 441:235-238,2006
40.Veldhoen M,Hocking RJ,Atkins CJ,Locksley RM,Stockinger B.TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity 24:179-189,2006
41.Acosta-Rodriguez EV,Napolitani G,Lanzavecchia A,Sallusto F.Interleukins lbeta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.Nat Immunol 8:942-949,2007
44.Chen Z,Tato CM,Muul L,Laurence A,O'Shea JJ.Distinct regulation of IL-17 in human helper T lymphocytes.Arthritis Rheum 56:2936-2946,2007
45.Wilson NJ,Boniface K,Chan JR,McKenzie BS,Blumenschein WM,Mattson JD,Basham B,Smith K,Chen T,Morel F,Lecron JC,Kastelein RA,Cua DJ,McClanahan TK,Bowman EP,de Waal Malefyt R.Development,cytokine profile and function of human interleukin 17-producing helper T cells.Nat Immunol 8:950-957,2007
46.Fontenot JD,Rasmussen JP,Williams LM,Dooley JL,Farr AG,Rudensky AY.Regulatory T cell lineage specification by the forkhead transcription factor FoxP3.Immunity 22:329-341,2005
47.Sakaguchi S.Naturally arising CD4 regulatory T cells for immunologic selftolerance and negative control of immune responses.Annu Rev Immunol 22:531-562,2004
48.Aggarwal S,Pittenger MF.Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood 105:1815-1822,2005
49.Meisel R,Zibert A,Laryea M,G(o|)bel U,D(a|)ubener W,Dilloo D.Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenasemediated tryptophan degradation.Blood 103:4619-4621,2004
50.Glennie S,Soeiro I,Dyson PJ,Lam EW,Dazzi F.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 105:2821-2827,2005
51.Dong C.TH17 cells in development:an updated viewof their molecular identity and genetic programming.Nat Rev Immunol 8:337-348,2008
52.McGeachy MJ,Cua DJ.Th17 cell differentiation:the long and winding road.Immunity 28:445-453,2008
53.Zhou L,Ivanov Ⅱ,Spolski R,Min R,Shenderov K,Egawa T,Levy DE,Leonard WJ,Littman DR.IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways.Nat Immunol 8:967-974,2007
54.Veldhoen M,Hocking RJ,Atkins CJ,Locksley RM,Stockinger B.TGFb in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity 4:179-189,2006
55.Matusevicius D,Kivis(a|)kk P,He B,Kostulas N,Ozenci V,Fredrikson S,Link H.Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.Mult Scler 5:101-104,1999
56.Lind(?)n A,Hoshino H,Laan M.Airway neutrophils and interleukin-17.Eur Respir J 15:973-977,2000
57.Wong CK,Ho CY,Li EK,Lam CW.Elevation of proinflammatory cytokine (IL-18,IL-17,IL-12) and Th2 cytokine(IL-4) concentrations in patients with systemic lupus erythema- tosus.Lupus 9:589-593,2000
58.Laan M,Lotvall J,Chung KF,Linden A.IL-17-induced cytokine release in human bronchial epithelial cells in vitro:role of mitogen-activated protein(MAP) kinases.Br J Pharmacol 133:200-206,2001
59.Hwang sg,Kim JY,Kim KW,Park MK,Moon Y,Kim WU,Kim HY.IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kB- and PI3- kinase/Akt-dependent pathways.Arthritis Res Ther 6:R120-R128,2004
60.Schwandner R,Yamaguchi K,Cao Z.Requirement of tumor necrosis factor receptor-associated factor(TRAF)6 in interleukin 17 signal transduction.J Exp Med 191:1233-1240,2000
61.Shen F,Hu Z,Goswami J,Gaffen SL.Identification of common transcriptional regulatory elements in interleukin-17 target genes.J Biol Chem 281:24138-24148,2006
62.Uccelli A,Moretta L,Pistoia V.Uesenchymal stem cells in health and disease.Nat Rev Immunol 8:726-36,2008
63.Aggarwal S,Pittenger MF.Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood 105:1815-1822,2005
64.Di Ianni M,Del Papa B,De Ioanni M,Moretti L,Bonifacio E,Cecchini D,Sportoletti P,Falzetti F,Tabilio A.Mesenchymal cells recruit and regulate T regulatory cells.Exp Hematol 36:309-318,2008
1.Prockop DJ.Marrow stromal cells as stem cells for nonhematopoietic tissues.Science 276:71-74,1997
2.Dennis JE,AIC.Stem Cells Handbook.Totowa,NJ,Human Press,2004
3.Friedenstein AJ,Piatetzky S Ⅱ,Petrakova KV.Osteogenesis in transplants of bone marrow cells.J Embryol Exp Morphol 16:381-390,1966
4.Friedenstein AJ,Petrakova KV,Kurolesova AI,Frolova GP.Heterotopic of bone marrow:analysis of precursor cells for osteogenic and hematopoietic tissues.Transplantation 6:230-247,1968
5.Owen M.Marrow stromal stem cells.J Cell Sci Suppl 10:63-76,1988
6.Friedenstein AJ,Chailakhyan RK,Latsinik NV,Panasyuk AF,Keiliss-Borok IV.Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues.Cloning in vitro and retransplantation in vivo.Transplantation 17:331-340,1974
7.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
8.Kopen GC,Prockop DJ,Phinney DG.Marrow stromal cells migrate throughout forebrain and cerebellum,and they differentiate into astrocytes after injection into neonatal mouse brains.Proc Natl Acad Sci USA 96:10711-10716,1999
9.Dennis JE,Charbord P.Origin and differentiation of human and murine stroma.Stem Cells 20:205-214,2002
10.Takashima Y,Era T,Nakao K,Kondo S,Kasuga M,Smith AG,Nishikawa S.Neuroepithelial cells supply an initial transient wave of MSC differentiation.Cell 129:1377-1388,2007
11.Phinney DG,Hill K,Michelson C,DuTreil M,Hughes C,Humphries S,Wilkinson R,Baddoo M,Bayly E.Biological activities encoded by the murine mesenchymal stem cell transcriptome provide a basis for their developmental potential and broad therapeutic efficacy.Stem Cells 24:186-198,2006
12.Pedemonte E,Benvenuto F,Casazza S,Mancardi G,Oksenberg JR,Uccelli A,Baranzini SE.The molecular signature of therapeutic mesenchymal stem cells exposes the architecture of the hematopoietic stem cell niche synapse.BMC Genomics 8:65,2007
13.Phinney DG,Prockop D J.Mesenchymal stem/multi-potent stromal cells (MSCs):the state of transdifferentiation and modes of tissue repair —current views.Stem Cells 25:2896-2902,2007
14.Pedemonte E,Benvenuto F,Casazza S,Mancardi G,Oksenberg JR,Uccelli A,Baranzini SE.Repair of large bone defects with the use of autologous bone marrow stromal cells.N Engl J Med 344:385-386,2001
15.Caplan AI.Mesenchymal stem cells.J Orthop Res 9:641-650,1991
16.Horwitz EM,Le Blanc K,Dominici M,Mueller I,Slaper-Cortenbach I,Marini FC,Deans RJ,Krause DS,Keating A.Clarification of the nomenclature for MSC:The International Society for Cellular Therapy position statement.Cytotherapy 7:393-395,2005
17.Pittenger MF,Martin BJ.Mesenchymal stem cells and their potential as cardiac therapeutics.Circ Res 95:9-20,2004
18.Sacchetti B,Funari A,Michienzi S,Di Cesare S,Piersanti S,Saggio I,Tagliafico E,Ferrari S,Robey PG,Riminucci M,Bianco P.Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.Cell 131:324-336,2007
19.Fibbe WE.Mesenchymal stem cells:a potential source for skeletal repair.Ann Rheum Dis 61(Suppl.2):ii29-ii31,2002
20.da Silva Meirelles L,Chagastelles PC,Nardi NB.Mesenchymal stem cells reside in virtually all post-natal organs and tissues.J Cell Sci 119:2204-2213,2006
21.Keyser KA,Beagles KE,Kiem HP.Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation.Cell Transplant 16:555-562,2007
22.Sugiyama T,Kohara H,Noda M,Nagasawa T.Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches.Immunity 25:977-988,2006
23.Chamberlain G,Fox J,Ashton B,Middleton J.Concise review:mesenchymal stem cells:their phenotype,differentiation capacity,immunological features,and potential for homing.Stem Cells 25:2739-2749,2007
24.Pittenger MF,Mackay AM,Beck SC,Jaiswal RK,Douglas R,Mosca JD,Moorman MA,Simonetti DW,Craig S,Marshak DR.Multilineage potential of adult human mesenchymal stem cells.Science 284:143-147,1999
25.Tyndall A,Walker UA,Cope A,Dazzi F,De Bari C,Fibbe W,Guiducci S,Jones S,Jorgensen C,Le Blanc K,Luyten F,McGonagle D,Martin I,Bocelli-Tyndall C,Pennesi G,Pistoia V,Pitzalis C,Uccelli A,Wulffraat N,Feldmann M.Immunomodulatory properties of mesenchymal stem cells:a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division,London,UK,31 October 2005.Arthritis Res Ther9:301,2007
26.Schofield R.The relationship between the spleen colony-forming cell and the haemopoietic stem cell.Blood Cells 4:7-25,1978
27.Bocelli-Tyndall C,Barbero A,Candrian C,Ceredig R,Tyndall A,Martin I.Human articular chondrocytes suppress in vitro proliferation of anti-CD3 activated peripheral blood mononuclear cells.J Cell Physiol 209:732-734,2006
28.Jones S,Horwood N,Cope A,Dazzi F.The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells.J.Immunol.179:2824-2831,2007
29.Haniffa MA,Wang XN,Holtick U,Rae M,Isaacs JD,Dickinson AM,Hilkens CM,Collin MP.Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells.J.Immunol.179:1595-1604,2007
30.Parsonage G,Filer AD,Haworth O,Nash GB,Rainger GE,Salmon M,Buckley CD.A stromal address code defined by fibroblasts.Trends Immunol 26:150-156,2005
31.Bartholomew A,Sturgeon C,Siatskas M,Ferrer K,Mcintosh K,Patil S,Hardy W,Devine S,Ucker D,Deans R,Moseley A,Hoffman R.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol 30:42-48,2002
32.Le Blanc K,Tammik L,Sundberg B,Haynesworth SE,Ringden O.Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex.Scand J Immunol 57:11-20,2003
33.Krampera M,Glennie S,Dyson J,Scott D,Laylor R,Simpson E,Dazzi F.Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.Blood 101:3722-3729,2003
34.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood 110:3499-3506,2007
35.Meisel R,Zibert A,Laryea M,Gobel U,Daubener W,Dilloo D.Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation.Blood 103:4619-4621,2004
36.Sato K,Ozaki K,Oh I,Meguro A,Hatanaka K,Nagai T,Muroi K,Ozawa K.Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells.Blood 109:228-234,2007
37.Chabannes D,Hill M,Merieau E,Rossignol J,Brion R,SoulillouJP,Anegon I,Cuturi MC.A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells.Blood 110:3691-3694,2007
38.Ryan JM,Barry FP,Murphy JM,Mahon BP.Mesenchymal stem cells avoid allogeneic 'rejection.J Inflamm (Lond)2:8,2005
39.Nauta AJ,Kruisselbrink AB,Lurvink E,Willemze R,Fibbe WE.Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells.J Immunol 177:2080-2087,2006
40.Jiang XX,Zhang Y,Liu B,Zhang SX,Wu Y,Yu XD,Mao N.Human mesenchymal stem cells inhibit differentiation and function of monocytederived dendritic cells.Blood 105:4120-4126,2005
41.Ramasamy R,Fazekasova H,Lam EW,Soeiro I,Lombardi G,Dazzi F.Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle.Transplantation 83:71-76,2007
42.Aggarwal S,Pittenger MF.Human mesenchymal stem cells modulate allogeneic immune cell responses.Blood 105:1815-1822,2005
43.Beyth S,Borovsky Z,Mevorach D,Liebergall M,Gazit Z,Asian H,Galun E,Rachmilewitz J.Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness.Blood 105:2214-2219,2005
44.Maccario R,Podesta M,Moretta A,Cometa A,Comoli P,Montagna D,Daudt L,Ibatici A,Piaggio G,Pozzi S,Frassoni F,Locatelli F.Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype.Haematologica 90:516-525,2005
45.Moretta A.Natural killer cells and dendritic cells:rendezvous in abused tissues.Nature Rev Immunol 2:957-964,2002
46.Moretta A,Bottino C,Vitale M,Pende D,Biassoni R,Mingari MC,Moretta L.Receptors for HLA class-I molecules in human natural killer cells.Annu Rev Immunol 14:619-648,1996
47.Moretta A,Bottino C,Vitale M,Pende D,Cantoni C,Mingari MC,Biassoni R,Moretta L.Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.Annu Rev Immuno 19:197-223,2001
48.Spaggiari GM,Capobianco A,Becchetti S,Mingari MC,Moretta L.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.Blood 107:1484-1490,2006
49.Spaggiari GM,Capobianco A,Abdelrazik H,Becchetti F,Mingari MC,Moretta L.Mesenchymal stem cells inhibit natural killer-cell proliferation,cytotoxicity,and cytokine production:role of indoleamine 2,3-dioxygenase and prostaglandin E2.Blood 111:1327-1333,2008
50.Sotiropoulou PA,Perez SA,Gritzapis AD,Baxevanis CN,Papamichail M.Interactions between human mesenchymal stem cells and natural killer cells.Stem Cells 24:74-85,2006
51.Selmani Z,Naji A,Zidi I,Favier B,Gaiffe E,Obert L,Borg C,Saas P,Tiberghien P,Rouas-Freiss N,Carosella ED,Deschaseaux F.Human leukocyte antigen~G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highF0XP3+ regulatory T cells.Stem Cells 2§:2\2-222,2008
52.Rasmusson I,Ringden 0,Sundberg B,Le Blanc K.Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes,but not activated cytotoxic T lymphocytes or natural killer cells.Transplantation 76:1208-1213,2003
53.Krampera M,Cosmi L,Angeli R,Pasini A,LiottaF,Andreini A,Santarlasci V,Mazzinghi B,Pizzolo G,Vinante F,Romagnani P,Maggi E,Romagnani S,Annunziato F.Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells.Stem Cells 24:386-398,2006
54.Poggi A,Prevosto C,Massaro AM,Negrini S,Urbani S,Pierri I,Saccardi R,Gobbi M,Zocchi MR.Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering:role of NKp30 and NKG2D receptors.J Immunol 175:6352-6360,2005
55.Raffaghello L,Bianchi G,Bertolotto M,Montecucco F,Busca A,Dallegri F,Ottonello L,Pistoia V.Human mesenchymal stem cells inhibit neutrophil apoptosis:a model for neutrophil preservation in the bone marrow niche.Stem Cells 26:151-162,2008
56.Fadeel B,Ahlin A,Henter JI,Orrenius S,Hampton MB.Involvement of caspases in neutrophil apoptosis:regulation by reactive oxygen species.Blood 92:4808-4818,1998
57.Craddock CG,Jr Perry S,Ventzke LE,Lawrence JS.Evaluation of marrow granulocytic reserves in normal and disease states.Blood 15:840-855,1960
58.Di Nicola M,Carlo-Stella C,Magni M,Milanesi M,Longoni PD,Matteucci P,Grisanti S,Gianni AM.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.Blood 99:3838-3843,2002
59.Tse WT,Pendleton JD,Beyer WM,Egalka MC,Guinan EC.Suppression of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation.Transplantation 75:389-397,2003
60.Rasmusson I,Ringden 0,Sundberg B,Le Blanc K.Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms.Exp Cell Res 305:33-41,2005
61.Glennie S,Soeiro I,Dyson PJ,Lam EW,Dazzi F.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 105:2821-2827,2005
62.Ren G,Zhang L,Zhao X,Xu G,Zhang Y,Roberts AI,Zhao RC,Shi Y.Mesenchymal stem-cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.Cell Stew Cell 2:141-150,2008
63.Benvenuto F,Ferrari S,Gerdoni E,Gualandi F,Frassoni F,Pistoia V,Mancardi G,Uccelli A.Human mesenchymal stem cells promote survival of T cells in a quiescent state.Stem Cells 25:1753-1760,2007
64.Augello A,Tasso R,Negrini SM,Amateis A,Indiveri F,Cancedda R,Pennesi G.Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway.Eur J Immunol 35:1482-1490,2005
65.Rasmusson I,Uhlin M,Le Blanc K,Levitsky V.Mesenchymal stem cells fail to trigger effector functions of cytotoxic T lymphocytes.J Leukocyte Biol 82:887-893,2007
66.Morandi F,Raffaghello L,Bianchi G,Meloni F,Salis A,Millo E,Ferrone S,Barnaba V,Pistoia V.Immunogenicity of human mesenchymal stem cells in HLA-class-I-restricted T-cell responses against viral or tumor-associated antigens.Stem Cells 26:1275-1287,2008
67.Pevsner-Fischer M,Morad V,Cohen-Sfady M,Rousso-Noori L,Zanin-Zhorov A,Cohen S,Cohen IR,Zipori D.Toll-like receptors and their ligands control mesenchymal stem cell functions.Blood 109:1422-1422,2007
68.Tomchuck SL,Zwezdaryk KJ,Coffelt SB,Waterman RS,Danka ES,Scandurro AB.Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses.Stem Cells 26:99-107,2008
69.Hwa ChoH,Bae YC,Jung JS.Role of Toll-like receptors on human adipose-derived stromal cells.Stem Cells 24:2744-2752,2006
70.Liotta F,Angeli R,Cosmi L,Fill L,Manuelli C,Frosali F,Mazzinghi B,Maggi L,Pasini A,Lisi V,Santarlasci V,Consoloni L,Angelottr ML,Romagnani P,Parronchi P,Krampera M,Maggi E,Romagnani S,Annunziato F.Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling.Stem Cells 26:279-289,2008
71.Svensson M,Kaye PM.Stromal-cell regulation of dendritic-cell differentiation and function.Trends Immunol 27:580-587,2006
72.Traggiai E,Volpi S,Schena F,Gattorno M,Ferlito F,Moretta L,Martini A.Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients.Stem Cells 26:562-569,2008
73.Corcione A,Benvenuto F,Ferretti E,Giunti D,Cappiello V,Cazzanti F,Risso M,Gualandi F,Mancardi GL,Pistoia V,Uccelli A.Human mesenchymal stem cells modulate B-cell functions.Blood 107:367-372,2006
74.Rasmusson I,Le Blanc K,Sundberg B,Ringden 0.Mesenchymal stem cells stimulate antibody secretion in human B cells.Scand J Immunol 65:336-343,2007
75.Gerdoni E,GalloB,Casazza S,Musio S,Bonanni I,Pedemonte E,Mantegazza R,Frassoni F,Mancardi G,Pedotti R,Uccelli A.Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis.Ann Neurol 61:219-227,2007
76.Deng W,Han Q,Liao L,You S,Deng H,Zhao RC.Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice.DNA Cell Biol 24:458-463,2005
77.Stagg J,Pommey S,Eliopoulos N,Galipeau J.Interferon-y-stimulated marrow stromal cells:a new type of nonhematopoietic antigen-presenting cell.Blood 107:2570-2577,2006
78.Chan JL,Tang KC,Patel AP,Bonilla LM,Pierobon N,Ponzio NM,Rameshwar P.Antigen presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-y.Blood 107:4817-4824,2006
79.Feuerer M,Beckhove P,Garbi N,Mahnke Y,Limmer A,Hommel M,Hammerling GJ,Kyewski B,Hamann A,Umansky V,Schirrmacher V.Bone marrow as a priming site for T-cell responses to blood-borne antigen.Nature Med 9:1151-1157,2003
80.Fox JM,Chamberlain G,Ashton BA,M'iddleton J.Recent advances into the understanding of mesenchymal stem cell trafficking.Br J Haematol 137:491-502,2007
81.Nauta AJ,Westerhuis G,Kruisselbrink AB,Lurvink EG,Willemze R,Fibbe WE.Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting.Blood 108:2114-2120,2006
82.Le Blanc K,Tammik C,Rosendahl K,Zetterberg E,Ringden O.HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol 31:890-896,2003
83.Klyushnenkova E,Mosca JD,Zernetkina V,Majumdar MK,Beggs KJ,Simonetti DW,Deans RJ,Mcintosh KR.T cell responses to allogeneic human mesenchymal stem cells:immunogenicity,tolerance,and suppression.J Biomed Sci 12:47-57,2005
84.Le Blanc K,Ringden 0.Immunomodulation by mesenchymal stem cells and clinical experience.J In tern Med 262:509-525,2007
85.Morigi M,Imberti B,Zoja C,Corna D,Tomasoni S,Abbate M,Rottoli D,Angioletti S,Benigni A,Perico N,Alison M,Remuzzi G.Mesenchymal stem cells are renotropic,helping to repair the kidney and improve function in acute renal failure.J Am Soc Nephrol 15:1794-1804,2004
86.Duffield JS,Park KM,Hsiao LL,Kelley VR,Scadden DT,Ichimura T,Bonventre JV.Restoration of tubular epithelial cells during repair of the postischemic kidney occurs independently of bone marrow-derived stem cells.J Clin Invest 115:1743-1755,2005
87.Lee RH,Seo MJ,Reger RL,Spees JL,Pulin AA,Olson SD,Prockop DJ.Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice.Proc Natl Acad Sci USA 103:17438-17443,2006
88.Zappia E,Casazza S,Pedemonte E,Benvenuto F,Bonanni I,Gerdoni E,Giunti D,Ceravolo A,Cazzanti F,Frassoni F,Mancardi G,Uccelli A.Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy.Blood 106:1755-1761,2005
89.Augello A,Tasso R,Negrini SM,Cancedda R,Pennesi G.Cell Therapy Using Allogeneic Bone Marrow Mesenchymal Stem Cells Prevents Tissue Damage in Collagen-Induced Arthritis.Arthritis & Rheumatism 56:1175-1186,2007
90.Itakura S,Asari S,Rawson J,Ito T,Todorov I,Liu CP,Sasaki N,Kandeel F,Mullen Y.Mesenchymal stem cells facilitate the induction of mixed hematopoietic chimerism and islet allograft tolerance without GVHD in the rat.Am J Transplant 7:336-346,2007
91.Le Blanc K,Rasmusson I,Sundberg B,Gotherstrom C,Hassan M,Uzunel M,Ringden O.Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.Lancet 363:1439-1441,2004
92.Ringden 0,Uzunel M,Rasmusson I,Remberger M,Sundberg B,Lonnies H,Marschall HU,Dlugosz A,Szakos A,Hassan Z,Omazic B,Aschan J,Barkholt L,Le Blanc K.Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease.Transplantation 81:1390-1397,2006
93.Yanez R,Lamana ML,Garcia-Castro J,Colmenero I,Ramirez M,Bueren JA.Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease.Stem Cells Dev 24:2582-2591,2006
94.Sudres M,Norol F,Trenado A,Gregoire S,Charlotte F,Levacher B,Lataillade JJ,Bourin P,Holy X,Vernant JP,Klatzmann D,Cohen JL.Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice.J Immunol 176:7761-7767,2006
95.Inoue S,Popp FC,Koehl GE,Piso P,Schlitt HJ,Geissler EK,Dahlke MH.Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant mode1.Transplantation 81:1589-1595,2006
96.Ryan JM,Barry F,Murphy JM,Mahon BP.Interferon-y does not break,but promotes the immunosuppressive capacity of adult human mesenchymal stem cells.Clin Exp Immunol 149:353-363,2007
97.Kogler G,Radke TF,Lefort A,Sensken S,Fischer J,Sorg RV,Wernet P.Cytokine production and hematopoiesis supporting activity of cord bloodderived unrestricted somatic stem cells.Exp Hematol 33:573-583,2005
98.Djouad F,Charbonnier LM,Bouffi C,Louis-Plence P,Bony C,Apparailly F,Cantos C,Jorgensen C,Noel D.Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism.Stem Cells 25:2025-2032,2007
99.Almeida-Porada G,Porada CD,Tran N,Zanjani ED.Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation.Blood95:3620-3627,2000
100.Pereira RF,Halford KW,0'Hara MD,Leeper DB,Sokolov BP,Pollard MD,Bagasra 0,Prockop DJ.Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone,cartilage,and lung in irradiated mice.Proc Natl Acad Sci USA 92:4857-4861,1995
101.Eliopoulos N,Stagg J,Lejeune L,Pommey S,Galipeau J.Allogeneic marrow stromal cells are immune rejected by MHC class I-and class Ⅱ-mismatched recipient mice.Blood 106:4057-4065,2005
102.Murphy JM,Dixon K,Beck S,Fabian D,Feldman A,Barry F.Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis.Arthritis Rheum 46:704-713,2002
103.Papadaki HA,Tsagournisakis M,Mastorodemos V,Pontikoglou C,Damianaki A,Pyrovolaki K,Stamatopoulos K,Fassas A,Plaitakis A,Eliopoulos GD.Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis.Bone Marrow Transplant 36:1053-1063,2005
104.Kastrinaki MC,Sidiropoulos P,Roche S,Ringe J,Lehmann S,Kritikos H,Vlahava VM,Delorme B,Eliopoulos GD,Jorgensen C,Charbord P,H(a|¨)upl T, Boumpas DT,Papadaki HA.Functional,molecular and proteomic characterization of bone marrow mesenchymal stem cells in rheumatoid arthritis.Ann Rheum Dis 67:741-749,2008
105.Bacigalupo A,Valle M,Podesta M,Pitto A,Zocchi E,De Flora A,Pozzi S,Luchetti S,Frassoni F,Van Lint MT,Piaggio G.T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia.Exp Hematol 33:819-827,2005
106.Arnulf B,Lecourt S,Soulier J,Ternaux B,Lacassagne MN,Crinquette A,Dessoly J,Sciaini AK,Benbunan M,Chomienne C,Fermand JP,Marolleau JP,Larghero J.Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma.Leukemia 21:158-163,2007
107.Devine SM,Cobbs C,Jennings M,Bartholomew A,Hoffman R.Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into non-human primates.Blood 101:2999-3001,2003
108.Li Y,Chen J,Chen XG,Wang L,Gautam SC,Xu YX,Katakowski M,Zhang LJ,LuM,Janakiraman N,ChoppM.Human marrow stromal cell therapy for stroke in rat:neurotrophins and functional recovery.Neurology 59:514-523,2002
109.RUsterB,Gottig S,Ludwig RJ,Bistrian R,Müller S,Seifried E,Gille J,Henschler R.Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells.Blood 108:3938-3944,2006
110.Sordi V,Malosio ML,Marchesi F,Mercalli A,Melzi R,Giordano T,Belmonte N,Ferrari G,Leone BE,Bertuzzi F,Zerbini G,AllavenaP,Bonifacio E,Piemonti L.Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets.Blood 106:419-427,2005
111.Son BR,Marquez-Curtis LA,Kucia M,Wysoczynski M,Turner AR,Ratajczak J,Ratajczak MZ,Janowska-Wieczorek A.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~Met axes and involves matrix metalloproteinases.Stem Cells 24:1254-1264,2006
112.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol 28:219-226,2007
113.Munoz JR,Stoutenger BR,Robinson AP,Spees JL,Prockop DJ.Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice.Proc.Natl Acad.Sci.USA 102:18171-18176,2005
114.Rivera FJ,Couillard-Despres S,Pedre X,Ploetz S,Caioni M,Lois C,Bogdahn U,Aigner L Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells.Stem Cells 24:2209-2219,2006
115.Urbdn VS,Kiss J,Kovdcs J,G6cza E,Vas V,Monostori E,Uher F.Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes.Stem Cells 26:244-253,2008
116.Togel F,Hu Z,Weiss K,Isaac J,Lange C,Westenfelder C.Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.Am J Physiol Renal Physiol 289:F31-F42,2005
117.Ortiz LA,Dutreil M,Fattman C,Pandey AC,Torres G,Go K,Phinney DG.Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc.Natl Acad.Sci.USA 104:11002-11007,2007
118.Mirotsou M,Zhang Z,Deb A,Zhang L,Gnecchi M,Noiseux N,Mu H,Pachori A,Dzau V.Secreted frizzled related protein 2 (Sfrp2)is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair.Proc Natl Acad Sci USA 104:1643-1648,2007
119.Ramasamy R,Lam EW,Soeiro I,Tisato V,Bonnet D,Dazzi F.Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells:impact on in vivo tumor growth.Leukemia 21:304-310,2007
120.Djouad F,Plence P,Bony C,Tropel P,Apparailly F,Sany J,No(e|¨)l D,Jorgensen C.Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals.Blood 102:3837-3844,2003
121.Ame-Thomas P,Maby-El Hajjami H,Monvoisin C,Jean R,Monnier D,Caulet-MaugendreS,Guillaudeux T,Lamy T,Fest T,Tarte K.Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth:role of stromal cells in follicular lymphoma pathogenesis.Blood 109:693-702,2007
122.Khakoo AY,Pati S,Anderson SA,Reid W,Elshal MF,Rovira Ⅱ,Nguyen AT,Malide D,Combs CA,Hall G,Zhang J,Raff eld M,Rogers TB,Stetler-Stevenson W,Frank JA,Reitz M,Finkel T.Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 203:1235-1247,2006
123.Karnoub AE,Dash AB,Vo AP,Sullivan A,Brooks MW,Bell GW,Richardson AL,Polyak K,Tubo R,Weinberg RA.Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.Nature 449:557-563,2007
124.Liotta LA,Kohn EC.The microenvironment of the tumour-host interface.Nature 411:375-379,2001
125.Horwitz EM,Prockop DJ,Fitzpatrick LA,Koo WW,Gordon PL,Neel M,Sussman M,Orchard P,Marx JC,Pyeritz RE,Brenner MK.Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta.Nature Med 5:309-313,1999
126.Koc ON,Gerson SL,Cooper BW,Dyhouse SM,Haynesworth SE,Caplan AI,Lazarus HM.Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving highdose chemotherapy.J Clin Oncol 18:307-316,2000
127.Ning H,Yang F,Jiang M,Hu L,Feng K,Zhang J,Yu Z,Li B,Xu C,Li Y,Wang J,Hu J,Lou X,Chen H.The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients:outcome of a pilot clinical study.Leukemia 22:593-599,2008
128.Ball LM,Bernardo ME,Roelofs H,Lankester A,Cometa A,Egeler RM,Locatelli F,Fibbe WE.Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation.Blood 110:2764-2767,2007
129.Okamoto R,Yajima T,Yamazaki M,Kanai T,Mukai M,Okamoto S,Ikeda Y,Hibi T,Inazawa J,Watanabe M.Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract.Nature Med 8:1011-1017,2002
130.Mazzini L,Mareschi K,Ferrero I,Vassallo E,Oliveri G,Boccaletti R,Testa L,Livigni S,Fagioli F.Autologous mesenchymal stem cells:clinical applications in amyotrophic lateral sclerosis.Neurol Res 28:523-526,2006
131.Koc ON,Day J,Nieder M,Gerson SL,Lazarus HM,Krivit W.Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD)and Hurler syndrome (MPS-IH).Bone Marrow Transplant 30:215-222,2002
132.Numaguchi Y,Sone T,Okumura K,Ishii M,Morita Y,Kubota R,Yokouchi K,Imai H,Harada M,Osanai H,Kondo T,Murohara T.The impact of the capability of circulating progenitor cell to differentiate on myocardial salvage in patients with primary acute myocardial infarction.Circulation 114:1114-1119,2006
133.Tolar J,Nauta AJ,Osborn MJ,Panoskaltsis Mortari A,McElmurry RT,Bell S,XiaL,Zhou N,Riddle M,SchroederTM,Westendorf J J,Mclvor RS,Hogendoorn PC,Szuhai K,Oseth L,Hirsch B,Yant SR,Kay MA,Peister A,Prockop DJ,Fibbe WE,Blazar BR.Sarcoma derived from cultured mesenchymal stem cells.Stem Cells 25:371-379,2007
134.Breitbach M,Bostani T,Roell W,Xia Y,Dewald 0,Nygren JM,Fries JW,Tiemann K,Bohlen H,Hescheler J,Welz A,Bloch W,Jacobsen SE,Fleischmann BK.Potential risks of bone marrow cell transplantation into infarcted hearts.Blood 110:1362-1369,2007
135.Atsma DE,Fibbe WE,Rabelink TJ.Opportunities and challenges for mesenchymal stem cell-mediated heart repair.Curr Opin Lipidol 18:645-649,2007
136.Wilson A,TrumppA.Bone-marrow haematopoietic-stem-cell niches.Nature Rev Immunol 6:93-106,2006
137.Kiel MJ,Morrison SJ.Uncertainty in the niches that maintain haematopoietic stem cells.Nature Rev Immunol 8:290-301,2008
138.Stier S,Ko Y,Forkert R,Lutz C,Neuhaus T,Grünewald E,Cheng T,Dombkowski D,Calvi LM,Rittling SR,Scadden DT.Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size.J Exp Med 201:1781-1791,2005
139.Arai F,Hirao A,Ohmura M,Sato H,Matsuoka S,Takubo K,Ito K,Koh GY,Suda T.Tie2/angiopoietin-l signaling regulates hematopoietic stem cell quiescence in the bone marrow niche.Cell 118:149-161,2004
140.Martino G,Pluchino S.The therapeutic potential of neural stem cells.Nature Rev Neurosci 7:395-406,2006
141.Duncan AW,Rattis FM,DiMascio LN,Congdon KL,Pazianos G,Zhao C,Yoon K,Cook JM,Willert K,Gaiano N,Reya T.Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance.Nature Immunol 6:314-322, 2005
142.Rubio D,Garcia-Castro J,Martin MC,de la Fuente R,Cigudosa JC,Lloyd AC,Bernad A.Spontaneous human adult stem cell transformation.Cancer Res 65:3035-3039,2005
143.Bernardo ME,Zaffaroni N,Novara F,Cometa AM,Avanzini MA,Moretta A,Montagna D,Maccario R,Villa R,Daidone MG,Zuffardi O,Locatelli F.Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms.Cancer Res 67:9142-9149,2007