异基因骨髓间充质干细胞移植对胶原诱导关节炎大鼠治疗作用机制的研究
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摘要
【背景】
类风湿关节炎(Rheumatoid arthritis,RA)是一种高度致残性自身免疫性疾病,在我国RA的发病率约0.34%,患病总人数达500万,每年直接用于RA的治疗费用和因劳动力丧失带来的间接经济损失很大。近年的研究发现间充质干细胞(Mesenchymal Stem Cells,MSCs)具有免疫调节作用,同时MSCs可迁移到损伤和炎症部位,在局部微环境作用下分化为外胚层、中胚层细胞,甚至内胚层细胞,参与组织重建和修复,这些为RA患者的免疫抑制治疗,以及受损关节的修复带来了新的希望。
【目的】
通过对RA动物模型胶原诱导关节炎(CIA)大鼠的实验研究,观察异基因MSCs移植对(早期、晚期)CIA大鼠免疫细胞和分子的免疫学作用,并探讨其在体内发挥免疫调节作用的机制;观察异基因MSCs移植在CIA大鼠免疫器官和关节炎症部位的归巢和分布,并探讨其修复损伤关节可能的机制。
【方法】
第一部分:采用密度梯度离心结合贴壁培养法体外分离、培养大鼠MSCs,细胞表型鉴定。
第二部分:(1)弗氏完全佐剂+Ⅱ型胶原初次免疫雌性Wistar大鼠,14d弗氏完全佐剂+Ⅱ型胶原第2次免疫动物,建立CIA大鼠模型。(2)大鼠分为早期治疗组(佐剂初次诱导时治疗组)和晚期治疗组(再次诱导时治疗组),同时设立正常组和早、晚期CIA对照组,每组8只。(3)MSCs移植均采用尾静脉注射,每只大鼠移植的细胞数为1×10~7个/Kg;对照组以同样方法给予等容量的生理盐水。(4)观察42天不同分组大鼠的关节症状及进行关节炎指数和肿胀度测定。(5)MSCs移植后第42天全部处死动物取脾,通过CCK-8测定T细胞、B细胞的增殖;RT-PCR测定Foxp3 mRNA的表达水平;流式细胞术测定CD4~+CD25~+调节性T细胞的变化,ELISA测定外周血TGF-β、IL-17和TNF-α,收集数据并做统计分析。
第三部分:(1) PKH-26和Brdu标记MSCs。(2)将64只大鼠随即分成正常组和CIA组,均给予MSCs移植。(3)移植后第3、11、30、42天分别处死8只动物,取不同分组大鼠的胸腺、脾和关节组织制作病理切片,共聚焦显微镜联合免疫组化技术,观察MSCs移植后不同时点在不同脏器的迁移和分布。
【结果】
1.大鼠MSCs为均一的梭形的成纤维细胞样生长,贴壁及增殖能力强,生长曲线呈S型;流式细胞术鉴定为间充质干细胞。
2.早晚期MSCs治疗组AI、后肢足肿胀度均较CIA对照组明显改善(P＜0.05),早期治疗组与晚期治疗组比较,关节炎指数较低,差异有统计学意义(P＜0.05)。
3.早晚期CIA对照组Treg水平低于正常组和治疗组,差异有统计学意义(P＜0.05);早期治疗组Treg比晚期治疗组有所升高,差异有统计学意义(P＜0.05)。
4.早晚期CIA对照组Foxp3 mRNA的表达水平比正常组和治疗组低,差异有统计学意义(P＜0.05);早期治疗组与晚期治疗组比较差异无统计学意义(P＞0.05),Foxp3 mRNA的表达水平与正常组接近。
5.早晚期CIA对照组T、Bcell增殖水平明显高于正常组和治疗组,差异有统计学意义(P＜0.05);早期MSCs治疗组Tcell水平低于晚期治疗组(P＜0.05),早晚期治疗组Bcell水平接近(P＞0.05)。
7.早晚期CIA对照组TGF-β1水平较正常组和治疗组低(P＜0.05),早期治疗组TGF-β1水平高于晚期治疗组,差异有统计学意义(P＜0.05)。早晚期CIA对照组血清IL-17和TNF-α水平较正常组和治疗组升高(P＜0.05),其中早期治疗组MSCs对IL-17的抑制优于晚期治疗组,差异有统计学意义(P＜0.05);早晚期MSCs治疗组TNF-α被抑制的程度接近,差异无统计学意义(P＞0.05)。
8.异基因骨髓MSCs移植在CIA大鼠的脾脏、胸腺、关节炎症部位可较长期(42天)的存在,归巢的MSCs细胞数量明显高于正常组。
【结论】
1.体外分离、培养大鼠骨髓MSCs呈现均一的成纤维细胞样生长,贴壁及增殖能力强。
2.异基因MSCs移植对(早期、晚期)CIA大鼠的关节炎症状、滑膜病理都有所改善,并通过上调CIA大鼠体内Treg水平,促进Foxp3 mRNA的表达及TGF-β的分泌,抑制T、B淋巴细胞的增殖,减少血清中TNF-α、IL-17的含量,而发挥其在体内的免疫调节作用;早期治疗组的疗效优于晚期治疗组。
3.异基因骨髓MSCs移植在CIA大鼠的脾脏、胸腺、关节炎症部位可较长期(42天)的存在;移植的MSCs优先定位于受损伤的组织和器官而发挥其治疗作用。
Background
Rheumatoid arthritis is a highly disabled autoimmune disease.Disease incidence is about 0.34%in China and the total patients are 5 millions.There is a big indirect economic loss because of treatment and loss of work ability.Recent study showed that mesenchymal stem cells have immuno-regulation effect,at the same time MSCs can move to injury and inflammatory area in microenvironment.It can differentiate to dermal layer,mesoblast and endoderm,participating in tissue rebuilding and restoration.All of these bring a hope for RA patients.
Objective
To observe the immunologic effect of transplantation of MSCs through studying early and later period of Collagen-induced-arthritis;to observe homing of MSCs in immune organs and inflammatory joints in CIA rats.In this view we discuss the mechanisms of underlying immunomodulating properties and potential applications.
Methods
In the first part,rats MSCs were isolated and expanded from bone marrow cells by density gradient cent rifugation and adhering to the culture plastic,and identified with cell morphology, and the phenotypes were assessed by flow cytometry.In the second part,we established collagen-induced-arthritis rats model immuned by Freund's complete adjuvant and typeⅡcollagen for two times.40 rats were randomly divided into 5 groups,including:early MSCs treatment group(MSCs were transplanted by the time the rats were induced for the first time), later MSCs treatment group(MSCs were transplanted by the time the rats were induced for the second time),normal control group,early CIA control group and later CIA control group.MSCs were injected through tail Venus.Treatment effects were assessed clinically and histologically before sacrificed.All of rats were sacrificed at 42 days after transplantation of MSCs.We detected the proliferation of lymphocyte to ConA and LPS with CCK-8,observed the expression of Foxp3 mRNA using RT-PCR,assayed the level of CD4~+CD25~+ T cell by means of flow cytometry.In the third part,MSCs were labled by PKH-26 and Brdu.64 rats were randomly divided into normal group and CIA group.Every 8 rats were sacrificed at 3,11,30,42 days after transplantation of MSCs.At the end of the experiment,the specimens of thymus gland,spleen, ankle joints were exposed,fixed,decalcified,wrapped and cut into slices.We use confocal laser scanning microscope and immuno-histochemical methed to observe migration and distribution of MSCs in different organs.
Results
1.Uniform spindle-shaped in appearance and showed active proliferative capacity and had S shape of growth curve.
2.The improvement of arthritis index of early and later treatment groups was higher than CIA control group,which showed statistically significant difference(P＜0.05).Arthritis index of early treatment group was lower than later treatment group,which showed statistically significant difference(P＜0.05).
3.The percentage of Treg in early and later CIA groups was lower than normal control group and treatment groups,which showed statistically significant difference(P＜0.05).The level of Treg in early MSCs treatment group was higher than the later MSNs treatment group,which showed statistically significant difference(P＜0.05).
4.Compared to the normal group and treatment groups,the expression level of Foxp3 mRNA in early and later CIA groups was decreased markedly.While the early MSNs treatment group versus the later treatment group showed no statistically significant difference(P＞0.05).The intensity of Foxp3 mRNA in treatment groups was close to normal group.
5.The proliferation level of T cell and B cell was higher in CIA control groups than normal and treatment groups,which showed statistically significant difference(P＜0.05).Compared to the later treatment group,the percentage of T cell was decreased markedly.While the level of B cell in early and later MSNs treatment groups showed no statistically significant difference(P＞0.05).
6.The level of TGF-β1 was lower in early and later CIA control groups than normal and treatment groups(P＜0.05).Rats serum TGF-β1 level of the early treatment group was higher than that of the later treatment group,which showed statistically significant difference(P＜0.05). The levels of TNF-αand IL-17,which were increased in CIA control groups,higher than normal and treatment groups(P＜0.05).Compared to the later treatment group,IL-17 in the early treatment group was increased markedly(P＜0.05).TNF-αof treatment groups showed no statistically significant difference(P＞0.05).
7.It was found that allogenic MSCs could stay in spleen,thymus gland and joints of CIA rats for a relatively long period(42 days).The quantity of MSCs was higher in CIA group than normal group.
Conclusions
1.Rats MSCs were isolated and expanded from bone marrow cells.MSCs were uniform spindle-shaped in appearance and showed actively proliferative capacity,with S shape of growth curve. After MSCs were labeled by PKH-26 and Brdu,biological properties were not changed.
2.Our results proved that allogenie MSCs transplantation can relieve inflammatory symptoms of joints and pathology of synovial membrane.Moreover,in our experiments,MSCs showed significant immunomodulatory effects,to upregulate the level of Treg in CIA rats,accelerate the expression of Foxp3 mRNA,inhibit the proliferation of T cell and B cell,stimulate secretion of TGF-β,decrease the content of TNF-αand IL-17 in serum.The early treatment group was more effective than the later treatment group.
3.It was found that allogenic MSCs can stay in spleen,thymus gland and joints of CIA rats, whatever later or early groups,for a relatively long period(42 days).MSCs stayed in injured tissue and organs preferentially.
类风湿关节炎(Rheumatoid arthritis,RA)是一种高度致残性自身免疫性疾病,在我国RA的发病率约0.34%,患病总人数达500万,每年直接用于RA的治疗费用和因劳动力丧失带来的间接经济损失很大。近年的研究发现间充质干细胞(Mesenchymal Stem Cells,MSCs)具有免疫调节作用,同时MSCs可迁移到损伤和炎症部位,在局部微环境作用下分化为外胚层、中胚层细胞,甚至内胚层细胞,参与组织重建和修复,这些为RA患者的免疫抑制治疗,以及受损关节的修复带来了新的希望。
【目的】
通过对RA动物模型胶原诱导关节炎(CIA)大鼠的实验研究,观察异基因MSCs移植对(早期、晚期)CIA大鼠免疫细胞和分子的免疫学作用,并探讨其在体内发挥免疫调节作用的机制;观察异基因MSCs移植在CIA大鼠免疫器官和关节炎症部位的归巢和分布,并探讨其修复损伤关节可能的机制。
【方法】
第一部分:采用密度梯度离心结合贴壁培养法体外分离、培养大鼠MSCs,细胞表型鉴定。
第二部分:(1)弗氏完全佐剂+Ⅱ型胶原初次免疫雌性Wistar大鼠,14d弗氏完全佐剂+Ⅱ型胶原第2次免疫动物,建立CIA大鼠模型。(2)大鼠分为早期治疗组(佐剂初次诱导时治疗组)和晚期治疗组(再次诱导时治疗组),同时设立正常组和早、晚期CIA对照组,每组8只。(3)MSCs移植均采用尾静脉注射,每只大鼠移植的细胞数为1×10~7个/Kg;对照组以同样方法给予等容量的生理盐水。(4)观察42天不同分组大鼠的关节症状及进行关节炎指数和肿胀度测定。(5)MSCs移植后第42天全部处死动物取脾,通过CCK-8测定T细胞、B细胞的增殖;RT-PCR测定Foxp3 mRNA的表达水平;流式细胞术测定CD4~+CD25~+调节性T细胞的变化,ELISA测定外周血TGF-β、IL-17和TNF-α,收集数据并做统计分析。
第三部分:(1) PKH-26和Brdu标记MSCs。(2)将64只大鼠随即分成正常组和CIA组,均给予MSCs移植。(3)移植后第3、11、30、42天分别处死8只动物,取不同分组大鼠的胸腺、脾和关节组织制作病理切片,共聚焦显微镜联合免疫组化技术,观察MSCs移植后不同时点在不同脏器的迁移和分布。
【结果】
1.大鼠MSCs为均一的梭形的成纤维细胞样生长,贴壁及增殖能力强,生长曲线呈S型;流式细胞术鉴定为间充质干细胞。
2.早晚期MSCs治疗组AI、后肢足肿胀度均较CIA对照组明显改善(P＜0.05),早期治疗组与晚期治疗组比较,关节炎指数较低,差异有统计学意义(P＜0.05)。
3.早晚期CIA对照组Treg水平低于正常组和治疗组,差异有统计学意义(P＜0.05);早期治疗组Treg比晚期治疗组有所升高,差异有统计学意义(P＜0.05)。
4.早晚期CIA对照组Foxp3 mRNA的表达水平比正常组和治疗组低,差异有统计学意义(P＜0.05);早期治疗组与晚期治疗组比较差异无统计学意义(P＞0.05),Foxp3 mRNA的表达水平与正常组接近。
5.早晚期CIA对照组T、Bcell增殖水平明显高于正常组和治疗组,差异有统计学意义(P＜0.05);早期MSCs治疗组Tcell水平低于晚期治疗组(P＜0.05),早晚期治疗组Bcell水平接近(P＞0.05)。
7.早晚期CIA对照组TGF-β1水平较正常组和治疗组低(P＜0.05),早期治疗组TGF-β1水平高于晚期治疗组,差异有统计学意义(P＜0.05)。早晚期CIA对照组血清IL-17和TNF-α水平较正常组和治疗组升高(P＜0.05),其中早期治疗组MSCs对IL-17的抑制优于晚期治疗组,差异有统计学意义(P＜0.05);早晚期MSCs治疗组TNF-α被抑制的程度接近,差异无统计学意义(P＞0.05)。
8.异基因骨髓MSCs移植在CIA大鼠的脾脏、胸腺、关节炎症部位可较长期(42天)的存在,归巢的MSCs细胞数量明显高于正常组。
【结论】
1.体外分离、培养大鼠骨髓MSCs呈现均一的成纤维细胞样生长,贴壁及增殖能力强。
2.异基因MSCs移植对(早期、晚期)CIA大鼠的关节炎症状、滑膜病理都有所改善,并通过上调CIA大鼠体内Treg水平,促进Foxp3 mRNA的表达及TGF-β的分泌,抑制T、B淋巴细胞的增殖,减少血清中TNF-α、IL-17的含量,而发挥其在体内的免疫调节作用;早期治疗组的疗效优于晚期治疗组。
3.异基因骨髓MSCs移植在CIA大鼠的脾脏、胸腺、关节炎症部位可较长期(42天)的存在;移植的MSCs优先定位于受损伤的组织和器官而发挥其治疗作用。
Background
Rheumatoid arthritis is a highly disabled autoimmune disease.Disease incidence is about 0.34%in China and the total patients are 5 millions.There is a big indirect economic loss because of treatment and loss of work ability.Recent study showed that mesenchymal stem cells have immuno-regulation effect,at the same time MSCs can move to injury and inflammatory area in microenvironment.It can differentiate to dermal layer,mesoblast and endoderm,participating in tissue rebuilding and restoration.All of these bring a hope for RA patients.
Objective
To observe the immunologic effect of transplantation of MSCs through studying early and later period of Collagen-induced-arthritis;to observe homing of MSCs in immune organs and inflammatory joints in CIA rats.In this view we discuss the mechanisms of underlying immunomodulating properties and potential applications.
Methods
In the first part,rats MSCs were isolated and expanded from bone marrow cells by density gradient cent rifugation and adhering to the culture plastic,and identified with cell morphology, and the phenotypes were assessed by flow cytometry.In the second part,we established collagen-induced-arthritis rats model immuned by Freund's complete adjuvant and typeⅡcollagen for two times.40 rats were randomly divided into 5 groups,including:early MSCs treatment group(MSCs were transplanted by the time the rats were induced for the first time), later MSCs treatment group(MSCs were transplanted by the time the rats were induced for the second time),normal control group,early CIA control group and later CIA control group.MSCs were injected through tail Venus.Treatment effects were assessed clinically and histologically before sacrificed.All of rats were sacrificed at 42 days after transplantation of MSCs.We detected the proliferation of lymphocyte to ConA and LPS with CCK-8,observed the expression of Foxp3 mRNA using RT-PCR,assayed the level of CD4~+CD25~+ T cell by means of flow cytometry.In the third part,MSCs were labled by PKH-26 and Brdu.64 rats were randomly divided into normal group and CIA group.Every 8 rats were sacrificed at 3,11,30,42 days after transplantation of MSCs.At the end of the experiment,the specimens of thymus gland,spleen, ankle joints were exposed,fixed,decalcified,wrapped and cut into slices.We use confocal laser scanning microscope and immuno-histochemical methed to observe migration and distribution of MSCs in different organs.
Results
1.Uniform spindle-shaped in appearance and showed active proliferative capacity and had S shape of growth curve.
2.The improvement of arthritis index of early and later treatment groups was higher than CIA control group,which showed statistically significant difference(P＜0.05).Arthritis index of early treatment group was lower than later treatment group,which showed statistically significant difference(P＜0.05).
3.The percentage of Treg in early and later CIA groups was lower than normal control group and treatment groups,which showed statistically significant difference(P＜0.05).The level of Treg in early MSCs treatment group was higher than the later MSNs treatment group,which showed statistically significant difference(P＜0.05).
4.Compared to the normal group and treatment groups,the expression level of Foxp3 mRNA in early and later CIA groups was decreased markedly.While the early MSNs treatment group versus the later treatment group showed no statistically significant difference(P＞0.05).The intensity of Foxp3 mRNA in treatment groups was close to normal group.
5.The proliferation level of T cell and B cell was higher in CIA control groups than normal and treatment groups,which showed statistically significant difference(P＜0.05).Compared to the later treatment group,the percentage of T cell was decreased markedly.While the level of B cell in early and later MSNs treatment groups showed no statistically significant difference(P＞0.05).
6.The level of TGF-β1 was lower in early and later CIA control groups than normal and treatment groups(P＜0.05).Rats serum TGF-β1 level of the early treatment group was higher than that of the later treatment group,which showed statistically significant difference(P＜0.05). The levels of TNF-αand IL-17,which were increased in CIA control groups,higher than normal and treatment groups(P＜0.05).Compared to the later treatment group,IL-17 in the early treatment group was increased markedly(P＜0.05).TNF-αof treatment groups showed no statistically significant difference(P＞0.05).
7.It was found that allogenic MSCs could stay in spleen,thymus gland and joints of CIA rats for a relatively long period(42 days).The quantity of MSCs was higher in CIA group than normal group.
Conclusions
1.Rats MSCs were isolated and expanded from bone marrow cells.MSCs were uniform spindle-shaped in appearance and showed actively proliferative capacity,with S shape of growth curve. After MSCs were labeled by PKH-26 and Brdu,biological properties were not changed.
2.Our results proved that allogenie MSCs transplantation can relieve inflammatory symptoms of joints and pathology of synovial membrane.Moreover,in our experiments,MSCs showed significant immunomodulatory effects,to upregulate the level of Treg in CIA rats,accelerate the expression of Foxp3 mRNA,inhibit the proliferation of T cell and B cell,stimulate secretion of TGF-β,decrease the content of TNF-αand IL-17 in serum.The early treatment group was more effective than the later treatment group.
3.It was found that allogenic MSCs can stay in spleen,thymus gland and joints of CIA rats, whatever later or early groups,for a relatively long period(42 days).MSCs stayed in injured tissue and organs preferentially.
引文
1.李小峰.重视类风湿关节炎发病机制及治疗的研究进展.中华风湿病学杂志.2008,12(1).1-3.
2.Le Blanc K,Ringd(?)n O.Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med.2007,Nov;262(5):509-25.
3.Ozaki K,Sato K,Oh I,et al.Mechanisms of immunomodulation by mesenchymal stem cells.Int J Hematol.2007,Jul;86(1):5-7.
4.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood.2007 Nov 15;110(10):3499-506.
5.Fibbe WE,Nauta A J,Roelofs H.Modulation of immune responses by mesenchymal stem cells.Ann N Y Acad Sci.2007 Jun;1106:272-8.
6.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol.2007 May;28(5):219-26.Epub 2007 Apr 2.
7.McTaggart S J,Atkinson K.Mesenchymal stem cells:immunobiology and therapeutic potential in kidney disease.Nephrology(Carlton).2007 Feb;12(1):44-52.
8.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):435-41.
9.Djouad F,Fritz V,Apparailly F,et al.Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.Arthritis Rheum.2005 May;52(5):1595-603.
10.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
11.T(o|¨)gel F,Hu Z,Weiss K,et al.Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.Am J Physiol Renal Physiol.2005 Jul;289(1):F31-42.Epub 2005 Feb 15.
12.Kim HS,Zhang X,Choi YS.Activation and proliferation of follicular dendritic cell-like cells by activated T lymphocytes.J Immunol.1994 Oct 1;153(7):2951-61.
13.Chen X,Armstrong MA,Li G Mesenchymal stem cells in immunoregulation.Immunol Cell Biol.2006 Oct;84(5):413-21.
14.Glennie S,Soeiro I,Dyson PJ,et al.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 2005;105:2821-7.
15.Kraus KH,Kadiyala S,Wotton H,et al.Critically sized osteo-periosteal femoral defects:a dog model.J Invest Surg.1999 Mar-Apr;12(2):115-24.
16.Pereira RF,O'Hara MD,Laptev AV,et al.Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta.Proc Natl Acad Sci USA.1998 Feb 3;95(3):1142-7.
17.焦强,卫小春,陆向东,等.转化生长因子-β1 和血清对人骨髓基质干细胞增殖及向软骨细胞诱导分化的影响.中华创伤骨科杂志。2005,10:960-962.
1.Friedenstein AJ,Piatetzky2Shapiro Ⅱ,Pet rakova KV.Ostreogenesis in transplants of bone marrow cells[J].J Embryol Exp Morphol,1966,16:381-390.
2.Barry FP,Murphy JM.Mesenehymal stem cells:clinical applications and biological characterization[J].Int J Bioehem Cell Biol,2004,36:568-584.
3.Pittenger MF,Mackay AM,Beck SC,et al.Multilineage potential of adult human mesenehymal stem cells[J].Science,1999,284:143-147.
4.Le Blank K,Rasmusson I,Sundberg B,et al.Treatment of severe acute graftversushost disease with third party haploidentieal mesenehymal stem cells[J]Lancet,2004,363:1439-1441.
5.Friedens tein A J,Deriglasova UF,Kulagina NN,et al.Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony as say method.Exp Hematol 1974;2(2):83-92
6.Lis ignoli G,Remiddi G,Cattini L,et al.An elevated number of differentiated os teoblas t colonies can be obtained from rat bone marrow stromal cells using a gradient isolation procedure.Connect Tis sue Res 2001;42(1):49-58
7.Eneina NR,Billotte WG,Hofmann MC.Immunomagnetie isolation of osteoprogenitors from human bone marrow s troma.Lab Invest 1999;79(4):449-457
8.魏会平,张世敏,刘继云,等.大鼠骨髓间充质干细胞的分离、培养及生物学鉴定[J].河北北方学院学报:医学版,2005,22(1):23-25
9.吴洁莹,廖灿,许遵鹏,等.人骨髓间充质干细胞分离鉴定方法的改进[J].中国实验血液学杂志,2006,14(3):557-560
10.Wulf GG,Jackson KA,Goodell MA.Somatic stem cell plasticity:current evidence and emerging concepts.Exp Hemato12001;29(12):1361-1370
11.康新勤,臧伟进,宋土生,等.大鼠骨髓间充质干细胞分离培养及其形态观察[J].西安交通大学学报:医学版,2003,24(5):518-519
12.Barry FP.Mesenchymal stem cell therapy in joint disease.Novartis Found Symp 2003;249:86-96
13.Anokhina EB,Buravkova LB.Heterogeneity of s tromal precursor cells isolated from rat bone marrow.Ts itologiia 2007;49(1):40-47
14.Dominici M,Le Blanc K,Mueller I,et al.Minimal criteria for defining multipotent mesenchymal s tromal cells.The Intemational Society for Cellular Therapy pos ition s tatement.Cytotherapy 2006;8(4):315-317
1.Trentham DE,Townes AS,Kang AH.Autoimmunity to type Ⅱ collagen an experimental model ofarthritis.J Exp Med,1977 Sep 1;146(3):857-68.
2.Courtenay JS,Dallman MJ,Dayan AD,Martin A,Mosedale B.Immunisation against heterologous type Ⅱ collagen induces arthritis in mice.Nature,1980 Feb 14;283(5748):666-8.
3.Myers LK,Rosloniec EF,Cremer MA,Kang AH.Collagen-induced arthritis,an animal model ofautoimmunity.Life Sci,1997;61(19):1861-78.
4.Brand DD,Kang AH,Rosloniec EF.The mouse model of collagen-induced arthritis.Methods Mol Med,2004;102:295-312.
5.Brahn E,Peacock D J,Banquedgo ML.Suppression of collagen-induced arthritis by combination cyclosporin A and methotrexate therapy.Arthritis Rheum,1991Oct;34(10):1282-8.
6.Schett G,Middleton S,Bolon B,et al.Additive bone-protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models.Arthritis Rheum,2005 May;52(5):1604-11.
7.Bakharevski O,Stein-Oakley AN,Thomson NM,Ryan PF.Collagen induced arthritis in rats.Contrasting effect of subcutaneous versus intradermal inoculation of type Ⅱ collagen..J Rheumatol,1998 Oct;25(10):1945-52.
8.Morgan ME,Flierman R,van Duivenvoorde LM,Witteveen H J,van Ewijk W,van Laar JM,de Vries RR,Toes RE.Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+regulatory T cells.Arthritis Rheum.,2005 Jul;52(7):2212-21.
9.李小峰.重视类风湿关节炎发病机制及治疗的研究进展.中华风湿病学杂志.2008,12(1).1-3.
10.Le Blanc K,Ringd(?)n O.Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med.2007,Nov;262(5):509-25.
11.Ozaki K,Sato K,Oh I,et al.Mechanisms of immunomodulation by mesenchymal stem cells.Int J Hematol.2007,Jul;86(1):5-7.
12.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood.2007 Nov 15;110(10):3499-506.
13.Fibbe WE,Nauta A J,Roelofs H.Modulation of immune responses by mesenchymal stem cells.Ann N Y Acad Sci.2007 Jun;1106:272-8.
14.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol.2007 May;28(5):219-26.Epub 2007 Apr.
15.McTaggart S J,Atkinson K.Mesenchymal stem cells:immunobiology and therapeutic potential in kidney disease.Nephrology(Carlton).2007 Feb;12(1):44-52.
16.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):435-41.
17.Djouad F,Fritz V,Apparailly F,et al.Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.Arthritis Rheum.2005 May;52(5):1595-603.
18.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
19.Leipe J,Skapenko A,Lipsky PE,Schulze-Koops H.Regulatory T cells in rheumatoid arthritis.Arthritis Res Ther.2005;7(3):93.
20.Roll P,Palanichamy A,Kneitz C,Domer T,Tony HP.Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis.Arthritis Rheum.2006 Aug;54(8):2377-86.
21.Yoshinori Nonomura,Hitoshi Kohsaka,Kenji Nagasaka.Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis.The Journal of Immunology,2003,171:4913-4919.
22.Arend WP,Dayer JM.Inhibition of the production and effects of intedeukin-1 and tumor necrosis factor alpha in rheumatoid arthritis.Arthritis rheum,1995,38:151-160
23.Mukherjee P,Yang SY,Wu B,et al.Tumour necrosis factor receptor gene therapy affects cellular immune responses in collagen induced arthritis in mice.Ann Rheum Dis.2005Nov;64(11):1550-6.
24.Catrina AI,af Klint E,Ernestam S,et al.Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis.Arthritis Rheum.2006Jan;54(1):76-81
25.Wislowska M,Jakubicz D.Preliminary evaluation in rheumatoid arthritis activity in patients treated with TNF-alpha blocker plus methotrexate versus methotrexate or leflunomide alone.Rheumatol Int.2007 Jan 18;[Epub ahead of print]
26.董怡,张卓莉.白细胞介素-1 家族在类风湿关节炎和骨关节炎中的作用.中华风湿病学杂志2004,5:257-258
27.Ainola MM,Mandelin JA,Liljestrom MP,et al.Pannus invasion and cartilage degradation in rheumatoid arthritis:involvement of MMP-3 and interleukin-lbeta.Clin Exp Rheumatol.2005 Sep-Oct;23(5):644-50.
28.Romagnani S.Regulation of the T cell response[J].Clin Exp Allergy,2006,36:1357-1366.
29.Me Innes IB,L iew FY.Cytokine networks towards new therapies for rheumatoid arthritis[J].Nat Clin Pract Rheumatol,2005,1:31-39.
30.HonoratiMC,Neri S,Cattini L,et al.Interleukin-17,a regulator of angiogenic factor release by synovial fibroblasts[J].Osteoarthritis Cartilage,2006,14:345-352.
31.Lubberts E,KoendersM I,van den BergWB.The role of Tcell interleukin-17 in conducting destructive arthritis:lessons from animalmodels[J].Arthritis Res Ther,2005,7:29-37.
32.Kirkham BW,LassereMN,Edmonds JP,et al.Synovial membrane cytokine expression is p redictive of joint damage progression in rheumatoid arthritis:a two-year prospective study (the damage study cohort)[J].Arthritis Rheum,2006,54:1122-1131.
33.Rohn TA,Jennings GT,HemandezM,et al.Vaccination against EL-17 supp resses autoimmune arthritis and encephalomyelitis[J].Eur J Immuno,2006,36 (11):2857-2867.
34.Szekanecz Z,Haines GK,Harlow LA,et al.Increased synovial exression of transforming growth factor (TGF)-receptor endoglin and TGF-pl in rheumatoid arthritis:possible interactions in the pathogenesis of the disease[J].Clin Immunopathol,1995,76(2):1872194.
35.Nakajima T,Aono H,Hasunuma T,et al.Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes[J].Arthritis Rheum,1995,38 (4):4852491.
36.Firestein GS,Yeo M,Zvaifler NJ.Apoptosis in Rheumatoid arthritis synovium[J].J Clin Invest,1995,96 (3).163121638.
37.Chen W,Jin W,Wahl SM.Engagement of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) induce transforming growth factorβ(TGF-β) production by murine CD4~+ T cell[J].J Exp Med,1998,188 (10):184921857.
38.Mcadam AJ,Schweitzer AN,Sharpe AH.The role of B7 co-stimulation in activation and diffrentiation of CD4~+ and CD8~+ T cell[J].Immunol Rev,1998,165 (2):2312247.
39.Mandelblbrot DA,McAdam AJ,Sharpe AH.B7-1 or B7-2 isrequied to produce the lymphoproferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)[J].J Exp Med,1999,189 (2):4352440.
40.Shevach EM,MuHugh RS,Piccirillo CA,et al.Control of T-cell activation by CD4~+CD25~+ suppressor T cells[J].Immunol Rev,2001,182:58-67
41.Leipe J,Skapenko A,Lipsky PE,et al.Regulatory T cells in rheumatoid arthritis[J].Arthritis Res Ther,2005,7(3):93-99
42.Minami R,Sakai K,Mivamura T,et al.The role of CD4~+CD25~+ regulatory T cells in patients with Rheumatoid Arthritis[J].Nihon Rinsho Meneki Gakkai Kaishi,2006,29(1):37-4
43.Gonzalez A,Andre-Schmutz I,Carnaud C,et al.Damage control,rather than unresponsiveness,effected by protective DX5+ T cells in autoimmune diabetes[J].Nature Immunol,2001,2(12):1117-1125
44.Taams L,Vukmanovic SM,Salmon M.Immune regulation by CD4~+CD25~+ regulatory T cells:implications for transplantation tolerance[J].Trans Immuno1,2003,11(3-4):277-285
45.Maloy KJ,Salaunl,Cahill R,et al.CD4~+CD25~+ T(R)cells suppress innate immune pathology through cytokine-dependent mechanisms[J].Exp Med,2003,197(1):111-119
46.Powrie F,Carlino J,Leach MW,et al.A critical role for transforming growth factor beta but not intedeukin 4 in the suppression of T helper tupe 1 mediated colitis by CD45RB(Iow)CD~(4+)T cells[J].J Exp Med,1996,183:2669-2674
47.Chen W,Jin W,Wahl SM.Engagement ofcytotoxic Tlymphocyte-associated antigen 4(CTLA-4)induces transforming growth factor beta(TGF-beta)production by murine CD4(+)T cells[J].J Exp Med,1998,188:1849-1857
48.Kukreja A,Cost G,Market J.et al.Multiple immuno-regulatory defects in type-1diabetes[J].Clin Invest,2002,109(1):131-140
49.Van Amelsfort JM,Jacobs KM,Bijlsma JW,et al.CD4~+CD25~+ regulatory T cells in rheumatoid arthritis:differences in the presence,phenotype,and function between peripheral blood and synovial fluid[J].Arthritis Rheum,2004,50(9):2775-85
50.Lawson CA,Brown AK,Bejarano V,et al.Early rheumatoid arthritis is associatal with a deficit in the CD~(4+)CD~(25)~(high)regulatory T cells population in peripheral blood [J].Rheumatology(Oxford),2006,45(10):1210-1217
51.Toubi E,Kessel A,Mahmudov I,et al.Increased spontaneous apoptosis of CD~(4+)CD~(25+)T cell in patients with active rheumatoid arthritis is reduced by infliximab[J].Ann N Y Acad Sci,2005,1051:506-514
52.李萍,毕黎琦,栗占国.表达 Foxp3的调节性 T 细胞在类风湿关节炎发病中的意义[J].中国免疫学杂志,2006,4(22):386-374.
53.de Kleer IM,Wedderbum LR,Taams LS,et al.CD~(4+)CD~(25)~(bright)regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis[J].J Imm unol,2004,172(10):6435-6443.
54.Zha Y,Blank C,Gajewski TF.Negative regulation of T-cell function by PD-1.Crit Rev Immunol.2004,24(4):229-237.
55.Minguell JJ,Erices A,Conget P.Mesenchymal stem cells.Exp Biol Med 2001,26(6):507
56.Hart Q,Deng W,Zhao RC,et al.Allogeneic adult s tern cells es-tablish longterm residence in recipient tissues and facilitate skin transplantation.ExpHematol,2003,31(7):158
57.Bartholomew A,Sturgeon C,Siatskas M,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol,2002,30:42-48.
58.Goncalves MA,de Vries AA.Human mesenchymal stem cells ectopically expressing full-length dystrophin can complement Duchenne muscula dystrophy myotubes by cell fusion.Hum Mol Genet,2006,15:213-221.
59.Tse WT,Pendleton JD,Beyer WM,et al.Suppres s ion of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation.Transplantation,2003,75(3):389-397.
1.HaasJ,Bauer P,Rolfs A,et al.Immunocytochemical characterization of in Vitro PKH26-1abelled and intracerebrally transplanted neonatal cells[J].Acta Histochem,2000,102:273-280.
2.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):435-41.
3.Kraus KH,Kadiyala S,Wotton H,et al.Critically sized osteo-periosteal femoral defects:a dog model.J Invest Surg.1999 Mar-Apr;12(2):115-24.
4.Nagaya N,Fujii T,Iwase T,et al.Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis.Am J Physiol Heart Circ Physioi,2004,287:2670-2676.
5.Pereira RF,O'Hara MD,Laptev AV,et al.Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta.Proc Natl Acad Sci USA.1998 Feb 3;95(3):1142-7.
6.焦强,卫小春,陆向东,等.转化生长因子-β1 和血清对人骨髓基质干细胞增殖及向软骨细胞诱导分化的影响冲华创伤骨科杂志。2005,10:960.962.
7.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
1.Friedenstein AJ,Piatetzky2Shapiro Ⅱ,Pet rakova KV.Ostreogenesis in transplants of bone marrow cells[J].J Embryol Exp Morphol,1966,16:381-390.
2.Barry FP,Murphy JM.Mesenchymal stem cells:clinical applications and biological characterization[J].Int J Biochem Cell Biol,2004,36:568-584.
3.Pittenger MF,Mackay AM,Beck SC,et al.Multilineage potential of adult human mesenchymal stem cells[J].Science,1999,284:143-147.
4.Le Blank K,Rasmusson I,Sundberg B,et al.Treatment of severe acute graftversushost disease with third party haploidentical mesenchymal stem cells[J]Lancet,2004,363:1439-1441.
5.Tse WT,Pendleton JD,BeyerWM,et al.[J].Transp lantation,2003,75(3):389-3971.
6.Elena K,Joseph DM,Valentina Z,et al.[J].Biomed Sci,2005,12(1):47-57.
7.Eliopoulos N,Stagg J,Lejeune L,et al.[J].Blood,2005,106(13):4057-4065.
8.Mills KH.Regulatory Tcells:friend or foe in immunity to infection[J].Nat Rev Immunol,2004,4:841-855.
9.Steinman RM,Nussenzweig MC.Avoiding horror autotoxicus:the importance of dendritic cells in peripheral T cell tolerance[J].Proc Natl Acad Sci USA,2002,99:351-358.
10.Zhang W,Ge W,Li C,et al.Effects of mesenchymal stemcells on differentiation,maturation,and function of human monocyte-derived dendritic cells[J].Stem Cells Dev,2004,13:263-271.
11.J iang XX,Zhang Y,Liu B,et al.Human mesenchymal stem cells inhibit differentiation and function of monocytederived dentritic cells.Blood,2005,105:4120-4126.
12.何津,张毅,江小霞等.人骨髓间充质干细胞对脐血 T 淋巴细胞转化的影响.中国实验血液学杂志,2003,11:11-14.
13.Deng W,Han Q,Zhao RC,et al.Longterm Distribution of Adult Stem Cells in Different Tissues after Transplantation.Stem Cell and Cellular Therapy,2003,1:62-65.
14.Devine SM,Cobbs C,Jennings M.Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates.Blood,2003,101:2999-3001.
15.Azizi SA,Stokes D,Augelli B J,et al.Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats2similarities to astrocyte gratis.Proc Natl Acad Sci USA,1998,95:3908-3913.
16.Toma C,Pittenger MF,Cahill KS,et al.Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.Circulation,2002,105:93-98.
17.Saito T,Kuang JQ,Bittira B,et al.Xenotransplant cardiac chimera:immune tolerance of adult stem cells.Ann Thorac Surg,2002,74:19-24.
18.Liechty KW,MacKenzie TC,Shaaban AF,et al.Human mesenchymal stem cells engraft and demonstrate site2specific differentiation after in utero transplantation in sheep.Nat Med,2000,6:1282-1286.
19.Han Q,Deng W,Zhao RC,et al.Allogeneic adult stem cells establish longterm residence in recipient tissues and facilitate skin transplantation.Exp Hematol,2003,31:158.
20.Bartholomew A,Sturgeon C,Siatskas M,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol,2002,30:42-48
21.Zanjani ED,AlmeidaPorada G,Ascensao JL,et al.Transplantation of hematopoietic stem cells in utero.Stem cells,1997,15(Suppl):79-92.
22.Li Y,Hisha H,Inaba M,et al.Evidence for migration of donorbone marrow stromal cells into recipient thymus after bone marrowtransplantation plus bone grafts:a role of stromal cells in positive selection.Exp Hematol,2000,28:950-960.
23.BardaSaad M,Rozenszajn LA,Ashush H,et al.Adhesion molecules involved in the interactions between early T cells and mesenchymal bone marrow stromal cells.Exp Hematol,1999,27:834-844.
24.Ruegemer JJ,Ho SN,Augustine JA,et al.Regulatory effects of transforming growth factor-P on IL-22 and IL-4-dependent T cell cycle progression.J Immunol,1990,144:1769-1776.
25.Ahuja SS,Paliogianni F,Yarnada H,et al.Effect of transforming growth factor-P on early and late activation events in human T cells.J Immunol,1993,150:3109-3118.
26.Fox FE,Ford HC,Douglas R,et al.Evidence that TGF-P can inhibit T-lymphocyte proliferation through paracrine and autocrine mechanisms.Cell Immunol,1993,150:45-58.
27.Mossalayi MD,Mentz F,Ouaaz F,et al.Early human thymocyte proliferation is regulated by an externally controlled autocrine transforming growth factor-Pi mechanism.Blood,1995,85:3594-3601.
28.BardaSaad M,Rozenszajn LA,Globerson A,et al.Selective adhesion of immature thymocytes to bone marrowstromal cells:relevance to T cell lymphopoiesis.Exp Hematol,1996,4:386-391.
29.Sarun S,Dalloul AH,Laurent C,et al.Human CD34+thymocyte maturation:pre-T and NK cell differentiation on neonatal thymic stromal cell culture.Cell Immunol,1998,190:23-32.
30.Zha Y,Blank C,Gajewski TF.Negative regulation of T-cell function by PD-l.Crit Rev Immunol.2004,24(4):229-237.
31.Minguell JJ,Erices A,Conget P.Mesenchymal stem cells.Exp Biol Med 2001,26(6):507
32.Han Q,Deng W,Zhao RC,et al.Allogeneic adult s tern cells es-tablish longterm residence in recipient tissues and facilitate skin transplantation.ExpHematol,2003,31(7):158
33.Bartholomew A,Sturgeon C,Siatskas M,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol,2002,30:42-48.
34.Goncalves MA,de Vries AA.Human mesenchymal stem cells ectopically expressing full-length dystrophin can complement Duchenne muscula dystrophy myotubes by cell fusion.Hum Mol Genet,2006,15:213-221.
35.Tse WT,Pendleton JD,Beyer WM,et al.Suppres s ion of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation.Transplantation,2003,75(3):389-397.
36.Krampera M,Glennie S,Dyson J,et al.Bone marrow mesenchymal stem cells inhibit there sponse of nave and memory antigen specific T cells to their cognate peptide.Blood,2003,101:3722-3729.
37.Blanc KL,Rasmusson I,Gotherstrom C,et al.[J].Scand J Immunol,2004,60(3):307-315.
38.DiNicolaM,Carlo2Stella C,MagniM,et al.[J].Blood,2002,99(10):3838-3843.
39.GrohME,Maitra B,Szekely E,et al.[J].Exp Hematol,2005,33(8):928-934.
40.Aggarwal S,Pittenger F.[J].Blood,2005,105(4):18151822.
41.Rasmusson I,Ringden O,SundbergB,et al.[J].Exp Cell Res,2005,305(1):33-41.
42.Cecilia G,Olle R,Charlotte T,et al.[J].Am J Obstet Gynecol,2004,190(1):239-245.
43．金建刚,危江伟,宁红梅,等．[J]．中华血液学杂志,2005,26(6)：339-341．
44.Krampera M,Lorenzo Cosmi L,Angeli R,et al.[J].Stem Cells,2006,24(2):386-398.
45.Meisel R,ZibertA,LarycaM,et al.[J].Blood,2004,103(12):4619-462.
46.Andrea A,Roberta T,Simone MN,et al.[J].Eur J Immunol,2005,35 (5):1482-1490.
47.Sarah G,Ines S,Peter JD,et al.[J].Blood,2005,105(7):2821-2827.
48.Maccario R,Podesta M,Moretta A,et al.Interaction of humanmesenchymal stem cells with cells involved in alloantigen specific immune response favors the differentiation of CD4~+Tcell subsets expressing a regulatory/suppressive phenotype.Haematologica,2005,90:516-525.
49.Aggarwal S,PittengerMF.Human mesenchymal stem cellsmodulate allogeneic immune cell response.Blood,2005,105:1815-1822.
50.Beyth S,Borovsk Z,Mevorach D,et al.Human mesenchymal stem cells alter antigen presenting cellmaturation and induce Tcell unresponsiveness.Blood,2005,105:2214-2219.
51.Andrea A,Roberta T,Simone MN,etal.[J].Eur J Immunol,2005,35 (5):1482-1490.
52.DengWM,Han Q,L iao L,et al.[J].DNA Cell Biol,2005,24(7):458-463.
53.Corcione A,Federica B,Elisa F,et al.[J].Blood,2006,107(1):367-372.
54.Rasmusson I,Ringden O,Simdberg B,et al.Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes,but not activated cytotoxic T lymphocytes or natural killer cells.Transp lantation,2003,76:1208-1213
55.Potian JA,Aviv H,Ponzio NM,et al.Vetolike activity of mesenchymal stem cells:functional discrimination between cellular responses to alloantigens and recall antigens.J Immunol,2003,171:3426-3434.
56.Angoulvant D,Clerc A,Benchalal S,et al.Human mesenchymal stem cells supp ress induction of cytotoxic response to alloantigens.Biorheology,2004,41:469-476.
57.Aggarwal S,PittengerMF.Human mesenchymal stem cellsmodulate allogeneic immune cell response.Blood,2005,105:1815-1822.
58.Silva WA Jr,Covas DT,Panepucci RA,et al.The profile of gene expression of human marrow mesenchymal stem cells[J].Stem Cells,2003,21:661-669.
59.Neuss S,Becher E,Woltje M,et al.Functional expression of HGF and HGF receptor/cmet in adult human mesenchymal stem cells suggests a role in cell mobilization,tissue repair,and wound healing[J].Stem Cells,2004,22:405-414.
60.Chunmeng S,Tianmin C,Yongping S,et al.Effects of dermal multipotent cell transplantation on skin wound healing[J].J Surg Res,2004,121:13-19.
61.Azuma H,Takahara S,Mat sumoto K,et al.Hepatocyte growth factor prevents the development of chronic allograft nephropathy in rats[J].J Am Soc Nephrol,2001,12:1280-1292.
62.Asseman C,Powrie F.Interleukin-10 is a growth factor for a population of regulatory T cells[J].Gut,1998,42:157-158.
63.Di Nicola M,CarloStella C,Magni M,et al.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J].J Cell Physiol,2004,200:400-406.
64.Aggarwal SM,Ittenger FP.Human mesenchymal stem cells modulate allogeneic immune cell responses[J].Blood,2005,105:1815-1822.
65.Arilkawa T,Omural K.Morita,Regulation of bone morphogenetic protein-expression by endogenous prostaglandin E2 inhuman mesenchymal stem cells.[J].J Cell Physiol,2004,200:400-406.
66.Stagg J,Pommey S,Eliopoulos N,et al.Interferon-gammastimulated marrow stromal cells:a new type of nonhematopoietic antigen-presenting cell[J].Blood,2006,107:2570-2577.
67.Frumento G,Rotondo R,Tonetti M,et al.Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,32 dioxygenase[J].J Exp Med,2002,196:459^68.
68.Nagaya N,Fujii T,Iwase T,et al.Intravenous administration of mesenchymal stem cells imp roves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis.Am J Physiol Heart Circ Physiol,2004,287:2670-2676.
69.Devine SM,Cobbs C,JenningsM,et al.Mesenchymal stem cells distribute to a wide range of tissue following systemic infusion into nonhuman primates.Blood,2003,101:2999-3001.
70.DengW,Han Q,Zhao RC,et al.Longterm distribution of adult stem cells in different tissues after transp lantation.Stem Cell Cellular Ther,2003,1:62-65.
71.向国安,张刚庆,方驰华等.同种异体骨髓间质干细胞移植在大鼠肝内定居能力初步研究.第一军医大学学报,2005,25:994-997.
72.Campagnoli C,Roberts IA,Kumar S,et al.Identification of mesenchymal stem rogenitor cells in human firsttrimester fetal blood,liver and bone marrow.Blood,2001,98:2396-2402.
73.Lee K,MajumdarMK,BuyanerD,et al.Human mesenchymal stem cells maintain transgene expression during expansion and differentiation.Mol Ther;2001;3:857-866.
74.Paul B,Morgan D,Wechsler A,et al.Chemokine induced migration of human mesenchymal stem cells:a strategy for directing cardiac repair.J American College Surgeons,2004,199:33-38.
75.Tsuchiya K,Chen G,Ushid T,et al.Effects of cell adhesion molecules on adhesion of ehondrocytes,ligament cells and mesenchymal stem cells.Mater Sci Engin,2001,17:79-82.
76.SegersVF,van2Riet I,Andries LJ,et al.Mesenehymal stem cell adhesion to cardiac microvascular endothelium:activators and mechanisms.Am J Physiol Heart Circ Physiol,2006,290:1370-1377.
77.HonezarenkoM,Le Y,SwierkowskiM,et al.Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors.Stem Cells,2006,24:1030-1041.
78.赛音其木格,侯相麟,赵丽,等.成人骨髓间充质干细胞分化为成骨细胞的研究[J].临床血液学杂志,2005,18(4):200-203.
79.Jaiswal N,Haynesworth SE,Caplan AI,et al.Osteogenic differentiation of purified,culture-expanded human mesenehymal stem cells in vitro.J Cell Biochem 1997,64(2):295-312.
80.易敬林,杨海军,丁伟荣,等.人骨髓间充质干细胞的分离培养及其生物学特性的研究[J].江西医学院学报,2005,45(6):1-5.
81.唐文洁,李玛琳,邱垂源,等.F6F-2对人骨髓间充质干细胞增殖和向成骨细胞分化的影响[J].细胞生物学杂志,2005,27(6):673-678.
82.Asahara T,Murohara T,Sullivan A,et al.Isolation of putative progenitor endothelial cells for angiogenesis[J].Science,1997,275(5302):964-967.
83.J iang Y,Jahagirdar BN,Reinhardt RL,et al.Pluripotency of mesenchymal stem cells derived from adult marrow[J].Nature,2002,418(6893):41-49.
84.Levenberg S,Golub JS,Langer R,et al.Endothelial cells derived from human embryonic stem cells[J].Proc Natl Acad Sci USA,2002,99 (7):4391-4396.
85.Yong BG,Butler DL,Weber W,et al.Mesenchymal stem cells-based repair achiles tendon[J].Trans Orthop Res Soc,1997,22:249-254.
86.Yoo JU,Barthel TS,Nishimura K,et al.The chondrogenic potential of human bonemarrow-derived mesenchymal progenitor cells[J].J Bone Joint Surg(Am),1998,80:1745-1747.
87.Glatz F,Neumeister M,Sucky H,et al.A tissue-engineering technique for vascularized laryngotracheal reconstruction[J].Arch Otolaryngol Head Neck Surg,2003,129:201-206.
88．杨志明主编．组织工程基础与临床[M]．成都：四川科学技术出版社,2000,37-57．
89.Barry F,Boynton RE,Liu B,et al.Chondrogenic differentiation of mesenchymal stem cells from bone marrow;Differentiation 2dependent gene expression of matrix components[J].Exp Cell Res,2001,268:189-200.
90.Shea CM,Edgar CM,Einhorn TA,et al.BMP treatment of mesenchymal stem cells induces both chondrogenesis and osteogenesis[J].J Cell Biochem,2003,90:1112-1127.
91.Ma HL,Hung SC,Lin SY,et al.Chondrogenesis of human mesenchymal stem cells encapsulated in alginate beads[J].J Biomed Mater Res,2003,64A:273-281.
92.Worster AA,Nixon AJ,Brower-Toland BD,et al.Effect of transforming growth factor-beta on chondrogenic differentiation of cultured equine mesenchymal stem cells[J].Am J Vet Res,2000,61(9):1003.
93.Watanabe H,de Caestecker MP,Yammada Y.Transcriptional crosstalk between smad,ERK1/2,and p38 mitogen-activated protein kinsae pathways regulates transforming growth factor2beta2induced aggrecan gene expression in chondrogenic ATDC5 cells[J].J Biol Chem,2001,276:14466-14473.
94.Le Blanc K,Ringden O.Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med.2007,Nov;262(5):509-25.
95.Ozaki K,Sato K,Oh I,et al.Mechanisms of immunomodulation by mesenchymal stem cells.Int J Hematol.2007,Jul;86(1):5-7.
96.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood.2007,Nov 15;110(10):3499-506.
97.Fibbe WE,Nauta AJ,Roelofs H.Modulation of immune responses by mesenchymal stem cells.Ann N Y Acad Sci.2007 Jun;1106:272-8.
98.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression?Trends Immunol.2007 May;28(5):219-26.Epub 2007 Apr 2.
99.McTaggart SJ,Atkinson K.Mesenchymal stem cells:immunobiology and therapeutic potential in kidney disease.Nephrology (Carlton).2007 Feb;12(1):44-52.
100.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):43541.
101.Djouad F,Fritz V,Apparailly F,et al.Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.Arthritis Rheum.2005 May;52(5):1595-603.
102.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
103.Togel F,Hu Z,Weiss K,et al.Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.Am J Physiol Renal Physiol.2005 Jul;289(1):F3142.Epub 2005 Feb 15.
104.Kim HS,Zhang X,Choi YS.Activation and proliferation of follicular dendritic cell-like cells by activated T lymphocytes.J Immunol.1994 Oct 1;153(7):2951-61.
105.Chen X,Armstrong MA,Li G Mesenchymal stem cells in immunoregulation.Immunol Cell Biol.2006 Oct;84(5):413-21.
106.Glennie S,Soeiro I,Dyson PJ,et al.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 2005;105:2821-7.
107.Kraus KH,Kadiyala S,Wotton H,et al.Critically sized osteo-periosteal femoral defects:a dog modelJ Invest Surg.1999 Mar-Apr;12(2):115-24.
2.Le Blanc K,Ringd(?)n O.Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med.2007,Nov;262(5):509-25.
3.Ozaki K,Sato K,Oh I,et al.Mechanisms of immunomodulation by mesenchymal stem cells.Int J Hematol.2007,Jul;86(1):5-7.
4.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood.2007 Nov 15;110(10):3499-506.
5.Fibbe WE,Nauta A J,Roelofs H.Modulation of immune responses by mesenchymal stem cells.Ann N Y Acad Sci.2007 Jun;1106:272-8.
6.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol.2007 May;28(5):219-26.Epub 2007 Apr 2.
7.McTaggart S J,Atkinson K.Mesenchymal stem cells:immunobiology and therapeutic potential in kidney disease.Nephrology(Carlton).2007 Feb;12(1):44-52.
8.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):435-41.
9.Djouad F,Fritz V,Apparailly F,et al.Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.Arthritis Rheum.2005 May;52(5):1595-603.
10.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
11.T(o|¨)gel F,Hu Z,Weiss K,et al.Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.Am J Physiol Renal Physiol.2005 Jul;289(1):F31-42.Epub 2005 Feb 15.
12.Kim HS,Zhang X,Choi YS.Activation and proliferation of follicular dendritic cell-like cells by activated T lymphocytes.J Immunol.1994 Oct 1;153(7):2951-61.
13.Chen X,Armstrong MA,Li G Mesenchymal stem cells in immunoregulation.Immunol Cell Biol.2006 Oct;84(5):413-21.
14.Glennie S,Soeiro I,Dyson PJ,et al.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 2005;105:2821-7.
15.Kraus KH,Kadiyala S,Wotton H,et al.Critically sized osteo-periosteal femoral defects:a dog model.J Invest Surg.1999 Mar-Apr;12(2):115-24.
16.Pereira RF,O'Hara MD,Laptev AV,et al.Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta.Proc Natl Acad Sci USA.1998 Feb 3;95(3):1142-7.
17.焦强,卫小春,陆向东,等.转化生长因子-β1 和血清对人骨髓基质干细胞增殖及向软骨细胞诱导分化的影响.中华创伤骨科杂志。2005,10:960-962.
1.Friedenstein AJ,Piatetzky2Shapiro Ⅱ,Pet rakova KV.Ostreogenesis in transplants of bone marrow cells[J].J Embryol Exp Morphol,1966,16:381-390.
2.Barry FP,Murphy JM.Mesenehymal stem cells:clinical applications and biological characterization[J].Int J Bioehem Cell Biol,2004,36:568-584.
3.Pittenger MF,Mackay AM,Beck SC,et al.Multilineage potential of adult human mesenehymal stem cells[J].Science,1999,284:143-147.
4.Le Blank K,Rasmusson I,Sundberg B,et al.Treatment of severe acute graftversushost disease with third party haploidentieal mesenehymal stem cells[J]Lancet,2004,363:1439-1441.
5.Friedens tein A J,Deriglasova UF,Kulagina NN,et al.Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony as say method.Exp Hematol 1974;2(2):83-92
6.Lis ignoli G,Remiddi G,Cattini L,et al.An elevated number of differentiated os teoblas t colonies can be obtained from rat bone marrow stromal cells using a gradient isolation procedure.Connect Tis sue Res 2001;42(1):49-58
7.Eneina NR,Billotte WG,Hofmann MC.Immunomagnetie isolation of osteoprogenitors from human bone marrow s troma.Lab Invest 1999;79(4):449-457
8.魏会平,张世敏,刘继云,等.大鼠骨髓间充质干细胞的分离、培养及生物学鉴定[J].河北北方学院学报:医学版,2005,22(1):23-25
9.吴洁莹,廖灿,许遵鹏,等.人骨髓间充质干细胞分离鉴定方法的改进[J].中国实验血液学杂志,2006,14(3):557-560
10.Wulf GG,Jackson KA,Goodell MA.Somatic stem cell plasticity:current evidence and emerging concepts.Exp Hemato12001;29(12):1361-1370
11.康新勤,臧伟进,宋土生,等.大鼠骨髓间充质干细胞分离培养及其形态观察[J].西安交通大学学报:医学版,2003,24(5):518-519
12.Barry FP.Mesenchymal stem cell therapy in joint disease.Novartis Found Symp 2003;249:86-96
13.Anokhina EB,Buravkova LB.Heterogeneity of s tromal precursor cells isolated from rat bone marrow.Ts itologiia 2007;49(1):40-47
14.Dominici M,Le Blanc K,Mueller I,et al.Minimal criteria for defining multipotent mesenchymal s tromal cells.The Intemational Society for Cellular Therapy pos ition s tatement.Cytotherapy 2006;8(4):315-317
1.Trentham DE,Townes AS,Kang AH.Autoimmunity to type Ⅱ collagen an experimental model ofarthritis.J Exp Med,1977 Sep 1;146(3):857-68.
2.Courtenay JS,Dallman MJ,Dayan AD,Martin A,Mosedale B.Immunisation against heterologous type Ⅱ collagen induces arthritis in mice.Nature,1980 Feb 14;283(5748):666-8.
3.Myers LK,Rosloniec EF,Cremer MA,Kang AH.Collagen-induced arthritis,an animal model ofautoimmunity.Life Sci,1997;61(19):1861-78.
4.Brand DD,Kang AH,Rosloniec EF.The mouse model of collagen-induced arthritis.Methods Mol Med,2004;102:295-312.
5.Brahn E,Peacock D J,Banquedgo ML.Suppression of collagen-induced arthritis by combination cyclosporin A and methotrexate therapy.Arthritis Rheum,1991Oct;34(10):1282-8.
6.Schett G,Middleton S,Bolon B,et al.Additive bone-protective effects of anabolic treatment when used in conjunction with RANKL and tumor necrosis factor inhibition in two rat arthritis models.Arthritis Rheum,2005 May;52(5):1604-11.
7.Bakharevski O,Stein-Oakley AN,Thomson NM,Ryan PF.Collagen induced arthritis in rats.Contrasting effect of subcutaneous versus intradermal inoculation of type Ⅱ collagen..J Rheumatol,1998 Oct;25(10):1945-52.
8.Morgan ME,Flierman R,van Duivenvoorde LM,Witteveen H J,van Ewijk W,van Laar JM,de Vries RR,Toes RE.Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+regulatory T cells.Arthritis Rheum.,2005 Jul;52(7):2212-21.
9.李小峰.重视类风湿关节炎发病机制及治疗的研究进展.中华风湿病学杂志.2008,12(1).1-3.
10.Le Blanc K,Ringd(?)n O.Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med.2007,Nov;262(5):509-25.
11.Ozaki K,Sato K,Oh I,et al.Mechanisms of immunomodulation by mesenchymal stem cells.Int J Hematol.2007,Jul;86(1):5-7.
12.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood.2007 Nov 15;110(10):3499-506.
13.Fibbe WE,Nauta A J,Roelofs H.Modulation of immune responses by mesenchymal stem cells.Ann N Y Acad Sci.2007 Jun;1106:272-8.
14.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression? Trends Immunol.2007 May;28(5):219-26.Epub 2007 Apr.
15.McTaggart S J,Atkinson K.Mesenchymal stem cells:immunobiology and therapeutic potential in kidney disease.Nephrology(Carlton).2007 Feb;12(1):44-52.
16.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):435-41.
17.Djouad F,Fritz V,Apparailly F,et al.Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.Arthritis Rheum.2005 May;52(5):1595-603.
18.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
19.Leipe J,Skapenko A,Lipsky PE,Schulze-Koops H.Regulatory T cells in rheumatoid arthritis.Arthritis Res Ther.2005;7(3):93.
20.Roll P,Palanichamy A,Kneitz C,Domer T,Tony HP.Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis.Arthritis Rheum.2006 Aug;54(8):2377-86.
21.Yoshinori Nonomura,Hitoshi Kohsaka,Kenji Nagasaka.Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis.The Journal of Immunology,2003,171:4913-4919.
22.Arend WP,Dayer JM.Inhibition of the production and effects of intedeukin-1 and tumor necrosis factor alpha in rheumatoid arthritis.Arthritis rheum,1995,38:151-160
23.Mukherjee P,Yang SY,Wu B,et al.Tumour necrosis factor receptor gene therapy affects cellular immune responses in collagen induced arthritis in mice.Ann Rheum Dis.2005Nov;64(11):1550-6.
24.Catrina AI,af Klint E,Ernestam S,et al.Anti-tumor necrosis factor therapy increases synovial osteoprotegerin expression in rheumatoid arthritis.Arthritis Rheum.2006Jan;54(1):76-81
25.Wislowska M,Jakubicz D.Preliminary evaluation in rheumatoid arthritis activity in patients treated with TNF-alpha blocker plus methotrexate versus methotrexate or leflunomide alone.Rheumatol Int.2007 Jan 18;[Epub ahead of print]
26.董怡,张卓莉.白细胞介素-1 家族在类风湿关节炎和骨关节炎中的作用.中华风湿病学杂志2004,5:257-258
27.Ainola MM,Mandelin JA,Liljestrom MP,et al.Pannus invasion and cartilage degradation in rheumatoid arthritis:involvement of MMP-3 and interleukin-lbeta.Clin Exp Rheumatol.2005 Sep-Oct;23(5):644-50.
28.Romagnani S.Regulation of the T cell response[J].Clin Exp Allergy,2006,36:1357-1366.
29.Me Innes IB,L iew FY.Cytokine networks towards new therapies for rheumatoid arthritis[J].Nat Clin Pract Rheumatol,2005,1:31-39.
30.HonoratiMC,Neri S,Cattini L,et al.Interleukin-17,a regulator of angiogenic factor release by synovial fibroblasts[J].Osteoarthritis Cartilage,2006,14:345-352.
31.Lubberts E,KoendersM I,van den BergWB.The role of Tcell interleukin-17 in conducting destructive arthritis:lessons from animalmodels[J].Arthritis Res Ther,2005,7:29-37.
32.Kirkham BW,LassereMN,Edmonds JP,et al.Synovial membrane cytokine expression is p redictive of joint damage progression in rheumatoid arthritis:a two-year prospective study (the damage study cohort)[J].Arthritis Rheum,2006,54:1122-1131.
33.Rohn TA,Jennings GT,HemandezM,et al.Vaccination against EL-17 supp resses autoimmune arthritis and encephalomyelitis[J].Eur J Immuno,2006,36 (11):2857-2867.
34.Szekanecz Z,Haines GK,Harlow LA,et al.Increased synovial exression of transforming growth factor (TGF)-receptor endoglin and TGF-pl in rheumatoid arthritis:possible interactions in the pathogenesis of the disease[J].Clin Immunopathol,1995,76(2):1872194.
35.Nakajima T,Aono H,Hasunuma T,et al.Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes[J].Arthritis Rheum,1995,38 (4):4852491.
36.Firestein GS,Yeo M,Zvaifler NJ.Apoptosis in Rheumatoid arthritis synovium[J].J Clin Invest,1995,96 (3).163121638.
37.Chen W,Jin W,Wahl SM.Engagement of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) induce transforming growth factorβ(TGF-β) production by murine CD4~+ T cell[J].J Exp Med,1998,188 (10):184921857.
38.Mcadam AJ,Schweitzer AN,Sharpe AH.The role of B7 co-stimulation in activation and diffrentiation of CD4~+ and CD8~+ T cell[J].Immunol Rev,1998,165 (2):2312247.
39.Mandelblbrot DA,McAdam AJ,Sharpe AH.B7-1 or B7-2 isrequied to produce the lymphoproferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)[J].J Exp Med,1999,189 (2):4352440.
40.Shevach EM,MuHugh RS,Piccirillo CA,et al.Control of T-cell activation by CD4~+CD25~+ suppressor T cells[J].Immunol Rev,2001,182:58-67
41.Leipe J,Skapenko A,Lipsky PE,et al.Regulatory T cells in rheumatoid arthritis[J].Arthritis Res Ther,2005,7(3):93-99
42.Minami R,Sakai K,Mivamura T,et al.The role of CD4~+CD25~+ regulatory T cells in patients with Rheumatoid Arthritis[J].Nihon Rinsho Meneki Gakkai Kaishi,2006,29(1):37-4
43.Gonzalez A,Andre-Schmutz I,Carnaud C,et al.Damage control,rather than unresponsiveness,effected by protective DX5+ T cells in autoimmune diabetes[J].Nature Immunol,2001,2(12):1117-1125
44.Taams L,Vukmanovic SM,Salmon M.Immune regulation by CD4~+CD25~+ regulatory T cells:implications for transplantation tolerance[J].Trans Immuno1,2003,11(3-4):277-285
45.Maloy KJ,Salaunl,Cahill R,et al.CD4~+CD25~+ T(R)cells suppress innate immune pathology through cytokine-dependent mechanisms[J].Exp Med,2003,197(1):111-119
46.Powrie F,Carlino J,Leach MW,et al.A critical role for transforming growth factor beta but not intedeukin 4 in the suppression of T helper tupe 1 mediated colitis by CD45RB(Iow)CD~(4+)T cells[J].J Exp Med,1996,183:2669-2674
47.Chen W,Jin W,Wahl SM.Engagement ofcytotoxic Tlymphocyte-associated antigen 4(CTLA-4)induces transforming growth factor beta(TGF-beta)production by murine CD4(+)T cells[J].J Exp Med,1998,188:1849-1857
48.Kukreja A,Cost G,Market J.et al.Multiple immuno-regulatory defects in type-1diabetes[J].Clin Invest,2002,109(1):131-140
49.Van Amelsfort JM,Jacobs KM,Bijlsma JW,et al.CD4~+CD25~+ regulatory T cells in rheumatoid arthritis:differences in the presence,phenotype,and function between peripheral blood and synovial fluid[J].Arthritis Rheum,2004,50(9):2775-85
50.Lawson CA,Brown AK,Bejarano V,et al.Early rheumatoid arthritis is associatal with a deficit in the CD~(4+)CD~(25)~(high)regulatory T cells population in peripheral blood [J].Rheumatology(Oxford),2006,45(10):1210-1217
51.Toubi E,Kessel A,Mahmudov I,et al.Increased spontaneous apoptosis of CD~(4+)CD~(25+)T cell in patients with active rheumatoid arthritis is reduced by infliximab[J].Ann N Y Acad Sci,2005,1051:506-514
52.李萍,毕黎琦,栗占国.表达 Foxp3的调节性 T 细胞在类风湿关节炎发病中的意义[J].中国免疫学杂志,2006,4(22):386-374.
53.de Kleer IM,Wedderbum LR,Taams LS,et al.CD~(4+)CD~(25)~(bright)regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis[J].J Imm unol,2004,172(10):6435-6443.
54.Zha Y,Blank C,Gajewski TF.Negative regulation of T-cell function by PD-1.Crit Rev Immunol.2004,24(4):229-237.
55.Minguell JJ,Erices A,Conget P.Mesenchymal stem cells.Exp Biol Med 2001,26(6):507
56.Hart Q,Deng W,Zhao RC,et al.Allogeneic adult s tern cells es-tablish longterm residence in recipient tissues and facilitate skin transplantation.ExpHematol,2003,31(7):158
57.Bartholomew A,Sturgeon C,Siatskas M,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol,2002,30:42-48.
58.Goncalves MA,de Vries AA.Human mesenchymal stem cells ectopically expressing full-length dystrophin can complement Duchenne muscula dystrophy myotubes by cell fusion.Hum Mol Genet,2006,15:213-221.
59.Tse WT,Pendleton JD,Beyer WM,et al.Suppres s ion of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation.Transplantation,2003,75(3):389-397.
1.HaasJ,Bauer P,Rolfs A,et al.Immunocytochemical characterization of in Vitro PKH26-1abelled and intracerebrally transplanted neonatal cells[J].Acta Histochem,2000,102:273-280.
2.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):435-41.
3.Kraus KH,Kadiyala S,Wotton H,et al.Critically sized osteo-periosteal femoral defects:a dog model.J Invest Surg.1999 Mar-Apr;12(2):115-24.
4.Nagaya N,Fujii T,Iwase T,et al.Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis.Am J Physiol Heart Circ Physioi,2004,287:2670-2676.
5.Pereira RF,O'Hara MD,Laptev AV,et al.Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta.Proc Natl Acad Sci USA.1998 Feb 3;95(3):1142-7.
6.焦强,卫小春,陆向东,等.转化生长因子-β1 和血清对人骨髓基质干细胞增殖及向软骨细胞诱导分化的影响冲华创伤骨科杂志。2005,10:960.962.
7.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
1.Friedenstein AJ,Piatetzky2Shapiro Ⅱ,Pet rakova KV.Ostreogenesis in transplants of bone marrow cells[J].J Embryol Exp Morphol,1966,16:381-390.
2.Barry FP,Murphy JM.Mesenchymal stem cells:clinical applications and biological characterization[J].Int J Biochem Cell Biol,2004,36:568-584.
3.Pittenger MF,Mackay AM,Beck SC,et al.Multilineage potential of adult human mesenchymal stem cells[J].Science,1999,284:143-147.
4.Le Blank K,Rasmusson I,Sundberg B,et al.Treatment of severe acute graftversushost disease with third party haploidentical mesenchymal stem cells[J]Lancet,2004,363:1439-1441.
5.Tse WT,Pendleton JD,BeyerWM,et al.[J].Transp lantation,2003,75(3):389-3971.
6.Elena K,Joseph DM,Valentina Z,et al.[J].Biomed Sci,2005,12(1):47-57.
7.Eliopoulos N,Stagg J,Lejeune L,et al.[J].Blood,2005,106(13):4057-4065.
8.Mills KH.Regulatory Tcells:friend or foe in immunity to infection[J].Nat Rev Immunol,2004,4:841-855.
9.Steinman RM,Nussenzweig MC.Avoiding horror autotoxicus:the importance of dendritic cells in peripheral T cell tolerance[J].Proc Natl Acad Sci USA,2002,99:351-358.
10.Zhang W,Ge W,Li C,et al.Effects of mesenchymal stemcells on differentiation,maturation,and function of human monocyte-derived dendritic cells[J].Stem Cells Dev,2004,13:263-271.
11.J iang XX,Zhang Y,Liu B,et al.Human mesenchymal stem cells inhibit differentiation and function of monocytederived dentritic cells.Blood,2005,105:4120-4126.
12.何津,张毅,江小霞等.人骨髓间充质干细胞对脐血 T 淋巴细胞转化的影响.中国实验血液学杂志,2003,11:11-14.
13.Deng W,Han Q,Zhao RC,et al.Longterm Distribution of Adult Stem Cells in Different Tissues after Transplantation.Stem Cell and Cellular Therapy,2003,1:62-65.
14.Devine SM,Cobbs C,Jennings M.Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates.Blood,2003,101:2999-3001.
15.Azizi SA,Stokes D,Augelli B J,et al.Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats2similarities to astrocyte gratis.Proc Natl Acad Sci USA,1998,95:3908-3913.
16.Toma C,Pittenger MF,Cahill KS,et al.Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart.Circulation,2002,105:93-98.
17.Saito T,Kuang JQ,Bittira B,et al.Xenotransplant cardiac chimera:immune tolerance of adult stem cells.Ann Thorac Surg,2002,74:19-24.
18.Liechty KW,MacKenzie TC,Shaaban AF,et al.Human mesenchymal stem cells engraft and demonstrate site2specific differentiation after in utero transplantation in sheep.Nat Med,2000,6:1282-1286.
19.Han Q,Deng W,Zhao RC,et al.Allogeneic adult stem cells establish longterm residence in recipient tissues and facilitate skin transplantation.Exp Hematol,2003,31:158.
20.Bartholomew A,Sturgeon C,Siatskas M,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol,2002,30:42-48
21.Zanjani ED,AlmeidaPorada G,Ascensao JL,et al.Transplantation of hematopoietic stem cells in utero.Stem cells,1997,15(Suppl):79-92.
22.Li Y,Hisha H,Inaba M,et al.Evidence for migration of donorbone marrow stromal cells into recipient thymus after bone marrowtransplantation plus bone grafts:a role of stromal cells in positive selection.Exp Hematol,2000,28:950-960.
23.BardaSaad M,Rozenszajn LA,Ashush H,et al.Adhesion molecules involved in the interactions between early T cells and mesenchymal bone marrow stromal cells.Exp Hematol,1999,27:834-844.
24.Ruegemer JJ,Ho SN,Augustine JA,et al.Regulatory effects of transforming growth factor-P on IL-22 and IL-4-dependent T cell cycle progression.J Immunol,1990,144:1769-1776.
25.Ahuja SS,Paliogianni F,Yarnada H,et al.Effect of transforming growth factor-P on early and late activation events in human T cells.J Immunol,1993,150:3109-3118.
26.Fox FE,Ford HC,Douglas R,et al.Evidence that TGF-P can inhibit T-lymphocyte proliferation through paracrine and autocrine mechanisms.Cell Immunol,1993,150:45-58.
27.Mossalayi MD,Mentz F,Ouaaz F,et al.Early human thymocyte proliferation is regulated by an externally controlled autocrine transforming growth factor-Pi mechanism.Blood,1995,85:3594-3601.
28.BardaSaad M,Rozenszajn LA,Globerson A,et al.Selective adhesion of immature thymocytes to bone marrowstromal cells:relevance to T cell lymphopoiesis.Exp Hematol,1996,4:386-391.
29.Sarun S,Dalloul AH,Laurent C,et al.Human CD34+thymocyte maturation:pre-T and NK cell differentiation on neonatal thymic stromal cell culture.Cell Immunol,1998,190:23-32.
30.Zha Y,Blank C,Gajewski TF.Negative regulation of T-cell function by PD-l.Crit Rev Immunol.2004,24(4):229-237.
31.Minguell JJ,Erices A,Conget P.Mesenchymal stem cells.Exp Biol Med 2001,26(6):507
32.Han Q,Deng W,Zhao RC,et al.Allogeneic adult s tern cells es-tablish longterm residence in recipient tissues and facilitate skin transplantation.ExpHematol,2003,31(7):158
33.Bartholomew A,Sturgeon C,Siatskas M,et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol,2002,30:42-48.
34.Goncalves MA,de Vries AA.Human mesenchymal stem cells ectopically expressing full-length dystrophin can complement Duchenne muscula dystrophy myotubes by cell fusion.Hum Mol Genet,2006,15:213-221.
35.Tse WT,Pendleton JD,Beyer WM,et al.Suppres s ion of allogeneic T-cell proliferation by human marrow stromal cells:implications in transplantation.Transplantation,2003,75(3):389-397.
36.Krampera M,Glennie S,Dyson J,et al.Bone marrow mesenchymal stem cells inhibit there sponse of nave and memory antigen specific T cells to their cognate peptide.Blood,2003,101:3722-3729.
37.Blanc KL,Rasmusson I,Gotherstrom C,et al.[J].Scand J Immunol,2004,60(3):307-315.
38.DiNicolaM,Carlo2Stella C,MagniM,et al.[J].Blood,2002,99(10):3838-3843.
39.GrohME,Maitra B,Szekely E,et al.[J].Exp Hematol,2005,33(8):928-934.
40.Aggarwal S,Pittenger F.[J].Blood,2005,105(4):18151822.
41.Rasmusson I,Ringden O,SundbergB,et al.[J].Exp Cell Res,2005,305(1):33-41.
42.Cecilia G,Olle R,Charlotte T,et al.[J].Am J Obstet Gynecol,2004,190(1):239-245.
43．金建刚,危江伟,宁红梅,等．[J]．中华血液学杂志,2005,26(6)：339-341．
44.Krampera M,Lorenzo Cosmi L,Angeli R,et al.[J].Stem Cells,2006,24(2):386-398.
45.Meisel R,ZibertA,LarycaM,et al.[J].Blood,2004,103(12):4619-462.
46.Andrea A,Roberta T,Simone MN,et al.[J].Eur J Immunol,2005,35 (5):1482-1490.
47.Sarah G,Ines S,Peter JD,et al.[J].Blood,2005,105(7):2821-2827.
48.Maccario R,Podesta M,Moretta A,et al.Interaction of humanmesenchymal stem cells with cells involved in alloantigen specific immune response favors the differentiation of CD4~+Tcell subsets expressing a regulatory/suppressive phenotype.Haematologica,2005,90:516-525.
49.Aggarwal S,PittengerMF.Human mesenchymal stem cellsmodulate allogeneic immune cell response.Blood,2005,105:1815-1822.
50.Beyth S,Borovsk Z,Mevorach D,et al.Human mesenchymal stem cells alter antigen presenting cellmaturation and induce Tcell unresponsiveness.Blood,2005,105:2214-2219.
51.Andrea A,Roberta T,Simone MN,etal.[J].Eur J Immunol,2005,35 (5):1482-1490.
52.DengWM,Han Q,L iao L,et al.[J].DNA Cell Biol,2005,24(7):458-463.
53.Corcione A,Federica B,Elisa F,et al.[J].Blood,2006,107(1):367-372.
54.Rasmusson I,Ringden O,Simdberg B,et al.Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes,but not activated cytotoxic T lymphocytes or natural killer cells.Transp lantation,2003,76:1208-1213
55.Potian JA,Aviv H,Ponzio NM,et al.Vetolike activity of mesenchymal stem cells:functional discrimination between cellular responses to alloantigens and recall antigens.J Immunol,2003,171:3426-3434.
56.Angoulvant D,Clerc A,Benchalal S,et al.Human mesenchymal stem cells supp ress induction of cytotoxic response to alloantigens.Biorheology,2004,41:469-476.
57.Aggarwal S,PittengerMF.Human mesenchymal stem cellsmodulate allogeneic immune cell response.Blood,2005,105:1815-1822.
58.Silva WA Jr,Covas DT,Panepucci RA,et al.The profile of gene expression of human marrow mesenchymal stem cells[J].Stem Cells,2003,21:661-669.
59.Neuss S,Becher E,Woltje M,et al.Functional expression of HGF and HGF receptor/cmet in adult human mesenchymal stem cells suggests a role in cell mobilization,tissue repair,and wound healing[J].Stem Cells,2004,22:405-414.
60.Chunmeng S,Tianmin C,Yongping S,et al.Effects of dermal multipotent cell transplantation on skin wound healing[J].J Surg Res,2004,121:13-19.
61.Azuma H,Takahara S,Mat sumoto K,et al.Hepatocyte growth factor prevents the development of chronic allograft nephropathy in rats[J].J Am Soc Nephrol,2001,12:1280-1292.
62.Asseman C,Powrie F.Interleukin-10 is a growth factor for a population of regulatory T cells[J].Gut,1998,42:157-158.
63.Di Nicola M,CarloStella C,Magni M,et al.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J].J Cell Physiol,2004,200:400-406.
64.Aggarwal SM,Ittenger FP.Human mesenchymal stem cells modulate allogeneic immune cell responses[J].Blood,2005,105:1815-1822.
65.Arilkawa T,Omural K.Morita,Regulation of bone morphogenetic protein-expression by endogenous prostaglandin E2 inhuman mesenchymal stem cells.[J].J Cell Physiol,2004,200:400-406.
66.Stagg J,Pommey S,Eliopoulos N,et al.Interferon-gammastimulated marrow stromal cells:a new type of nonhematopoietic antigen-presenting cell[J].Blood,2006,107:2570-2577.
67.Frumento G,Rotondo R,Tonetti M,et al.Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,32 dioxygenase[J].J Exp Med,2002,196:459^68.
68.Nagaya N,Fujii T,Iwase T,et al.Intravenous administration of mesenchymal stem cells imp roves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis.Am J Physiol Heart Circ Physiol,2004,287:2670-2676.
69.Devine SM,Cobbs C,JenningsM,et al.Mesenchymal stem cells distribute to a wide range of tissue following systemic infusion into nonhuman primates.Blood,2003,101:2999-3001.
70.DengW,Han Q,Zhao RC,et al.Longterm distribution of adult stem cells in different tissues after transp lantation.Stem Cell Cellular Ther,2003,1:62-65.
71.向国安,张刚庆,方驰华等.同种异体骨髓间质干细胞移植在大鼠肝内定居能力初步研究.第一军医大学学报,2005,25:994-997.
72.Campagnoli C,Roberts IA,Kumar S,et al.Identification of mesenchymal stem rogenitor cells in human firsttrimester fetal blood,liver and bone marrow.Blood,2001,98:2396-2402.
73.Lee K,MajumdarMK,BuyanerD,et al.Human mesenchymal stem cells maintain transgene expression during expansion and differentiation.Mol Ther;2001;3:857-866.
74.Paul B,Morgan D,Wechsler A,et al.Chemokine induced migration of human mesenchymal stem cells:a strategy for directing cardiac repair.J American College Surgeons,2004,199:33-38.
75.Tsuchiya K,Chen G,Ushid T,et al.Effects of cell adhesion molecules on adhesion of ehondrocytes,ligament cells and mesenchymal stem cells.Mater Sci Engin,2001,17:79-82.
76.SegersVF,van2Riet I,Andries LJ,et al.Mesenehymal stem cell adhesion to cardiac microvascular endothelium:activators and mechanisms.Am J Physiol Heart Circ Physiol,2006,290:1370-1377.
77.HonezarenkoM,Le Y,SwierkowskiM,et al.Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors.Stem Cells,2006,24:1030-1041.
78.赛音其木格,侯相麟,赵丽,等.成人骨髓间充质干细胞分化为成骨细胞的研究[J].临床血液学杂志,2005,18(4):200-203.
79.Jaiswal N,Haynesworth SE,Caplan AI,et al.Osteogenic differentiation of purified,culture-expanded human mesenehymal stem cells in vitro.J Cell Biochem 1997,64(2):295-312.
80.易敬林,杨海军,丁伟荣,等.人骨髓间充质干细胞的分离培养及其生物学特性的研究[J].江西医学院学报,2005,45(6):1-5.
81.唐文洁,李玛琳,邱垂源,等.F6F-2对人骨髓间充质干细胞增殖和向成骨细胞分化的影响[J].细胞生物学杂志,2005,27(6):673-678.
82.Asahara T,Murohara T,Sullivan A,et al.Isolation of putative progenitor endothelial cells for angiogenesis[J].Science,1997,275(5302):964-967.
83.J iang Y,Jahagirdar BN,Reinhardt RL,et al.Pluripotency of mesenchymal stem cells derived from adult marrow[J].Nature,2002,418(6893):41-49.
84.Levenberg S,Golub JS,Langer R,et al.Endothelial cells derived from human embryonic stem cells[J].Proc Natl Acad Sci USA,2002,99 (7):4391-4396.
85.Yong BG,Butler DL,Weber W,et al.Mesenchymal stem cells-based repair achiles tendon[J].Trans Orthop Res Soc,1997,22:249-254.
86.Yoo JU,Barthel TS,Nishimura K,et al.The chondrogenic potential of human bonemarrow-derived mesenchymal progenitor cells[J].J Bone Joint Surg(Am),1998,80:1745-1747.
87.Glatz F,Neumeister M,Sucky H,et al.A tissue-engineering technique for vascularized laryngotracheal reconstruction[J].Arch Otolaryngol Head Neck Surg,2003,129:201-206.
88．杨志明主编．组织工程基础与临床[M]．成都：四川科学技术出版社,2000,37-57．
89.Barry F,Boynton RE,Liu B,et al.Chondrogenic differentiation of mesenchymal stem cells from bone marrow;Differentiation 2dependent gene expression of matrix components[J].Exp Cell Res,2001,268:189-200.
90.Shea CM,Edgar CM,Einhorn TA,et al.BMP treatment of mesenchymal stem cells induces both chondrogenesis and osteogenesis[J].J Cell Biochem,2003,90:1112-1127.
91.Ma HL,Hung SC,Lin SY,et al.Chondrogenesis of human mesenchymal stem cells encapsulated in alginate beads[J].J Biomed Mater Res,2003,64A:273-281.
92.Worster AA,Nixon AJ,Brower-Toland BD,et al.Effect of transforming growth factor-beta on chondrogenic differentiation of cultured equine mesenchymal stem cells[J].Am J Vet Res,2000,61(9):1003.
93.Watanabe H,de Caestecker MP,Yammada Y.Transcriptional crosstalk between smad,ERK1/2,and p38 mitogen-activated protein kinsae pathways regulates transforming growth factor2beta2induced aggrecan gene expression in chondrogenic ATDC5 cells[J].J Biol Chem,2001,276:14466-14473.
94.Le Blanc K,Ringden O.Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med.2007,Nov;262(5):509-25.
95.Ozaki K,Sato K,Oh I,et al.Mechanisms of immunomodulation by mesenchymal stem cells.Int J Hematol.2007,Jul;86(1):5-7.
96.Nauta AJ,Fibbe WE.Immunomodulatory properties of mesenchymal stromal cells.Blood.2007,Nov 15;110(10):3499-506.
97.Fibbe WE,Nauta AJ,Roelofs H.Modulation of immune responses by mesenchymal stem cells.Ann N Y Acad Sci.2007 Jun;1106:272-8.
98.Uccelli A,Pistoia V,Moretta L.Mesenchymal stem cells:a new strategy for immunosuppression?Trends Immunol.2007 May;28(5):219-26.Epub 2007 Apr 2.
99.McTaggart SJ,Atkinson K.Mesenchymal stem cells:immunobiology and therapeutic potential in kidney disease.Nephrology (Carlton).2007 Feb;12(1):44-52.
100.Krampera M,Pasini A,Pizzolo G,et al.Regenerative and immunomodulatory potential of mesenchymal stem cells.Curr Opin Pharmacol.2006 Aug;6(4):43541.
101.Djouad F,Fritz V,Apparailly F,et al.Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis.Arthritis Rheum.2005 May;52(5):1595-603.
102.Augello A,Tasso R,Negrini SM,et al.Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis.Arthritis Rheum.2007 Apr;56(4):1175-86.
103.Togel F,Hu Z,Weiss K,et al.Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.Am J Physiol Renal Physiol.2005 Jul;289(1):F3142.Epub 2005 Feb 15.
104.Kim HS,Zhang X,Choi YS.Activation and proliferation of follicular dendritic cell-like cells by activated T lymphocytes.J Immunol.1994 Oct 1;153(7):2951-61.
105.Chen X,Armstrong MA,Li G Mesenchymal stem cells in immunoregulation.Immunol Cell Biol.2006 Oct;84(5):413-21.
106.Glennie S,Soeiro I,Dyson PJ,et al.Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells.Blood 2005;105:2821-7.
107.Kraus KH,Kadiyala S,Wotton H,et al.Critically sized osteo-periosteal femoral defects:a dog modelJ Invest Surg.1999 Mar-Apr;12(2):115-24.