系统性红斑狼疮干细胞的基础和临床应用研究
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摘要
第一部分系统性红斑狼疮患者骨髓CD34~+细胞表面标志及与病情活动的相关性分析
目的：研究系统性红斑狼疮(SLE)患者骨髓CD34~+细胞表面标志的变化，了解SLE患者造血干细胞是否存在异常。
方法：应用流式细胞术CD45／SSC设门分析10例SLE患者和10例正常人骨髓CD34~+细胞CD90、CD117、CD123、CD164、CD166、CD95(FAS)、FAS-L、HLA-DR等表面分子的表达及其与病情活动指标的相关性。
结果：活动期SLE患者骨髓CD34~+细胞比例(1.48±0.41％，n=7)明显低于正常人(2.31±0.75％，P＜0.01，n=10)，非活动期患者(2.04±0.44％，n=3)与正常人相比差异无显著性。SLE患者CD34~+CD95~+的表达明显高于正常人(48.31±10.59％vs24.33±11.1％，P＜0.05)，患者CD123和CD166也明显高于正常人(44.9±21.5％vs19.5±4.4％，P＜0.05；30.9±19.54％vs 10.7±5.5％，P＜0.05)。其余表面标志的表达与正常人相比无明显差异。CD123表达率与患者外周血白细胞计数负相关(r=-0.700，P＜0.05)，与SLE疾病活动指数(SLEDAI)评分无相关性。CD166表达与SLEDAI(r=+0.472，P＜0.05)，血清C3(r=-0.712，P＜0.01)，24小时尿蛋白(r=+0.558，P＜0.05)显著相关。
结论：SLE患者骨髓CD34~+细胞CD95、CD123、CD166的表达率增加，CD123的表达率与外周血白细胞计数显著负相关；CD166的表达率与SLEDAI评分、24小时尿蛋白显著正相关，与血清C3显著负相关，CD166可能是一个新的SLE疾病活动性标志。
第二部分人骨髓间充质干细胞移植治疗MRL／Ipr狼疮鼠的疗效和机制
目的：探讨人骨髓间充质干细胞(MSC)移植对MRL／lpr狼疮鼠的疗效及作用机制。
方法：体外分离、培养、扩增正常人MSC。MRL／lpr鼠随机分为对照组、环磷酰胺(CTX)治疗组、MSC治疗组和MSC＋CTX治疗组。16周龄时，CTX组和MSC＋CTX组给予CTX 100mg／kg×2d腹腔注射，24h后MSC组和MSC＋CTX组经尾静脉输入人MSC。考马斯亮蓝法检测24h尿蛋白含量，间接免疫荧光检测血清抗核抗体(ANA)、抗双链DNA(ds-DNA)抗体滴度，流式细胞仪检测外周血T细胞亚群，RT-PCR检测脾脏B淋巴细胞活化因子(BAFF)mRNA表达水平，免疫组化检测肾脏转化生长因子β(TGF-β)，纤维连接蛋白(FN)，血管内皮生长因子(VEGF)的表达，免疫荧光检测肾小球补体C3沉积。
结果：①24、28、32周24h尿蛋白定量MSC组(4.3±0.8mg，5.4±0.8mg，5.8±0.8mg)和MSC＋CTX组(2.8±1.0mg，3.9±0.4mg，4.5±1.0mg)均显著低于对照组(9.0±1.3mg，9.3±0.6mg，10.0±1.6mg)(P＜0.05)；MSC＋CTX组(2.8±1.0mg，3.9±0.4mg，4.5±1.0mg)显著低于CTX组(5.1±1.0mg，7.7±1.1mg，9.6±1.9mg)(P＜0.05)。②28周龄时抗ds-DNA抗体滴度MSC＋CTX组(2.7±0.8)显著低于对照组(4.6±0.9)(P＜0.05)。③32周龄时体重MSC组(38.6±3.3g)和MSC＋CTX组(35.8±3.7g)显著高于对照组(32.8±3.0g)(P＜0.05)。④32周龄时，血清肌酐MSC组(13.5±2.2μmol／L)和MSC＋CTX组(12.7±4.2μmol／L)均显著低于对照组(20.8±5.1μmol／L)(P＜0.05)。⑤32周龄时CD4~+T细胞和Th2亚群MSC组(76.4％±1.9％，58.4％±1.8％)和MSC＋CTX组(73.9％±3.2％，57.6％±3.2％)均显著低于对照组(82.7％±2.9％，64.2％±2.8％)(P＜0.05)。⑥治疗组脾脏BAFF mRNA表达显著降低。⑦治疗组肾组织TGF-β、FN、VEGF表达降低，肾小球中C3的沉积显著减少，肾脏组织学病变改善。
结论：人MSC移植治疗MRL／lpr鼠有效，调节Th1／Th2平衡，降低脾脏BAFFmRNA表达，抑制B细胞抗体产生，抑制TGF-β、FN、VEGF表达，减轻肾小球硬化，可能是MSC移植治疗MRL／lpr鼠有效的机制之一。
Part 1 Abnormal surface markers expression on bone marrow CD34~+ cells and correlation with disease activity in patients with systemic lupus erythematosus
Objective: To explore the phenotypic characteristics of bone marrow (BM) CD34+ cells in patients with SLE and its relationship with SLE disease activity.
Methods: 10 SLE patients and 10 healthy subjects were recruited, their BM CD34+ cells were analyzed by flow cytometric analysis with CD45/SSC gating for the expression of CD90, CD95, CD117, CD123, CD164, CD166, FAS-L and HLA-DR.
Results: The percentage of BM CD34+ cells was significantly decreased in active SLE patients (1.48±0.41%, n=7) compared to healthy controls (2.31±0.75%, n=10, p＜0.01), but no significant difference was found between the inactive patients (2.04±0.44%, n=3) and the controls. The expression of CD95, CD123 and CD166 on BM CD34+ cells were significantly increased in SLE patients (48.31±10.59%, 44.9±21.5%, 30.9±19.54%, n=10) when compared with control subjects (24.33±11.1%, 19.5±4.4%, 10.7±5.5%, respectively, n=10, p＜0.05). The increased CD123 expression was negatively correlated with the number of peripheral white blood cells (r=-0.700, p＜0.05, n=10). The percentage of CD166 expression was found significantly correlated with the index of SLE disease activity (r=0.472, p＜0.05, n=10), and 24 hour proteinuria (r=0.558, p＜0.05, n=10), but negatively with serum C3 level (r=-0.712, p＜0.01, n=10).
Conclusion: The expression percentage of CD95, CD123 and CD166 on BM CD34+ cells were significantly increased in patients. This supports the hypothesis that there are abnormalities of hematopoietic stem cell (HSC) in SLE. Since CD166 and CD123 correlated with the overall lupus activity, their role as a biomarker of inflammatory disease activity also requires further study.
Part 2 The therapeutic effect and mechanism of human bone marrow mesenchymal stem cells transplantation in MRL/lpr mice
Objective: To investigate the therapeutic effects and mechanism of human bone marrow mesenchymal stem cells(MSC) transplantation in MRL/lpr mice.
Methods: Human MSCs were expanded ex vivo. MRL/lpr mice were divided into cyclophosphamide (CTX) group, MSC group, CTX+MSC group, and control group. At the age of 16 weeks, the mice in CTX group and MSC+CTX group received intraperitoneal injection of CTX 100mg/kg×2d. 24 hours after injection, the MSCs were transplanted in MSC group and CTX+MSC group through tail vein. The 24-hour proteinuria was detected with Coomassi brilliant blue method. Indirect immunofluorescence was used to detect the antinuclear antibody (ANA) and anti-double-stranded DNA (ds-DNA) antibody. Flow cytometry was used to detect the changes of CD4~+ T cells and Thl/Th2 subpopulation. The expression of BAFF mRNA was analyzed by RT-PCR. The expression of fibronectin (FN), transforming growth factor-β(TGF-β), vascular endothelial growth factor (VEGF), complement C3 of the murine kidney was estimated by immunohistochemistry and immunofluorescence.
Results:①At 24, 28, 32 weeks, the 24 hours proteinuria in MSC group (4.3±0.8mg, 5.4±0.8 mg, 5.8±0.8 mg) and MSC+CTX group (2.8±1.0mg, 3.9±0.4mg, 4.5±1.0mg) were significantly decreased than in control group (9.0±1.3mg, 9.3±0.6mg, 10.0±1.6mg) (P＜0.05), and they were also significantly decreased in MSC+CTX group (2.8±1.0mg, 3.9±0.4mg, 4.5±1.0mg) than in CTX group (5.1±1.0mg, 7.7±1.1mg, 9.6±1.9mg) (P＜0.05).②At 28 weeks, the anti ds-DNA antibodies were significantly decreased in MSC+CTX group (2.7±0.8) than in control group (4.6±0.9) (P＜0.05).③At 32 weeks, the bodyweight of MSC group (38.6±3.3g) and MSC+CTX (35.8±3.7g) group increased significantly than the control group (32.8±3.0g) (P＜0.05).④At 32 weeks, serum creatinine decreased significantly in MSC group (13.5±2.2μmol/L) and MSC+CTX (12.7±4.2μmol/L) group than in control group (20.8±5.1μmol/L) (P＜0.05).⑤The number of CD4~+ T cells and Th2 subpopulation decreased significantly in MSC group (76.4%±1.9%, 58.4%±1.8%) and MSC+CTX group (73.9%±3.2%, 57.6%±3.2%) than in control group (82.7%±2.9%, 64.2%±2.8%) (P＜0.05).⑥The expression of BAFF mRaNA in spleen was significantly decreased in MSC and MSC+CTX group.⑦The expression of TGF-β, FN, VEGF and the deposition of complement C3 in renal tissue were decreased significantly in MSC and MSC+CTX treated group.
Conclusion: human MSC transplantation is effective treatment for MRL/lpr mice. The regulation of Th1/Th2 balance and inhibition the antibodies of B cells, mediated by human MSCs may be the mechanisms of effective treatment with MSC transplantation. The decrement of glomerulosclerosis probably due to its suppressive effect on the expression of local TGF-β, FN, VEGF and ameliorated the renal histological injury.
目的：研究系统性红斑狼疮(SLE)患者骨髓CD34~+细胞表面标志的变化，了解SLE患者造血干细胞是否存在异常。
方法：应用流式细胞术CD45／SSC设门分析10例SLE患者和10例正常人骨髓CD34~+细胞CD90、CD117、CD123、CD164、CD166、CD95(FAS)、FAS-L、HLA-DR等表面分子的表达及其与病情活动指标的相关性。
结果：活动期SLE患者骨髓CD34~+细胞比例(1.48±0.41％，n=7)明显低于正常人(2.31±0.75％，P＜0.01，n=10)，非活动期患者(2.04±0.44％，n=3)与正常人相比差异无显著性。SLE患者CD34~+CD95~+的表达明显高于正常人(48.31±10.59％vs24.33±11.1％，P＜0.05)，患者CD123和CD166也明显高于正常人(44.9±21.5％vs19.5±4.4％，P＜0.05；30.9±19.54％vs 10.7±5.5％，P＜0.05)。其余表面标志的表达与正常人相比无明显差异。CD123表达率与患者外周血白细胞计数负相关(r=-0.700，P＜0.05)，与SLE疾病活动指数(SLEDAI)评分无相关性。CD166表达与SLEDAI(r=+0.472，P＜0.05)，血清C3(r=-0.712，P＜0.01)，24小时尿蛋白(r=+0.558，P＜0.05)显著相关。
结论：SLE患者骨髓CD34~+细胞CD95、CD123、CD166的表达率增加，CD123的表达率与外周血白细胞计数显著负相关；CD166的表达率与SLEDAI评分、24小时尿蛋白显著正相关，与血清C3显著负相关，CD166可能是一个新的SLE疾病活动性标志。
第二部分人骨髓间充质干细胞移植治疗MRL／Ipr狼疮鼠的疗效和机制
目的：探讨人骨髓间充质干细胞(MSC)移植对MRL／lpr狼疮鼠的疗效及作用机制。
方法：体外分离、培养、扩增正常人MSC。MRL／lpr鼠随机分为对照组、环磷酰胺(CTX)治疗组、MSC治疗组和MSC＋CTX治疗组。16周龄时，CTX组和MSC＋CTX组给予CTX 100mg／kg×2d腹腔注射，24h后MSC组和MSC＋CTX组经尾静脉输入人MSC。考马斯亮蓝法检测24h尿蛋白含量，间接免疫荧光检测血清抗核抗体(ANA)、抗双链DNA(ds-DNA)抗体滴度，流式细胞仪检测外周血T细胞亚群，RT-PCR检测脾脏B淋巴细胞活化因子(BAFF)mRNA表达水平，免疫组化检测肾脏转化生长因子β(TGF-β)，纤维连接蛋白(FN)，血管内皮生长因子(VEGF)的表达，免疫荧光检测肾小球补体C3沉积。
结果：①24、28、32周24h尿蛋白定量MSC组(4.3±0.8mg，5.4±0.8mg，5.8±0.8mg)和MSC＋CTX组(2.8±1.0mg，3.9±0.4mg，4.5±1.0mg)均显著低于对照组(9.0±1.3mg，9.3±0.6mg，10.0±1.6mg)(P＜0.05)；MSC＋CTX组(2.8±1.0mg，3.9±0.4mg，4.5±1.0mg)显著低于CTX组(5.1±1.0mg，7.7±1.1mg，9.6±1.9mg)(P＜0.05)。②28周龄时抗ds-DNA抗体滴度MSC＋CTX组(2.7±0.8)显著低于对照组(4.6±0.9)(P＜0.05)。③32周龄时体重MSC组(38.6±3.3g)和MSC＋CTX组(35.8±3.7g)显著高于对照组(32.8±3.0g)(P＜0.05)。④32周龄时，血清肌酐MSC组(13.5±2.2μmol／L)和MSC＋CTX组(12.7±4.2μmol／L)均显著低于对照组(20.8±5.1μmol／L)(P＜0.05)。⑤32周龄时CD4~+T细胞和Th2亚群MSC组(76.4％±1.9％，58.4％±1.8％)和MSC＋CTX组(73.9％±3.2％，57.6％±3.2％)均显著低于对照组(82.7％±2.9％，64.2％±2.8％)(P＜0.05)。⑥治疗组脾脏BAFF mRNA表达显著降低。⑦治疗组肾组织TGF-β、FN、VEGF表达降低，肾小球中C3的沉积显著减少，肾脏组织学病变改善。
结论：人MSC移植治疗MRL／lpr鼠有效，调节Th1／Th2平衡，降低脾脏BAFFmRNA表达，抑制B细胞抗体产生，抑制TGF-β、FN、VEGF表达，减轻肾小球硬化，可能是MSC移植治疗MRL／lpr鼠有效的机制之一。
Part 1 Abnormal surface markers expression on bone marrow CD34~+ cells and correlation with disease activity in patients with systemic lupus erythematosus
Objective: To explore the phenotypic characteristics of bone marrow (BM) CD34+ cells in patients with SLE and its relationship with SLE disease activity.
Methods: 10 SLE patients and 10 healthy subjects were recruited, their BM CD34+ cells were analyzed by flow cytometric analysis with CD45/SSC gating for the expression of CD90, CD95, CD117, CD123, CD164, CD166, FAS-L and HLA-DR.
Results: The percentage of BM CD34+ cells was significantly decreased in active SLE patients (1.48±0.41%, n=7) compared to healthy controls (2.31±0.75%, n=10, p＜0.01), but no significant difference was found between the inactive patients (2.04±0.44%, n=3) and the controls. The expression of CD95, CD123 and CD166 on BM CD34+ cells were significantly increased in SLE patients (48.31±10.59%, 44.9±21.5%, 30.9±19.54%, n=10) when compared with control subjects (24.33±11.1%, 19.5±4.4%, 10.7±5.5%, respectively, n=10, p＜0.05). The increased CD123 expression was negatively correlated with the number of peripheral white blood cells (r=-0.700, p＜0.05, n=10). The percentage of CD166 expression was found significantly correlated with the index of SLE disease activity (r=0.472, p＜0.05, n=10), and 24 hour proteinuria (r=0.558, p＜0.05, n=10), but negatively with serum C3 level (r=-0.712, p＜0.01, n=10).
Conclusion: The expression percentage of CD95, CD123 and CD166 on BM CD34+ cells were significantly increased in patients. This supports the hypothesis that there are abnormalities of hematopoietic stem cell (HSC) in SLE. Since CD166 and CD123 correlated with the overall lupus activity, their role as a biomarker of inflammatory disease activity also requires further study.
Part 2 The therapeutic effect and mechanism of human bone marrow mesenchymal stem cells transplantation in MRL/lpr mice
Objective: To investigate the therapeutic effects and mechanism of human bone marrow mesenchymal stem cells(MSC) transplantation in MRL/lpr mice.
Methods: Human MSCs were expanded ex vivo. MRL/lpr mice were divided into cyclophosphamide (CTX) group, MSC group, CTX+MSC group, and control group. At the age of 16 weeks, the mice in CTX group and MSC+CTX group received intraperitoneal injection of CTX 100mg/kg×2d. 24 hours after injection, the MSCs were transplanted in MSC group and CTX+MSC group through tail vein. The 24-hour proteinuria was detected with Coomassi brilliant blue method. Indirect immunofluorescence was used to detect the antinuclear antibody (ANA) and anti-double-stranded DNA (ds-DNA) antibody. Flow cytometry was used to detect the changes of CD4~+ T cells and Thl/Th2 subpopulation. The expression of BAFF mRNA was analyzed by RT-PCR. The expression of fibronectin (FN), transforming growth factor-β(TGF-β), vascular endothelial growth factor (VEGF), complement C3 of the murine kidney was estimated by immunohistochemistry and immunofluorescence.
Results:①At 24, 28, 32 weeks, the 24 hours proteinuria in MSC group (4.3±0.8mg, 5.4±0.8 mg, 5.8±0.8 mg) and MSC+CTX group (2.8±1.0mg, 3.9±0.4mg, 4.5±1.0mg) were significantly decreased than in control group (9.0±1.3mg, 9.3±0.6mg, 10.0±1.6mg) (P＜0.05), and they were also significantly decreased in MSC+CTX group (2.8±1.0mg, 3.9±0.4mg, 4.5±1.0mg) than in CTX group (5.1±1.0mg, 7.7±1.1mg, 9.6±1.9mg) (P＜0.05).②At 28 weeks, the anti ds-DNA antibodies were significantly decreased in MSC+CTX group (2.7±0.8) than in control group (4.6±0.9) (P＜0.05).③At 32 weeks, the bodyweight of MSC group (38.6±3.3g) and MSC+CTX (35.8±3.7g) group increased significantly than the control group (32.8±3.0g) (P＜0.05).④At 32 weeks, serum creatinine decreased significantly in MSC group (13.5±2.2μmol/L) and MSC+CTX (12.7±4.2μmol/L) group than in control group (20.8±5.1μmol/L) (P＜0.05).⑤The number of CD4~+ T cells and Th2 subpopulation decreased significantly in MSC group (76.4%±1.9%, 58.4%±1.8%) and MSC+CTX group (73.9%±3.2%, 57.6%±3.2%) than in control group (82.7%±2.9%, 64.2%±2.8%) (P＜0.05).⑥The expression of BAFF mRaNA in spleen was significantly decreased in MSC and MSC+CTX group.⑦The expression of TGF-β, FN, VEGF and the deposition of complement C3 in renal tissue were decreased significantly in MSC and MSC+CTX treated group.
Conclusion: human MSC transplantation is effective treatment for MRL/lpr mice. The regulation of Th1/Th2 balance and inhibition the antibodies of B cells, mediated by human MSCs may be the mechanisms of effective treatment with MSC transplantation. The decrement of glomerulosclerosis probably due to its suppressive effect on the expression of local TGF-β, FN, VEGF and ameliorated the renal histological injury.
引文
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