人胎盤MSCs對異基因小鼠皮膚移植排斥的免疫調節作用_《中國修復重建外科雜志》

作者：

1 寧夏醫科大學檢驗學院（銀川，750004）;;
2 寧夏醫科大學總醫院干細胞研究所;

關鍵詞：

胎盤MSCs 皮膚移植免疫排斥異基因 ICR乳鼠小鼠

DOI：

10.7507/1002-1892.20130172

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目的觀察人胎盤MSCs（placental-derived MSCs，PMSCs）對異基因小鼠皮膚移植的影響。方法取自愿捐贈人胎盤胎兒側組織，分離培養PMSCs，并以第3代細胞進行實驗。選擇30只6～8周齡C57BL/6小鼠作為受體，背部制作直徑12 mm圓形皮膚缺損；以1～2日齡Vr∶CD1（ICR）乳鼠皮膚作為供體，建立小鼠異基因皮膚移植排斥模型。將30只受體小鼠隨機分為3組，每組10只。A組為自體皮膚移植組，B組為同種異體皮膚移植+ PBS尾靜脈注射組，C組為同種異體皮膚移植+人PMSCs（1 × 105個/只）尾靜脈注射組。觀察各組移植皮片成活情況，檢測術后7 d受體小鼠血液白細胞數量、腹腔液巨噬細胞活化率，采用ELISA、RT-PCR法檢測受體小鼠血液、脾臟中IL-4、IL-17及IFN-γ表達量的變化。結果A、B、C組移植皮片成活時間分別為（58.33 ± 4.04）、（3.80 ± 0.92）、（6.80 ± 0.82） d，A組明顯優于B、C組，C組優于B組，差異均有統計學意義（P lt; 0.05）。術后7 d，A、B、C組小鼠血液白細胞計數分別為（6.32 ± 0.45）× 109/L、（7.45 ± 0.52）× 109/L、（6.35 ± 0.39）×109/L ，A、C組顯著低于B組（P lt; 0.05），A、C組間差異無統計學意義（P gt; 0.05）。A、B、C組小鼠巨噬細胞活化率分別為6.87% ± 2.40%、7.84% ± 0.44%、15.98% ± 2.87%，C組顯著高于A、B組（P lt; 0.01）。ELISA檢測示，3組血液中IL-4含量差異無統計學意義（P gt; 0.05）；C組IL-17和IFN-γ含量顯著低于B組（P lt; 0.05）；B組IFN-γ含量明顯高于A組（P lt; 0.05）；其余各指標組間比較差異均無統計學意義（P gt; 0.05）。RT-PCR檢測示， B、C組IL-4、IL-17和IFN-γ mRNA相對表達量與A組比較差異均有統計學意義（P lt; 0.05）；C組IL-4和IFN-γ mRNA相對表達量明顯低于B組（P lt; 0.05），IL-17 mRNA相對表達量與B組比較差異無統計學意義（P gt; 0.05）。結論異基因小鼠皮膚移植后尾靜脈注射人PMSCs可抑制免疫排斥反應，其機制可能與減少IL-17及IFN-γ等相關細胞因子分泌有關。

引用本文： 王瓊,劉婷,張耀林,陳冬梅,王立斌,李玉奎,魏軍. 人胎盤MSCs對異基因小鼠皮膚移植排斥的免疫調節作用. 中國修復重建外科雜志, 2013, 27(7): 775-780. doi: 10.7507/1002-1892.20130172 復制

1.	（收稿：2012-11-30 修回：2013-04-19）.
2.	Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol, 2003, 31(10): 890-896.
3.	Soleymaninejadian E, Pramanik K, Samadian E. Immunomodulatory properities of mesenchymal stem cells: cytokines and factors. Am J Reprod Immunol, 2012, 67(1): 1-8.
4.	Maxson S, Lopez EA, Yoo D, et al. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Trans Med, 2012, 1(2): 142-149.
5.	Franquesa M, Hoogduijn MJ, Baan CC. The impact of mesenchymal stem cell therapy in transplant rejection and tolerance. Curr Opin Organ Transplant, 2012, 17(4): 355-361.
6.	楊銀學, 魏軍, 李玉奎, 等. 適于臨床應用的人胎盤間質細胞庫的建立方法: 中國, 200880115431 [P]. 2010-11-17.
7.	朱永朝, 馬海濱, 劉婷, 等. 干擾素-γ對人胎盤胎兒來源間充質干細胞免疫調節功能的影響. 細胞與分子免疫學雜志, 2012, 28(10): 1058-1061.
8.	馮繼紅, 孫萬邦, 羅軍敏, 等. 重組人白細胞介素10抗家兔同種異體皮膚移植排斥模型的建立. 中國組織工程研究與臨床康復, 2010, 14(31): 5758-5762.
9.	張鳳春, 陳云峰, 蘇顏珍, 等. 地龍對巨噬細胞免疫活性的增強作用. 中國藥學雜志, 1998, 33(9): 532-535.
10.	Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol, 2003, 57(1): 11-20.
11.	Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 2005, 105(4): 1815-1822.
12.	Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood, 2005, 105(10): 4120-4126.
13.	Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood, 2005, 105(5): 2214-2219.
14.	Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood, 2006, 107(1): 367-372.
15.	Stagg J, Pommey S, Eliopoulos N, et al. Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell . Blood, 2006, 107(6): 2570-2577.
16.	Stagg J. Immune regulation by mesenchymal stem cells: two sides to the coin. Tissue Antigens, 2007, 69(1): 1-9.
17.	Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejectionin a nonmyeloablative setting. Blood, 2006, 108(6): 2114-2120.
18.	Hoogduijn MJ, Crop MJ, Peeters AM, et al. Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. Stem Cells, 2007, 16(4): 597-604.
19.	Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases. Arthritis Res Ther, 2008, 10(5): 223.
20.	高富雷, 王丹茹, 張余光. 創傷愈合動物模型的研究進展. 中國美容醫學, 2007, 16(2): 278-281.
21.	Rowshani AT, Vereyken EJ. The role of macrophage lineage cells in kidney graft rejection and survival. Transplantation, 2012, 94(4): 309-318.
22.	Németh K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2—dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 2009, 15(1): 42-49.
23.	Kim J, Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol, 2009, 37(12): 1445-1453.
24.	Zhang QZ, Su WR, Shi SH, et al. Human Gingiva-derived mesenchymal stem cells elicit polarization of M2 macrophages and enhance cutaneous wound healing. Stem Cells, 2010, 28(10): 1856-1868.
25.	Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol, 2008, 8(12): 958-969.
26.	Maggini J, Mirkin G, Bognanni I, et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One, 2010, 5(2): e9252.
27.	Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins . J Immunol, 1986, 136(7): 2348-2357.
28.	Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol, 1989, 7: 145-173.
29.	Zhu J, Jankovic D, Oler AJ, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity, 2012, 37(4): 660-673.
30.	Wei S, Zhao E, Kryczek I, et al. Th17 cells have stem cell-like features and promote long-term immunity. Oncoimmunology, 2012, 1(4): 516-519.
31.	Hao L, Sun H, Wang J, et al. Mesenchymal stromal cells for cell therapy: besides supporting hematopoiesis. Int J Hematol, 2012, 95(1): 34-46.
32.	杜國盛, 鄭慧麗, 石炳毅, 等. IL-17在小鼠皮膚移植受者外周血及移植物中的表達. 解放軍醫學雜志, 2009, 34(11): 1285-1287.
33.	Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity, 2004, 21(4): 467-476.

1. （收稿：2012-11-30 修回：2013-04-19）.
2. Le Blanc K, Tammik C, Rosendahl K, et al. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol, 2003, 31(10): 890-896.
3. Soleymaninejadian E, Pramanik K, Samadian E. Immunomodulatory properities of mesenchymal stem cells: cytokines and factors. Am J Reprod Immunol, 2012, 67(1): 1-8.
4. Maxson S, Lopez EA, Yoo D, et al. Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Trans Med, 2012, 1(2): 142-149.
5. Franquesa M, Hoogduijn MJ, Baan CC. The impact of mesenchymal stem cell therapy in transplant rejection and tolerance. Curr Opin Organ Transplant, 2012, 17(4): 355-361.
6. 楊銀學, 魏軍, 李玉奎, 等. 適于臨床應用的人胎盤間質細胞庫的建立方法: 中國, 200880115431 [P]. 2010-11-17.
7. 朱永朝, 馬海濱, 劉婷, 等. 干擾素-γ對人胎盤胎兒來源間充質干細胞免疫調節功能的影響. 細胞與分子免疫學雜志, 2012, 28(10): 1058-1061.
8. 馮繼紅, 孫萬邦, 羅軍敏, 等. 重組人白細胞介素10抗家兔同種異體皮膚移植排斥模型的建立. 中國組織工程研究與臨床康復, 2010, 14(31): 5758-5762.
9. 張鳳春, 陳云峰, 蘇顏珍, 等. 地龍對巨噬細胞免疫活性的增強作用. 中國藥學雜志, 1998, 33(9): 532-535.
10. Le Blanc K, Tammik L, Sundberg B, et al. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol, 2003, 57(1): 11-20.
11. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 2005, 105(4): 1815-1822.
12. Jiang XX, Zhang Y, Liu B, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood, 2005, 105(10): 4120-4126.
13. Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood, 2005, 105(5): 2214-2219.
14. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood, 2006, 107(1): 367-372.
15. Stagg J, Pommey S, Eliopoulos N, et al. Interferon-γ-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell . Blood, 2006, 107(6): 2570-2577.
16. Stagg J. Immune regulation by mesenchymal stem cells: two sides to the coin. Tissue Antigens, 2007, 69(1): 1-9.
17. Nauta AJ, Westerhuis G, Kruisselbrink AB, et al. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejectionin a nonmyeloablative setting. Blood, 2006, 108(6): 2114-2120.
18. Hoogduijn MJ, Crop MJ, Peeters AM, et al. Human heart, spleen, and perirenal fat-derived mesenchymal stem cells have immunomodulatory capacities. Stem Cells, 2007, 16(4): 597-604.
19. Chen FH, Tuan RS. Mesenchymal stem cells in arthritic diseases. Arthritis Res Ther, 2008, 10(5): 223.
20. 高富雷, 王丹茹, 張余光. 創傷愈合動物模型的研究進展. 中國美容醫學, 2007, 16(2): 278-281.
21. Rowshani AT, Vereyken EJ. The role of macrophage lineage cells in kidney graft rejection and survival. Transplantation, 2012, 94(4): 309-318.
22. Németh K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2—dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 2009, 15(1): 42-49.
23. Kim J, Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol, 2009, 37(12): 1445-1453.
24. Zhang QZ, Su WR, Shi SH, et al. Human Gingiva-derived mesenchymal stem cells elicit polarization of M2 macrophages and enhance cutaneous wound healing. Stem Cells, 2010, 28(10): 1856-1868.
25. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol, 2008, 8(12): 958-969.
26. Maggini J, Mirkin G, Bognanni I, et al. Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One, 2010, 5(2): e9252.
27. Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins . J Immunol, 1986, 136(7): 2348-2357.
28. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol, 1989, 7: 145-173.
29. Zhu J, Jankovic D, Oler AJ, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity, 2012, 37(4): 660-673.
30. Wei S, Zhao E, Kryczek I, et al. Th17 cells have stem cell-like features and promote long-term immunity. Oncoimmunology, 2012, 1(4): 516-519.
31. Hao L, Sun H, Wang J, et al. Mesenchymal stromal cells for cell therapy: besides supporting hematopoiesis. Int J Hematol, 2012, 95(1): 34-46.
32. 杜國盛, 鄭慧麗, 石炳毅, 等. IL-17在小鼠皮膚移植受者外周血及移植物中的表達. 解放軍醫學雜志, 2009, 34(11): 1285-1287.
33. Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity, 2004, 21(4): 467-476.

《中國修復重建外科雜志》

人胎盤MSCs對異基因小鼠皮膚移植排斥的免疫調節作用

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《中國修復重建外科雜志》

人胎盤MSCs對異基因小鼠皮膚移植排斥的免疫調節作用

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