IMMUNOMODULATORY EFFECTS OF HUMAN PLACENTAL-DERIVED MESENCHYMAL STEM CELLS ON IMMUNE REJECTION IN MOUSE ALLOGENEIC SKIN TRANSPLANTATION_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

1Department of Medical Laboratory, Ningxia Medical University, Yinchuan Ningxia, 750004, P.R.China;;
2Ningxia Human Stem Cell Institute, General Hospital of Ningxia Medical University. Corresponding author: WEI Jun, E-mail: lydiajumwei@hotmail.com;

Corresponding author：

Keywords：

Placental-derived mesenchymal stem cells; Skin transplantation Immunological rejection; Allogeneic; ICR mice; Mouse

DOI：

10.7507/1002-1892.20130172

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Objective To investigate the effect of human placental-derived mesenchymal stem cells (PMSCs) on immunological rejection in mouse allogeneic skin transplantation. Methods The placenta fetal tissues from voluntary donors were used to isolate and culture the PMSCs, and the 3rd passage PMSCs were used in the experiment. Thirty Vr ∶ CD1 (ICR) mice at age of 1-2 days were used as skin donors for allogeneic skin transplantation. Thirty C57BL/6 mice at age of 6-8 weeks as recipients were made back skin defect of 12 mm in diameter and were randomly divided into 3 groups (n=10): group A, autograft; group B, allogeneic graft + PBS tail vein injection; and group C, allogeneic graft + human PMSCs (1 × 105 cells/mouse) tail vein injection. The flap survival was observed. At 7 days after skin transplantation, blood leukocyte counting, abdominal fluid macrophage activation, and the expression levels of interleukin 4 (IL-4), interleukin 17 (IL-17), and interferon γ (INF-γ) in blood and spleen were detected by ELISA and RT-PCR, respectively. Results The flap survival time was significantly longer in group A [(58.33 ± 4.04) days] than in groups B and C [(3.80 ± 0.92) days and (6.80 ± 0.82) days] (P lt; 0.05), and in group C than in group B (P lt; 0.05). At 7 days after transplantation, the blood leukocyte number was (6.32 ± 0.45) × 109/L in group A, (7.45 ± 0.52) × 109/L in group B, and (6.35 ± 0.39)× 109/ L in group C, and it was significantly more in group B than in groups A and C (P lt; 0.05). The macrophage activation rate of the abdominal fluid was 6.87% ± 2.40% in group A, 7.84% ± 0.44% in group B, and 15.98% ± 2.87% in group C; group C was significantly higher than groups A and B (P lt; 0.01). ELISA results showed that there was no significant difference in the concentrations of IL-4 among 3 groups (P gt; 0.05). Compared with group B, the concentrations of IL-17 and IFN-γ were significantly reduced in group C (P lt; 0.05), while the concentration of IFN-γ was significantly increased in group B when compared with group A (P lt; 0.05). RT-PCR results showed that there were significant differences in the expressions of IL-4, IL-17, and IFN-γ mRNA between groups B, C and group A (P lt; 0.05); the expressions of IL-4 and IFN-γ mRNA were significantly lower in group C than in group B (P lt; 0.05). Conclusion Human PMSCs transplantation can suppress the acute immunological rejection in allogeneic skin transplantation. The possible mechanism may be partially related to the inhibitory effect on the secretion of IL-17 and IFN-γ.

Citation： WANG Qiong,LIU Ting,ZHANG Yaolin,CHEN Dongmei,WANG Libin,LI Yukui,WEI Jun. IMMUNOMODULATORY EFFECTS OF HUMAN PLACENTAL-DERIVED MESENCHYMAL STEM CELLS ON IMMUNE REJECTION IN MOUSE ALLOGENEIC SKIN TRANSPLANTATION. Chinese Journal of Reparative and Reconstructive Surgery, 2013, 27(7): 775-780. doi: 10.7507/1002-1892.20130172 Copy

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.	杨银学, 魏军, 李玉奎, 等. 适于临床应用的人胎盘间质细胞库的建立方法: 中国, 200880115431 [P]. 2010-11-17.
7.	朱永朝, 马海滨, 刘婷, 等. 干扰素-γ对人胎盘胎儿来源间充质干细胞免疫调节功能的影响. 细胞与分子免疫学杂志, 2012, 28(10): 1058-1061.
8.	冯继红, 孙万邦, 罗军敏, 等. 重组人白细胞介素10抗家兔同种异体皮肤移植排斥模型的建立. 中国组织工程研究与临床康复, 2010, 14(31): 5758-5762.
9.	张凤春, 陈云峰, 苏颜珍, 等. 地龙对巨噬细胞免疫活性的增强作用. 中国药学杂志, 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, 张余光. 创伤愈合动物模型的研究进展. 中国美容医学, 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.	杜国盛, 郑慧丽, 石炳毅, 等. IL-17在小鼠皮肤移植受者外周血及移植物中的表达. 解放军医学杂志, 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. 杨银学, 魏军, 李玉奎, 等. 适于临床应用的人胎盘间质细胞库的建立方法: 中国, 200880115431 [P]. 2010-11-17.
7. 朱永朝, 马海滨, 刘婷, 等. 干扰素-γ对人胎盘胎儿来源间充质干细胞免疫调节功能的影响. 细胞与分子免疫学杂志, 2012, 28(10): 1058-1061.
8. 冯继红, 孙万邦, 罗军敏, 等. 重组人白细胞介素10抗家兔同种异体皮肤移植排斥模型的建立. 中国组织工程研究与临床康复, 2010, 14(31): 5758-5762.
9. 张凤春, 陈云峰, 苏颜珍, 等. 地龙对巨噬细胞免疫活性的增强作用. 中国药学杂志, 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, 张余光. 创伤愈合动物模型的研究进展. 中国美容医学, 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. 杜国盛, 郑慧丽, 石炳毅, 等. IL-17在小鼠皮肤移植受者外周血及移植物中的表达. 解放军医学杂志, 2009, 34(11): 1285-1287.
33. Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity, 2004, 21(4): 467-476.

Chinese Journal of Reparative and Reconstructive Surgery

IMMUNOMODULATORY EFFECTS OF HUMAN PLACENTAL-DERIVED MESENCHYMAL STEM CELLS ON IMMUNE REJECTION IN MOUSE ALLOGENEIC SKIN TRANSPLANTATION

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