Preserving Prostaglandin E2 Level Prevents Rejection of Implanted Allogeneic Mesenchymal Stem Cells and Restores Postinfarction Ventricular Function
Preserving Prostaglandin E2 Level Prevents Rejection of Implanted Allogeneic Mesenchymal Stem Cells and Restores Postinfarction Ventricular Function
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DOI：
10.1161/circulationaha.112.000324
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发表时间：
2013-09-10
期刊：
影响因子：
37.8
通讯作者：
Li, Ren-Ke
中科院分区：
文献类型：
--
作者：
Dhingra, Sanjiv;Li, Peng;Li, Ren-Ke
背景-在临床前和临床研究中，异基因间充质干细胞(MSCs)在心脏植入后早期被免疫排斥，并改善了心功能。然而，长期的临床前研究表明，同种异体骨髓间充质干细胞失去了免疫特权，在损伤的心肌中被排斥，导致复发性心功能不全。这项研究确定了导致MSCs免疫开关的一些机制，并提出了一种新的治疗方法来维持免疫特权和保护心脏功能。方法和结果-大鼠MSC的免疫特权是由前列腺素E2(PGE2)诱导的两种关键趋化因子CCL12和CCL5的分泌介导的。这些趋化因子刺激T细胞对MSCs的趋化作用，抑制细胞毒性T细胞的增殖，诱导T调节细胞的产生。5-氮胞苷作用24小时后，MSCs在2周后分化为肌源性细胞，这与PGE2和趋化因子的产生减少以及免疫功能丧失有关。用PGE2处理分化的MSCs后，趋化因子水平恢复，并保留了MSC的免疫功能。在大鼠心肌梗死模型中，将同种异基因间充质干细胞(3x10(6)细胞/只)注射到梗死区，无论有没有生物可降解水凝胶，缓慢释放PGE2。5周后，移植的MSCs表达肌源性细胞系标志物，对照组被排斥，而PGE2处理组移植细胞存活，心功能改善。结论：同种异体MSCs通过PGE2诱导的趋化因子CCL12和CCL5的分泌维持免疫特权。骨髓间充质干细胞分化后PGE2水平降低，免疫功能丧失。维持PGE2水平可保护分化后的免疫功能，防止移植的MSCs发生排斥反应，并恢复心功能。
Background-Allogeneic mesenchymal stem cells (MSCs) were immunoprivileged early after cardiac implantation and improved heart function in preclinical and clinical studies. However, long-term preclinical studies demonstrated that allogeneic MSCs lost their immunoprivilege and were rejected in the injured myocardium, resulting in recurrent ventricular dysfunction. This study identifies some of the mechanisms responsible for the immune switch in MSCs and suggests a new treatment to maintain immunoprivilege and preserve heart function.Methods and Results-Rat MSC immunoprivilege was mediated by prostaglandin E2 (PGE2)-induced secretion of 2 critical chemokines, CCL12 and CCL5. These chemokines stimulated the chemoattraction of T cells toward MSCs, suppressed cytotoxic T-cell proliferation, and induced the production of T regulatory cells. MSCs treated with 5-azacytidine for 24 hours differentiated into myogenic cells after 2 weeks, which was associated with decreased PGE2 and chemokine production and the loss of immunoprivilege. Treatment of differentiated MSCs with PGE2 restored chemokine levels and preserved MSC immunoprivilege. In a rat myocardial infarction model, allogeneic MSCs (3x10(6) cells/rat) were injected into the infarct region with or without a biodegradable hydrogel that slowly released PGE2. Five weeks later, the transplanted MSCs expressed myogenic lineage markers and were rejected in the control group, but in the PGE2-treated group, the transplanted cells survived and heart function improved.Conclusions-Allogeneic MSCs maintained immunoprivilege by PGE2-induced secretion of chemokines CCL12 and CCL5. Differentiation of MSCs decreased PGE2 levels, and immunoprivilege was lost. Maintaining PGE2 levels preserved immunoprivilege after differentiation, prevented rejection of implanted MSCs, and restored cardiac function.