Huang Xi-Ping, Ludke Ana, Dhingra Sanjiv, Guo Jian, Sun Zhuo, Zhang Li, Weisel Richard D, Li Ren-Ke
Division of Cardiovascular Surgery, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada; and.
FASEB J. 2016 Sep;30(9):3069-82. doi: 10.1096/fj.201600331R. Epub 2016 May 24.
This study was performed to investigate how to overcome immunorejection associated with allogeneic stem cell therapy in the infarcted heart. Allogeneic bone marrow mesenchymal stem cell (MSC) differentiation increases major histocompatibility complex II (MHC II) expression, inducing transition from immunoprivileged to immunogenic phenotype. MHC II expression is regulated by the class II transactivator (CIITA). We isolated and characterized mouse and human MSCs and knocked down CIITA expression. Wild-type (WT) or CIITA-knockout (CIITA(-)) mouse MSCs were implanted into infarcted mouse myocardia, and recipient allo-antibody formation, cell survival, and cardiac function were measured. WT mouse and human MSCs that were myogenically differentiated showed increased MHC II and CIITA expression. Differentiated CIITA(-) MSCs lacked MHC II induction and showed reduced cytotoxicity in allogeneic leukocyte coculture. Differentiation of human MSCs increased MHC II expression, which resulted in cytotoxicity in allogeneic leukocyte coculture and was prevented by CIITA small interfering RNA. In contrast to WT MSCs, CIITA(-) MSCs did not initiate recipient allo-antibody formation and instead survived in the injured myocardium and significantly improved ventricular function. Decreasing CIITA expression in allogeneic MSCs abolished MHC II induction during myogenic differentiation and prevented immunorejection of these cells from the infarcted myocardium, which enhanced beneficial functional effects of MSC implantation on myocardial repair.-Huang, X.-P., Ludke, A., Dhingra, S., Guo, J., Sun, Z., Zhang, L., Weisel, R. D., Li, R.-K. Class II transactivator knockdown limits major histocompatibility complex II expression, diminishes immune rejection, and improves survival of allogeneic bone marrow stem cells in the infarcted heart.
本研究旨在探讨如何克服梗死心脏中与异基因干细胞治疗相关的免疫排斥反应。异基因骨髓间充质干细胞（MSC）分化会增加主要组织相容性复合体II（MHC II）的表达，促使其从免疫赦免表型转变为免疫原性表型。MHC II的表达受II类反式激活因子（CIITA）调控。我们分离并鉴定了小鼠和人类的MSC，并敲低了CIITA的表达。将野生型（WT）或CIITA基因敲除（CIITA(-)）的小鼠MSC植入梗死的小鼠心肌中，检测受体同种异体抗体的形成、细胞存活情况及心脏功能。经肌源性分化的WT小鼠和人类MSC显示出MHC II和CIITA表达增加。分化后的CIITA(-) MSC缺乏MHC II诱导，且在同种异体白细胞共培养中显示出细胞毒性降低。人类MSC的分化增加了MHC II的表达，这导致在同种异体白细胞共培养中产生细胞毒性，而CIITA小干扰RNA可阻止这种情况发生。与WT MSC不同，CIITA(-) MSC不会引发受体同种异体抗体的形成，而是在受损心肌中存活，并显著改善心室功能。降低异基因MSC中CIITA的表达可消除肌源性分化过程中的MHC II诱导，并防止这些细胞被梗死心肌免疫排斥，从而增强了MSC植入对心肌修复的有益功能作用。-黄，X.-P.，路德克，A.，丁格拉，S.，郭，J.，孙，Z.，张，L.，魏塞尔，R. D.，李，R.-K. II类反式激活因子敲低限制主要组织相容性复合体II表达，减少免疫排斥，并提高异基因骨髓干细胞在梗死心脏中的存活率。
