Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction.
Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction.
复制标题
DOI：
10.1161/circulationaha.112.131110
复制
发表时间：
2013-01-15
期刊：
影响因子：
37.8
通讯作者：
Hare JM
中科院分区：
文献类型：
--
作者：
Williams AR;Hatzistergos KE;Addicott B;McCall F;Carvalho D;Suncion V;Morales AR;Da Silva J;Sussman MA;Heldman AW;Hare JM
由于间充质干细胞（MSCs）在体内和体外诱导c-kit+心脏干细胞（CSCs）的增殖和分化，我们假设在心肌梗死后，将人(h)MSCs与c-kit+ hCSCs联合使用比单独使用任何一种细胞都能产生更大的梗死面积缩小。约克郡猪接受LAD冠状动脉球囊闭塞后再灌注，并在心肌梗死后使用环孢子素和甲基强龙进行免疫抑制。心肌梗死后14天，心肌内注射hCSCs/hMSCs联合（1M/200M, n=5）、hCSCs单独（1M, n=5）、hMSCs单独（200M, n=5）或安慰剂（PBS, n=5）。通过心脏MRI和微压计电导导管血流动力学评估细胞治疗的表型反应。虽然与安慰剂相比，每个细胞治疗组心肌梗死大小减小（p<0.05），但联合治疗组心肌梗死大小减小是单独细胞治疗组的2倍（p<0.05）。联合用药猪的左室顺应性（舒张末压容积关系，p<0.01）和收缩力（负荷前可恢复的搏功和dP/dtmax， p<0.05）显著改善。细胞治疗组的左室功能恢复到基线水平，而安慰剂组的左室功能持续下降（p<0.05）。免疫组织化学显示，联合治疗组的干细胞植入量是单独治疗组的7倍（P<0.001）。结合hMSCs和hCSCs作为细胞治疗，可增强心肌梗死后疤痕大小的减小，并恢复舒张和收缩功能，使其恢复正常。综上所述，这些发现说明了c-kit+ CSCs和MSCs之间重要的生物学相互作用，可增强基于细胞的治疗反应。
As mesenchymal stem cells (MSCs) induce proliferation and differentiation of c-kit+ cardiac stem cells (CSCs) in vivo and in vitro, we hypothesized that combining human (h)MSCs with c-kit+ hCSCs produces greater infarct size reduction compared to either cell administered alone after MI. Yorkshire swine underwent balloon occlusion of the LAD coronary artery followed by reperfusion, and were immunosuppressed after MI with cyclosporine and methylprednisolone. Intramyocardial injection of either: combination hCSCs/hMSCs (1M/200M, n=5), hCSCs alone (1M, n=5), hMSCs alone (200M, n=5), or placebo (PBS, n=5) was administered to the infarct border zones at 14 days post-MI. Phenotypic response to cell therapy was assessed by cardiac MRI and micromanometer conductance catheterization hemodynamics. While each cell therapy group had reduced MI size relative to placebo (p<0.05), the MI size reduction was 2-fold greater in combination vs. either cell therapy alone (p<0.05). Accompanying enhanced MI size reduction was substantial improvement in LV chamber compliance (end-diastolic pressure volume relationship, p<0.01) and contractility (preload recruitable stroke work and dP/dtmax, p<0.05) in combination treated swine. EF was restored to baseline in cell treated pigs, while placebo pigs had persistently depressed LV function (p<0.05). Immunohistochemistry showed 7-fold enhanced engraftment of stem cells in the combination therapy group vs. either cell type alone (P<0.001). Combining hMSCs and hCSCs as a cell therapeutic enhances scar size reduction, and restores diastolic and systolic function toward normal after MI. Taken together these findings illustrate important biological interactions between c-kit+ CSCs and MSCs that enhance cell-based therapeutic responses.