From Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel-Aviv University, Israel (N.N.-S., L.-P.L.-K., D.P., U.A., D.K., N.L., J.L.); Tamman Cardiovascular Research Institute, Leviev Heart Center, Sheba Medical Center, Tel-Hashomer, Israel (N.N.-S., L.-P.L.-K., D.P., U.A., D.K., N.L., J.L.); Sheba Center for Regenerative Medicine, Stem Cell and Tissue Engineering, Tel-Hashomer, Israel (N.N.-S., L.-P.L.-K., D.P., U.A., D.K., N.L., J.L.); and Cardiac Research Laboratory, Department of Cardiothoracic Surgery, Felsenstein Medical Research Center, Rabin Medical Center, Tel-Aviv University, Petah Tikva, Israel (E.H.).
Circulation. 2017 Jun 6;135(23):2271-2287. doi: 10.1161/CIRCULATIONAHA.116.023527. Epub 2017 Mar 29.
Little is known about the potentially unfavorable effects of mesenchymal stromal cell (MSC) activation on the heart. MSCs can respond to tissue injury by anti- or proinflammatory activation. We aimed to study the potential negative interaction between left ventricular dysfunction (LVD) and MSC activation.
We isolated MSCs from cardiac and subcutaneous fat tissues of mice with LVD 28 days after myocardial infarction or sham operation. To evaluate the effect of LVD on MSCs, we characterized cardiac MSCs and subcutaneous MSCs in vitro. Subsequently, we injected MSCs or saline into the infarcted myocardium of mice and evaluated LV remodeling and function 28 days after myocardial infarction. To test the hypothesis that toll-like receptor 4 () mediates proinflammatory polarization of MSCs, we characterized cardiac MSCs from and wild-type (WT) mice after inflammatory stimulation in vitro. Next, we transplanted cardiac MSCs from and WT male mice into the infarcted myocardium of female WT mice and evaluated infarct size, MSC retention, inflammation, remodeling, and function after 7 days.
LVD switched cardiac MSCs toward an inflammatory phenotype, with increased secretion of inflammatory cytokines as well as chemokines. The effect of LVD on subcutaneous MSCs was less remarkable. Although transplantation of cardiac MSCs and subcutaneous MSCs from LVD and sham hearts did not improve LV remodeling and function, cardiac MSCs from LVD exacerbated anterior wall thinning 28 days after myocardial infarction. The inflammatory polarization of cardiac MSCs by LVD was mediated by , as we found less secretion of inflammatory cytokines and higher secretion of anti-inflammatory cytokines from activated cardiac MSCs of -deficient mice, compared with WT cardiac MSCs. Significantly, deficiency preserved the expression of CD47 (don't eat me signal) on cardiac MSCs after both stimulation in vitro and transplantation into the infarcted heart. Compared with WT cardiac MSCs and saline, cardiac MSCs survived in the cardiac tissue and maintained their reparative properties, reduced infarct size, increased scar thickness, and attenuated LV dilatation 7 days after myocardial infarction.
The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by .
目前对于间充质基质细胞（MSC）激活对心脏可能产生的不利影响知之甚少。MSC 可以通过抗炎或促炎激活来响应组织损伤。我们旨在研究左心室功能障碍（LVD）与 MSC 激活之间潜在的负相互作用。
我们从心肌梗死后 28 天的左心室功能障碍或假手术小鼠的心脏和皮下脂肪组织中分离出 MSC。为了评估 LVD 对 MSC 的影响，我们在体外对心脏 MSC 和皮下 MSC 进行了特征描述。随后，我们将 MSC 或生理盐水注射到心肌梗死小鼠的梗死心肌中，并在心肌梗死后 28 天评估 LV 重塑和功能。为了验证 Toll 样受体 4（TLR4）介导 MSC 促炎极化的假说，我们在体外对 TLR4 敲除（KO）和野生型（WT）小鼠的心脏 MSC 进行了特征描述。接下来，我们将 TLR4 KO 和 WT 雄性小鼠的心脏 MSC 移植到 WT 雌性小鼠的梗死心肌中，并在 7 天后评估梗死面积、MSC 保留、炎症、重塑和功能。
LVD 将心脏 MSC 向炎症表型转变，促炎细胞因子和趋化因子的分泌增加。LVD 对皮下 MSC 的影响则不那么显著。尽管来自 LVD 和假手术心脏的 MSC 移植并未改善 LV 重塑和功能，但心肌梗死后 28 天，LVD 来源的心脏 MSC 加重了前壁变薄。LVD 通过 TLR4 介导了心脏 MSC 的炎症极化，我们发现 TLR4 缺失的 MSC 体外激活后促炎细胞因子的分泌减少，抗炎细胞因子的分泌增加，而 WT 心脏 MSC 则相反。重要的是，与 WT 心脏 MSC 和生理盐水相比，在体外刺激和移植到梗死心脏后，TLR4 缺失的心脏 MSC 上 CD47（不要吃我信号）的表达得到了保留。与 WT 心脏 MSC 和生理盐水相比，TLR4 KO 心脏 MSC 在心肌梗死后 7 天在心脏组织中存活并保持其修复特性，减少梗死面积，增加疤痕厚度，并减轻 LV 扩张。
衰竭和梗死心肌的微环境促使驻留和移植的 MSC 向促炎表型转变，并通过 TLR4 介导的机制限制其存活和修复作用。
