Left Ventricular Dysfunction Switches Mesenchymal Stromal Cells Toward an Inflammatory Phenotype and Impairs Their Reparative Properties via Toll-like Receptor-4
Background—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 pro-inflammatory activation. We sought to study the potential negative interaction between left ventricular dysfunction (LVD) and MSC activation.
Methods—We isolated MSCs from cardiac (c) and subcutaneous (sc) fat tissues of mice with LVD, 28 days after myocardial infarction (MI), or sham operation. To evaluate the effect of LVD on MSCs, we characterized cMSCs and scMSCs in vitro. Subsequently, we injected MSCs or saline into the infarcted myocardium of mice and evaluated left ventricular (LV) remodeling, and function, 28 days after MI. To test the hypothesis that toll-like receptor 4 (TLR4) mediates pro-inflammatory polarization of MSCs, we characterized cMSCs from TLR4-/- and wild-type (WT) mice after inflammatory stimulation in vitro. Next, we transplanted cMSCs from TLR4-/- and WT male mice into the infarcted myocardium of female WT mice and evaluated infarct size, MSC retention, inflammation, remodeling and function, after seven days.
Results—LVD switched cMSCs toward an inflammatory phenotype, with increased secretion of inflammatory cytokines, as well as chemokines. The effect of LVD on scMSCs was less remarkable. While transplantation of cMSCs and scMSCs from LVD and sham hearts did not improve LV remodeling and function, cMSCs from LVD exacerbated anterior wall thinning, 28 days after MI. The inflammatory polarization of cMSCs by LVD was mediated by TLR4, as we found less secretion of inflammatory cytokines and higher secretion of anti-inflammatory cytokines from activated cMSCs of TLR4-deficient mice, compared with WT cMSCs. Significantly, TLR4-deficiency preserved the expression of CD47 ("don't eat me" signal) on cMSCs after both TLR4 stimulation in vitro and transplantation into the infarcted heart. Compared with WT cMSCs and saline, TLR4-/- cMSCs survived in the cardiac tissue and maintained their reparative properties, reduced infarct size, increased scar thickness and attenuated LV dilatation, seven days after MI.
Conclusions—The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a pro-inflammatory phenotype, and restricts their survival and reparative effects in a mechanism mediated by TLR4.
- Received May 15, 2016.
- Revision received January 22, 2017.
- Accepted March 17, 2017.