Abstract 12858: Left Ventricular Dysfunction Switches Cardiac Mesenchymal Stem/Stromal Cells Toward a Pro-Inflammatory Phenotype

Abstract

Introduction and Hypothesis: Mesenchymal stem/stromal cells (MSCs) are appealing candidates for cardiac cell therapy due to their ease of preparation, immunoprivilege properties, reparative potential and safety. We aimed to test the hypothesis that the inflammatory environment following myocardial infarction (MI) and left ventricular (LV) dysfunction could modulate the reparative properties of resident and transplanted MSCs. Methods and Results: To test this hypothesis, we isolated and cultured resident cardiac and subcutaneous (SC) fat tissue MSCs from mice, 28 days after MI (LVEF: 27.9%±3.8) or sham operation (LVEF: 54.9%±3.8). Proliferation rate was highest in cardiac MSCs after MI, compared with other groups (p<0.001 after 96 hours). Next, we measured the levels of secreted cytokines in the medium collected from the different cells and found that MI polarized cardiac MSCs toward a pro-inflammatory profile and stimulated secretion of the inflammatory cytokines IL1α, IL1β, IL-12, IL-6 and TNF-α (p<0.05), as well as the monocyte recruitment factors: MIP-1α, RANTES and MCP-1 (p<0.05). In contrast, SC fat MSCs were less affected by MI and LV dysfunction and mainly decreased their macrophage recruitment and anti-inflammatory factors. Surprisingly, transplantation of cardiac and adipose tissue MSCs from both MI and sham operated animals, into mice hearts immediately after MI (n=5-8 per group), did not improve cardiac remodeling and function, compared with saline. To determine the mechanism behind MSC polarization, we stimulated cardiac MSCs from toll-like receptor 4 ( TLR4 ) deficient and wild-type mice, with the secretome of LPS-activated macrophages. Significantly, there was less inflammatory cytokine secretion in TLR4-deficient MSCs, compared with control suggesting that cardiac MSC polarization is mediated by TLR4 activation. Conclusions: Post MI inflammatory environment switches resident cardiac and implanted MSCs toward a pro-inflammatory phenotype and impair their reparative properties. This effect is mediated by TLR4 . Our findings are relevant to the pathogenesis and progression of LV remodeling, and could guide the selection and engineering of MSCs for heart repair.