Background and Objective: 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 (pTLR4) 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: We show for the first time that post MI inflammatory environment switches resident cardiac MSCs toward a pro-inflammatory phenotype and impairs their reparative properties. This effect is mediated by TLR4. We suggest that inhibition of TLR4 in resident and implanted MSCs might prevent the destructive effect of cardiac inflammation and improve the outcome of cellular therapy after MI, especially when approaching autologous cell therapy in sick patients.
