Mesenchymal stem cells provide protection of cardiac ventricular myocytes by paracrine mechanism

Although human mesenchymal stem cells (hMSCs) are being used clinically to treat heart disease, their mechanism of cardiac repair is uncertain. This study explores the notion that hMSCs provide benefit to cardiac myocytes themselves. Cultured neonatal mouse cardiac myocytes (nMCM) were treated with bacterial endotoxin, LPS, and the proinflammatory cytokine, IL‐1β to induce cardiac stress. In fluo‐3 loaded nMCMs chaotic intracellular Ca 2+ signaling was seen following treatments with these agents. Normal Ca 2+ signaling was preserved when hMSCs were cocultured in transwell dishes for 24 hr, illuminating a paracrine mechanism in this protective effect. In addition, a 3 hr treatment of stressed nMCMs with conditioned hMSC media reversed the damage evoked by 24 hr treatments with either LPS or IL‐1β. Neutralizing antibody experiments were performed to identify potential mediators of this stress pathway. These studies reveal that IL‐18, and not TNF‐α, is a mediator of dysfunction caused by LPS and IL‐1β. We conclude that hMSCs are able to protect and repair MCMs via a soluble factor that acts by reprogramming of a cardiac signaling cascade involving IL‐18. Future studies will identify these soluble factors that underlie this protective mechanism. These new data provide a better understanding of the therapeutic benefits hMSCs in diseased heart. This work was funded by a grant from the Maryland Stem Cell Research Fund.