Human Cardiac Mesenchymal Stem Cells Remodel in Disease and Can Regulate Arrhythmia Substrates.

Sattayaprasert, Prasongchai; Vasireddi, Sunil K; Bektik, Emre; Jeon, Oju; Hajjiri, Mohammad; Mackall, Judith A; Moravec, Christine S; Alsberg, Eben; Fu, Jidong; Laurita, Kenneth R

Background - The mesenchymal stem cell (MSC), known to remodel in disease and have an extensive secretome, has recently been isolated from the human heart. However, the effects of normal and diseased cardiac MSCs on myocyte electrophysiology remain unclear. We hypothesize that in disease the inflammatory secretome of cardiac hMSCs remodels and can regulate arrhythmia substrates. Methods - Human cardiac MSCs (hMSCs) were isolated from patients with or without heart failure from tissue attached to extracted device leads and from samples taken from explanted/donor hearts. Failing hMSCs or non-failing hMSCs were co-cultured with normal human myocytes (hCM) derived from induced pluripotent stem cells. Using fluorescent indicators, APD, Ca2+ alternans, and spontaneous calcium release (SCR) incidence were determined. Results - Failing and non-failing hMSCs from both sources exhibited similar tri-lineage differentiation potential and cell surface marker expression as bone marrow hMSCs. Compared to non-failing hMSCs, failing hMSCs prolonged APD by 24% (p<0.001, n=15), increased Ca2+ alternans by 300% (p<0.001, n=18), and promoted SCR activity (n=14, p <0.013) in hCM. Failing hMSCs exhibited increased secretion of inflammatory cytokines IL-1β (98%, p<0.0001) and IL-6 (460%, p <0.02) compared to non-failing hMSCs. IL-1β or IL-6 in the absence of hMSCs prolonged APD but only IL-6 increased Ca2+ alternans and promoted SCR activity in hCM, replicating the effects of failing hMSCs. In contrast, non-failing hMSCs prevented Ca2+ alternans in hCM during oxidative stress. Finally, non-failing hMSCs exhibited >25 times higher secretion of IGF-1 compared to failing hMSCs. Importantly, IGF-1 supplementation or anti-IL-6 treatment rescued the arrhythmia substrates induced by failing hMSCs. Conclusions - We identified device leads as a novel source of cardiac hMSCs. Our findings show that cardiac hMSCs can regulate arrhythmia substrates by remodeling their secretome in disease. Importantly, therapy inhibiting (anti-IL-6) or mimicking (IGF-1) the cardiac hMSC secretome can rescue arrhythmia substrates.