Abstract 14859: Mesenchymal Stem Cells Rescue Patient-Specific Cardiomyocyte Viability and Function Following Doxorubicin Injury via Microvesicle Mediated Mitochondrial Transfer to Recapitulate Human Clinical Trial Results

Introduction: Anthracyclines are effective chemotherapeutic agents associated with cardiac toxicity. Anthracycline induced cardiomyopathy (AIC) carries a mortality of 20% at four years. Effective therapies for AIC have not been established. The NIH-sponsored Stem Cell Injection for Cancer Survivors (SENECA) Trial examined the role of allogeneic mesenchymal stem cells (MSC) to treat AIC. To predict the efficacy of MSC in the SENECA patients, we performed an in vitro clinical trial to study the restorative effects of MSC on patient-specific iPSC-derived cardiomyocytes (iCM) by assessing the effects in vitro following doxorubicin (dox) exposure. Hypothesis: MSC secretome will rescue SENECA Trial patient-specific iCM from dox injury. Methods and Results: We generated three SENECA patient-specific iPSC lines. In vitro iCM dox sensitivity was shown to be comparable to published values. iCM were cultured in 1μM dox for 24hrs, treated with MSC or MSC-secretome, and assessed for viability and apoptosis. Co-culture of MSC with iCM using a 1μm trans-well system improved iCM viability by 43% (p-value < 0.005) and reduced apoptosis (p-value = 0.013). To better define the paracrine mechanism, MSC-secretome was divided into microvesicles >200nm (MV) and exosomes in vitro findings. Conclusion: Allogeneic MSC attenuate apoptosis and restore contractility following dox injury in patient-specific iCM. MV and MT-transfer appear to be the putative mechanism. Our findings correlate with the SENECA results, demonstrating proof-of-concept that iPSC-derivatives can be used to predict trial outcomes.