Human Mesenchymal Stem Cells Attenuates Hypertrophy In Induced Pluripotent Stem Cells Derived Cardiomyocytes From Hypoplastic Left Heart Syndrome Patients
Yasir A. Mir, Ph.D., Xuebin Fu, Ph.D., Kristopher Deatrick, M.D., Sunjay Kaushal, M.D., Ph.D..
University of Maryland, Baltimore, BALTIMORE, MD, USA.
Objective(s): Hypoplastic left heart syndrome (HLHS) is the most severe form of single ventricle congenital heart disease. Surgical interventions have improved outcomes in HLHS patients but right ventricle (RV) dysfunction is still a major determinant of morbidity. One possible explanation is that abnormal loading and pressure conditions to the RV are compensated by cardiomyocyte hypertrophy which causes negative remodelling of RV and leads to dysfunction. We are currently performing a Phase I clinical trial to determine the efficacy of mesenchymal stem cell (MSC) therapy in HLHS patients after the second staged palliative surgery. Since there is no reproduceable HLHS animal model, we exploited induced pluripotent stem cells (iPSCs) derived from HLHS and normal patients.
Methods: The iPSCs were differentiated into cardiomyocytes (iPSC-CMs), exposed with a hypertrophic agonist endothelin-1, and subsequently treated with MSC or media control.
Results: Our results showed post-hypertrophy stimulation increased the expression of hypertrophic markers (ANF,BNP, β-MHC) and increased hypertrophy cardiomyocyte size in HLHS derived iPSC-CMs. Further, treatment with MSC significantly reduced the hypertrophic response in HLHS iPSC-CMs, and implicated the GDF-15 anti-hypertrophy pathway by the MSCs and not by control media.
Conclusions: Our preliminary results suggest that MSC treatment has a novel ability to reduce hypertrophy in HLHS iPCS-CMs through a GDF-15 anti-hypertrophy pathway. These results provide a rationale for possible MSC based treatment in HLHS patients.