Generation of Induced Cardiospheres via Reprogramming of Skin Fibroblasts for Myocardial Regeneration

Abstract

Recent pre-clinical and clinical studies have suggested that endogenous cardiospheres (eCS) are potentially safe and effective for cardiac regeneration following myocardial infarction (MI). Nevertheless the preparation of autologous eCS requires invasive myocardial biopsy with limited yield. We describe a novel approach to generate induced cardiospheres (iCS) from adult skin fibroblasts via somatic reprogramming. After infection with Sox2, Klf4, and Oct4, iCS were generated from mouse adult skin fibroblasts treated with Gsk3b inhibitor-(2 0 Z,0 -oxime and Oncostatin M. They resembled eCS, but contained a higher percentage of cells expressing Mesp1, Isl1, and Nkx2.5. They were differentiated into functional cardiomyocytes in vitro with similar electrophysiological properties, calcium transient and contractile function to eCS and mouse embryonic stem cell-derived cardiomyocytes. Transplantation of iCS (1 3 10 6 cells) into mouse myocardium following MI had similar effects to transplantation of eCS but significantly better than saline or fibroblast in improving left ventricular ejection fraction, increasing anterior/septal ventricular wall thickness and capillary density in the infarcted region 4 weeks after transplantation. No tumor formation was observed. iCS generated from adult skin fibroblasts by somatic reprogramming and a cocktail of Gsk3b inhibitor-6-Bromoindirubin-3 0 -oxime and Oncostatin M may represent a novel source for cell therapy in MI. STEM CELLS 2016;34:2693-2706 SIGNIFICANCE STATEMENTThis study provides the first proof-of-principle results that demonstrate the feasibility of generating donor-specific induced cardiospheres via a somatic reprogramming process, providing a new source of cell therapy for treatment of myocardial infarction

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Cardiac Progenitor Cells from Stem Cells: Learning from Genetics and Biomaterials

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