Abstract 345: Maturation of Cardiomyocytes via Rbfox1

Abstract

Background: Cardiovascular disease is the leading cause of death in the world with a dearth of effective therapies. Heart undergoes a complex differentiation and maturation process throughout embryonic and post-natal stages. Intense efforts have been made in the study of cardiomyocyte differentiation, maturation and pathological remodeling. With the aid of stem cells, investigators are able to recapitulate events in early cardiac development and gain valuable insight in transcriptional regulatory networks directing early cardiomyocyte differentiation. However, the molecular network that determine myocyte maturation in postnatal development, which are especially important for understanding diseases and developing cell based clinical applications, are far less well characterized. Human induced pluripotent stem cell derived cardiomyocytes (hIPSC-CMs) are lineage committed but remain immature and fetal-like in molecular, morphological and functional characteristics. Their application in cell based therapy or serving as a disease model for heart failure is limited, in part due to the lack of sufficient insight to promote their maturation into adult myocytes. Results: We find from previous studies that postnatal cardiomyocyte development is marked by global alternative splicing (AS) programming. In mouse heart, we find RNA splicing regulator RBFox1 is markedly induced in heart only in post-natal period and functions as a key regulator to post-natal global RNA alternative splicing reprogramming during cardiomyocyte maturation. Transcriptome analysis revealed that exogenous expression of RBFox1 promotes gene expression in neonatal ventricular myocytes reminiscent of mature adult heart, and results in cellular maturation based on sarcomere organization and calcium cycling characteristics. Furthermore, ectopic expression of rodent RBFox1 in human iPSC derived CMs resulted in similar maturation effects, implicating a conserved mechanism in human and rodent myocytes. Conclusion: RBFox1 mediated RNA splicing is an important contributor to post-natal myocyte maturation and it can be manipulated to promote cardiomyocyte maturation for cell-based therapy or disease modeling.