DIRECT REPROGRAMMING OF HUMAN FIBROBLASTS INTO CARDIOMYOCYTES

Abstract

Direct reprogramming of human fibroblasts into induced cardiomyocytes (iCMs) offers a potential therapeutic approach for cardiovascular disease yet hampered by low efficiency of human iCM generation. Here, we established an optimal culture condition by defining a chemically defined media (CDM). In addition, we screened 80 transcriptional regulators and found two new factors, SALL4 and YY1 significantly enhanced reprogramming efficiency in human dermal fibroblasts (HDFs) when working together with GATA4, MEF2C, TBX5, HAND2 and MYOCD (5F). HDFs-generated iCMs exhibited cardiac-like action potential and spontaneously contractility in-vitro. Importantly, SALL4, together with 5F, promotes adult human cardiac fibroblasts (aHCFs) into cardiac-like cells. Moreover, aHCFs-generated iCMs exhibited calcium oscillation and contractility when co-cultured with neonatal cardiomyocytes within one week of reprogramming. Mechanistically, SALL4 may enhance cardiac reprogramming through the upregulation of the AKT pathway. Our results showed that SALL4 enhance the efficiency of iCM generation, providing a valuable platform for direct cardiac reprogramming studies.