Investigation on the Mechanism of Cardiomyocyte Maturation
- Author(s): Lee, Josh Zixi
- Advisor(s): Wang, Yibin
- et al.
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; with valuable insight in transcriptional regulatory networks directing early cardiomyocyte differentiation.
However, circumstances that determine myocyte maturation in late stage development, which are especially important for understanding diseases and developing cell based clinical applications, are far less well characterized. Induced Pluripotent Stem cell derived cardiomyocytes (iPSC-CMs) are lineage committed but remain immature and fetal-like in molecular, morphological and functional characteristics. Their application in cell-based therapy for heart failure is limited, in part due to the lack of sufficient insight to promote their maturation into adult myocytes. Although manly discoveries have been made, the underlining mechanisms of the maturation process is still unknown.
In this study, I discovered that mRNA alternative splicing (AS) is a key event in cardiomyocyte maturation and that manipulating AS patterns via a splicing factor, Rbfox1 is sufficient for improved maturation of cardiomyocytes in vitro. Furthermore, using Rbfox1 as a case study on the overall maturation gene expression program, I found that a conserved enhancer sequence upstream of the Rbfox1 TSS may serve as a functional maturation transcription upregulation response element (MATURE). Additional investigation found that MATURE is seemingly regulated by a long non-coding RNA (lncRNA) we termed CARMER (Cardiac Maturation Enhancer RNA). Cardiomyocyte maturation is complex and convoluted, without a defined mechanism. Our findings shed light onto the mechanisms involved in shaping an adult heart, and I hope this knowledge will contribute in understanding how to engineer adolescence.