Towards translation of in vivo reprogramming at the heart of regeneration

Cardiovascular diseases (CVDs) remain amongst the leading causes of death worldwide resulting in more than 20 million deaths every year and with rising incidence rate. Therefore, profound interest lies in identifying ways that would enable heart regeneration through restoration of cardiomyocytes that are permanently lost after heart damage. Recently we showed that cardiomyocyte-specific reprogramming with the pluripotency factors OSKM instates heart regenerative potential by de-differentiating cardiomyocytes to a youthful, proliferation-competent state that is similar to embryonic cardiomyocytes. Timely termination of OSKM expression enables re-differentiation of cardiomyocytes back to the mature and division-incompetent state. Remarkably, if cardiomyocyte-specific OSKM expression is sustained, this gives rise to heart tumors with 100% penetrance, providing the first model of heart tumor formation. The conversion from the post-mitotic to mitotic state is progressive. Thereby, regenerative capacity increases but at one point then switches to complete tumorigenic conversion. In vivo synthesis of heart regenerative potential through cardiomyocyte-specific reprogramming occurs by epigenomic conversion (intrinsic) and relies on interaction with surrounding cells (extrinsic) in yet unknown ways. Our current goals aim to understand when and how the reprogrammed cardiomyocyte epigenome drives acquisition of both the regenerative and tumor (prone) state. I will deliberate on how we aim to develop translational perspectives towards synthesis of heart regenerative potential and prevention of cardiovascular disease.