Elucidating the regulatory mechanisms of mammalian cardiomyocyte cytokinesis to promote heart regeneration

• Applicant: Chi Chung Wu, Ph.D.
• Subject Area: Cardiology, Angiology ; Anatomy and Physiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521708989

Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Since the adult mammalian heart possesses very limited regenerative capacity, following heart attack, lost cardiomyocytes (CMs) are not replaced efficiently, which eventually leads to heart failure. Current therapies to cure or delay the progression of heart failure is limited; a robust therapy to regenerate CMs would benefit millions of patients each year. Two major barriers stand in the way of myocardial regeneration in adult mammals: 1) limited CM dedifferentiation and cell cycle entry, and 2) defective cytokinesis to generate new cells. CMs from regenerative model systems like zebrafish and embryonic mammals are able to proliferate and regenerate following heart injury. This ability to lost shortly after birth when CMs lose the ability to complete cytokinesis and become polyploid (i.e., multiplication of the genome). Similar to maturing CMs, cell cycle activity in adult mouse and human CMs (e.g., after myocardial infarction (MI)) usually results in increase in ploidy but not cytokinesis, which may account for their lack of regeneration. Importantly, experimental manipulations aim at promoting CM proliferation led to improved functional recovery following MI, highlighting their therapeutic potential. Hence, a mechanistic understanding of CM cell cycle regulation (i.e., re-entry and completion) will help devise new therapeutic strategy for heart failure. To this end, while much of the research in the past decades has focused on CM cell cycle re-entry, how CM cytokinesis is regulated remain poorly understood. In this proposal, we will use a combination of in vitro, in vivo, and OMICs approaches to elucidate the regulatory mechanisms of mammalian CM cytokinesis. Building on my previous and preliminary work, in Work Programme 1, I will 1) investigate the transcriptional control of CM cytokinesis, and 2) identify candidate cytokinesis regulators that are able to promote postnatal and adult CM cytokinesis. Furthermore, my previous work has identified a surprising role for the diffusible chemorepellent Slit Guidance Ligand 2 (SLIT2), in regulating postnatal CM cytokinesis. In Work Programme 2, I will 1) further investigate the in vivo function and 2) elucidate the underlying molecular mechanisms of Slit/Robo signaling in CM cytokinesis. Furthermore, I will manipulate the function of identified cytokinesis regulators and other CM cell cycle activity inducers to promote heart regeneration in the non-regenerative postnatal and adult mice. Altogether, my proposed research will provide significant insights into the regulation of mammalian CM cytokinesis, and help identify potential therapeutics to promote CM proliferation and regeneration in adult mammals. Therefore, we anticipate these findings to be of high relevance and translational value to heart regeneration research.

• DFG Programme: Independent Junior Research Groups