Mechanisms of proliferation in cell-cell contact removed cardiomyocytes
Description: Ischemic heart disease is one of the leading causes of morbidity and mortality in the world. Cardiac injury such as myocardial infarction is followed by pathological remodeling which leads to cardiomyocyte (CM) loss and subsequently to heart failure. The adult mammalian heart has low CM turnover rates, which limits endogenous CM replacement and myocardial regeneration. Current approaches to promote myocardial regeneration include injection of stem cell-derived cardiac progenitors or cardiomyocytes, transplantation of engineered cardiac tissue patches as well as utilization of small molecule cocktails and cardiac-specific expression of pluripotency factors, resulting in promising outcomes in revascularizing damaged myocardium and enhancing cardiac function. All approaches made to date – though using different techniques – are based on inducing cardiomyocyte proliferation. Understanding the key regulators involved in CM proliferation is therefore crucial to developing and establishing effective regenerative therapies for the heart. Previous studies from our group have shown that reduced cell-cell contact and Wnt activation lead to an extensive increase in proliferation rates of human induced pluripotent stem cell derived CMs (hiPSC-CMs) and thereby enabling large-scale tissue engineering and cell transplantation approaches. My goal for this proposal will be to characterize the molecular regulators underlying the release of inhibition of proliferation after cell-cell contact removal. My central hypothesis is that cell-cell contact is an essential regulator of CM cell cycle activity and removal of cell-cell contact induces defined pro-proliferative molecular and paracrine mechanisms in CMs. Identifying and understanding these mechanisms could furthermore be used to develop techniques to induce proliferation in dense CM networks. Therefore, I want to (1) Understand the involvement of cell adhesion molecules such as N-cadherin in cell-cell contact-mediated inhibition of proliferation in dense CM networks. Additionally, I aim to (2) identify and characterize paracrine mechanisms underlying higher proliferation rates after cell contact removal in CMs and explore their applications for overcoming contact inhibition in dense cell networks. Together, my research will significantly advance current understandings of mechanisms underlying CM proliferation and thereby push forward the AHA’s mission to be a relentless force for a world of longer healthier lives.
Funder: American Heart Association
Amount: $65,110
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2023-01-01
End date: 2025-12-02
Investigators: Paul Heinrich, Paul Heinrich
Institution: The Board of Trustees of the Leland Stanford Junior University
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 23PRE1018158
OpenAlex ID: G7150992587