Final Report Summary - CM TURNOVER (Uncovering the Mechanisms of Cardiomyocyte Differentiation and Dedifferentiation)
Ischemic heart disease is the most common postnatal cardiac ailment and the leading cause of death in the Western world today. The Tzahor lab combines novel approaches to study cardiomyocyte (CM) renewal by proliferation and/or and dedifferentiation of endogenous CMs. We focus on various signaling strategies: Growth factors: we have investigated the role of FGF-ERK, BMP, NRG-ErbB2 and Agrin-mediated signaling pathways to determine whether these signals can stimulate the re-entry of adult CMs into the cell cycle. These experiments aimed to maximize the heart’s regenerative response. We also focused on the microenvironment as a mean to enhance the regenerative potential of the heart. We manipulated biophysical properties of the cardiac microenvironment as well analyzing biochemical contents of the extracellular matrix (ECM) in search for conditions that facilitate CM proliferation. Our results demonstrated that CMs grown on soft substrates, as well as those grown in the presence of ECM particles, proliferate more extensively, suggesting an essential role for the microenvironment in the control of CM proliferation. We have been working to characterize novel compounds that promote CM renewal, both in vitro and in vivo by using a high-throughput small molecules screen. Further to exposing the valuable function of each factor on CM renewal, these studies enable us to examine multiple extrinsic factors and microenvironmental conditions that may act in concert to promote CM proliferative and regenerative potential. Taken together, understanding the underlying mechanisms of CM proliferation and dedifferentiation is expected to have an enormous impact on the field of cardiac regenerative medicine. In addition, understanding cellular and molecular dedifferentiation mechanisms and the suggested screening technology, hold the potential for development of novel therapies for other diseases.