Cardiac progenitor fates and directed reprogramming of non-cardiac cells

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): This proposal seeks to utilize dramatic new advances in both epigenetic reprogramming and cardiovascular lineage/cell fate determination to inform and empower our ability to harness regenerative medicine for cardiovascular therapies. In recent years, new discoveries have significantly altered our understanding of how the heart forms. It is now clear that several cardiac progenitor populations can be identified that contribute to the adult myocardium, though the precise relationships among these populations and their distinct lineages potential remain poorly defined. The description of induced pluripotential (iPS) cells demands a rethinking of cellular plasticity and suggests the possibility of reprogramming a differentiated cell to adopt the characteristics and potential of a cardiac progenitor and subsequently a functional myocyte (16, 21, 22, 32). However, a major challenge of this research is whether reprogramming of adult cells can be directed in such a way as to dedifferentiate to a committed precardiac progenitor state without reprogramming fully to a pluripotential state. We propose to assemble a team of collaborative investigators with established expertise in cardiac development and physiology, stem cell biology and regenerative medicine to elucidate and define progressive lineage restriction during embryonic cardiac development, including the roles of Wnt and Notch signaling in cardiac progenitor biology, and to define the necessary factors for directed reprogramming of adult cells to the cardiac progenitor state. We will pursue the following aims: Compare and contrast the prospective fates of distinct cardiovascular progenitor populations in vivo to allow for an accurate spatial and temporal accounting of genetically defined populations to generate mature cardiovascular cell types during progressive lineage restriction. Characterize the ability of Wnt and Notch signaling to regulate self-renewal and differentiation in different cardiovascular progenitor subpopulations. Utilizing known information and data gathered from studies in areas 1 and 2, determine the necessary factors for producing induced cardiac progenitor (iCPC) cells and their subsequent differentiation into functional cardiac myocytes.