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Role of GPCR signaling in cardiac progenitor cells


Heart disease is the leading cause of mortality in developed nations and imposes a tremendous cost on society. The relatively recent discoveries that the heart is a postmitotic organ capable of self-renewal and contains a pool of multipotent c-kit⁺ cardiac progenitor cells (CPCs) has opened doors for the development of new stem cell therapies. Our lab is interested in elucidating the ubiquitous roles of G-protein coupled receptor (GPCR) signaling on these endogenous cells. We were able to isolate c-kit⁺ cells from adult mouse hearts that demonstrated stem cell like characteristics and express the cardiac lineage markers GATA4 and MEF2C. A Taqman array was used to determine that these cells express a distinct set of GPCRs that differ from adult cardiomyocytes. Furthermore, the CPCs' receptor constellation is susceptible to receptor isotype switching following differentiation. Treatment with GPCR agonists such as Lysophosphatidic Acid (LPA) and Sphingosine-1- phosphate (S1P) induced proliferation in CPCs. Both S1P and LPA induce Rho dependent transcription as determined by the SRE.L luciferase reporter. In the CPCs, proliferation induced by S1P was determined to be Rho dependent while LPA is G[alpha]/i dependent. Addition of LPA potentiated dexamethasone induced differentiation of the CPCs towards a cardiac lineage based on changes in gene expression assayed by qPCR. However, addition of S1P failed to potentiate differentiation. Finally, cell death induced by oxidative stress was attenuated by S1P in CPCs. Our results demonstrate that S1P induces proliferation and survival possibly through Rho without effecting differentiation; while LPA induces proliferation and differentiation possibly through G[alpha]/i

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