The adult mammalian heart shows little or no significant natural regeneration of cardiac muscle after injury, and instead heals by scarring. This regenerative deficiency has enormous socioeconomic consequences, given that ischemic myocardial infarction is a leading cause of morbidity and mortality in the United States and over 5 million Americans suffer from heart failure. Many years ago, we found that the teleost zebrafish displays a robust regenerative response after partial resection of the cardiac ventricle, involving creation of new cardiomyocytes with little or no scarring. Pre-existing cardiomyocytes, not stem cells, are the primary source of new muscle during heart regeneration in zebrafish. Muscle regeneration is influenced by activities of the epicardium and endocardium, major non-muscle cells that line the cardiac chambers. Progress during the previous periods of this grant has opened several avenues of investigation to address hurdles to how and why heart regeneration occurs. Most importantly, we have generated new strategies and tools for exploring the gene regulatory mechanisms of heart regeneration, and to determine functions and mechanisms of secreted and systemic factors that activate cardiomyocyte proliferation in response to injury. The goals of this application are to address central questions about the regulation of bona fide heart regeneration, using cutting edge screening and analysis tools in zebrafish. 1) We will define chromatin regulatory signatures and enhancer elements for heart regeneration, using genome-wide chromatin structure profiles obtained from regenerating cardiac tissue. 2) We will use new tools to define responses in distant tissues that potentially impact heart regeneration. 3) We will define functions of new modulators of heart regeneration identified from an in vivo screening strategy that visualizes proliferating cardiomyocytes in live zebrafish. With this approach, we will test the hypothesis that local and distant injury responses control a mitogenic regulatory program for heart regeneration. Our work will provide a detailed understanding of cardiac regeneration and identify key regulators. These discoveries will inform approaches for comprehending and enhancing the limited regenerative response displayed by humans after myocardial infarction.

Public Health Relevance

Our work will provide a detailed understanding of heart regeneration that will inform approaches for comprehending and enhancing the limited cardiac regenerative response displayed by humans. They are also likely to extend beyond cardiovascular biology and have relevance to the repair of other tissues.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schwartz, Lisa
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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Mokalled, Mayssa H; Poss, Kenneth D (2018) A Regeneration Toolkit. Dev Cell 47:267-280
Cao, Jingli; Poss, Kenneth D (2018) The epicardium as a hub for heart regeneration. Nat Rev Cardiol 15:631-647
Walton, Eric M; Cronan, Mark R; Cambier, C J et al. (2018) Cyclopropane Modification of Trehalose Dimycolate Drives Granuloma Angiogenesis and Mycobacterial Growth through Vegf Signaling. Cell Host Microbe 24:514-525.e6
Karra, Ravi; Foglia, Matthew J; Choi, Wen-Yee et al. (2018) Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish. Proc Natl Acad Sci U S A 115:8805-8810
Goldman, Joseph Aaron; Kuzu, Guray; Lee, Nutishia et al. (2017) Resolving Heart Regeneration by Replacement Histone Profiling. Dev Cell 40:392-404.e5
Cao, Jingli; Wang, Jinhu; Jackman, Christopher P et al. (2017) Tension Creates an Endoreplication Wavefront that Leads Regeneration of Epicardial Tissue. Dev Cell 42:600-615.e4
Karra, Ravi; Poss, Kenneth D (2017) Redirecting cardiac growth mechanisms for therapeutic regeneration. J Clin Invest 127:427-436
Yang, Xinan H; Nadadur, Rangarajan D; Hilvering, Catharina Re et al. (2017) Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm. Elife 6:
Chen, Chen-Hui; Poss, Kenneth D (2017) Regeneration Genetics. Annu Rev Genet 51:63-82
Tzahor, Eldad; Poss, Kenneth D (2017) Cardiac regeneration strategies: Staying young at heart. Science 356:1035-1039

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