Although the adult mammalian myocardium exhibits a limited ability to undergo regenerative growth, the intrinsic renewal rate is insufficient to reverse pathophysiologic cardiomyocyte loss. The ability to reconstitute lost cardiac mass could thus be of considerable therapeutic value. One approach to accomplish this entails transplantation of donor cardiomyocytes or cardiomyogenic stem cells. This application focuses on cardiac-resident stem cells which express the Stem Cell Factor receptor c-kit. The proposed experiments are based on the recent observation that approximately 3% of the c-kit+ cells isolated from neonatal mouse hearts can give rise to well developed cardiomyocytes when co-cultured with fetal or neonatal cardiomyocytes. These cells appear to be either cardiomyogenic stem cells, or committed progenitor cells which require a heart-like environment to manifest a cardiac phenotype. Similar analyses using adult hearts suggested that the cardiomyogenic activity of c-kit+ cells is markedly limited or completely absent at later stages of development. The studies proposed in this competitive renewal application will establish the utility of cardiomyogenic c-kit+ cells (isolated from early post-natal hearts, from in vitro differentiating embryonic stem cells, and from adult hearts) for cell transplantation-based interventions aimed at repopulating the myocardium.
Specific Aim 1 will characterize the developmental profile of cardiomyogenic c-kit+ cells, determine the degree to which the c-kit+ cells can be amplified while maintaining cardiomyogenic potential, and test the hypothesis that these cells are better suited than fetal cardiomyocytes to repopulate the adult myocardium following intra-cardiac transplantation.
Specific Aim 2 will test the hypothesis that relaxation of epigenetic tags during prolonged culture will unmask cardiomyogenic potential in adult heart-derived c-kit+ cells. Ultimately these approaches might be useful to reconstitute myocardial mass following cardiac injury.

Public Health Relevance

Studies proposed in this application will determine if cardiac-resident stem cells which express the Stem Cell Factor receptor, c-kit, can be used to repopulate the adult myocardium with functional cardiomyocytes, as well as determine if relaxation of epigenetic tags during prolonged culture will unmask cardiomyogenic potential in adult heart-derived c-kit+ cells. Ultimately these approaches might be useful to reconstitute myocardial mass in diseased hearts, as for example, following myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083126-09
Application #
8770041
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Evans, Frank
Project Start
2006-02-15
Project End
2015-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Soonpaa, Mark H; Zebrowski, David C; Platt, Colin et al. (2015) Cardiomyocyte Cell-Cycle Activity during Preadolescence. Cell 163:781-2
Yang, Tao; Rubart, Michael; Soonpaa, Mark H et al. (2015) Cardiac engraftment of genetically-selected parthenogenetic stem cell-derived cardiomyocytes. PLoS One 10:e0131511
Reuter, Sean; Soonpaa, Mark H; Firulli, Anthony B et al. (2014) Recombinant neuregulin 1 does not activate cardiomyocyte DNA synthesis in normal or infarcted adult mice. PLoS One 9:e115871
DidiƩ, Michael; Christalla, Peter; Rubart, Michael et al. (2013) Parthenogenetic stem cells for tissue-engineered heart repair. J Clin Invest 123:1285-98
Soonpaa, Mark H; Rubart, Michael; Field, Loren J (2013) Challenges measuring cardiomyocyte renewal. Biochim Biophys Acta 1833:799-803
Tao, Wen; Soonpaa, Mark H; Field, Loren J et al. (2012) Functional screening of intracardiac cell transplants using two-photon fluorescence microscopy. Pediatr Cardiol 33:929-37
Zaruba, Marc-Michael; Zhu, Wuqiang; Soonpaa, Mark H et al. (2012) Granulocyte colony-stimulating factor treatment plus dipeptidylpeptidase-IV inhibition augments myocardial regeneration in mice expressing cyclin D2 in adult cardiomyocytes. Eur Heart J 33:129-37
Choi, Eue-Keun; Chang, Po-Cheng; Lee, Young-Soo et al. (2012) Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-?1. Circ J 76:1354-62
Ang, Keng-Leong; Shenje, Lincoln T; Reuter, Sean et al. (2010) Limitations of conventional approaches to identify myocyte nuclei in histologic sections of the heart. Am J Physiol Cell Physiol 298:C1603-9
Zaruba, Marc-Michael; Soonpaa, Mark; Reuter, Sean et al. (2010) Cardiomyogenic potential of C-kit(+)-expressing cells derived from neonatal and adult mouse hearts. Circulation 121:1992-2000

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