Cellular reprogramming of induced cardiomyocytes (iCMs) holds promise as a novel therapy for the treatment of heart failure, a common and morbid disease that is caused by irreversible loss of functional cardiomyocytes (CMs). We and others have showed that in a murine model of acute myocardial infarction, delivery of three transcription factors, Gata4, Mef2c and Tbx5, converted endogenous cardiac fibroblasts into functional iCMs. These iCMs integrated electrically and mechanically with surrounding myocardium, resulting in a reduction in scar size and an improvement in heart function. These findings suggest that iCM reprogramming might be a promising novel approach to regenerate functional CMs in vivo for patients with heart disease. However, our limited understanding of the underlying molecular mechanisms of iCM reprogramming has significantly hindered its clinical applicability. In this proposal, we will take advantage of our expertise in iCM reprogramming, knowledge in developmental biology, unique new tools that we have built to define the molecular mechanisms of how a CM fate is established in a non-CM cell without transiting through the traditional developmental CM specification and differentiation route. Based on our preliminary data, we hypothesize that reprogramming factors Gata4, Mef2c and Tbx5 act in a stoichiometrically and temporally coordinated fashion upon a privileged subpopulation of CFs to overcome major epigenetic barrier(s) and induce CM fate. Successful completion of this proposal will define the molecular components and determine the optimal condition for iCM reprogramming. Our studies will provide novel insights into fundamental molecular mechanisms underlying cardiac cell fate acquisition and cell plasticity regulation.

Public Health Relevance

Heart disease is the leading cause of morbidity and mortality in the developed world. Because cardiomyocytes in the heart have limited regenerative potential in response to injury, loss of cardiomyocytes results in impaired pump function and heart failure. Our strategy to reprogram endogenous cardiac fibroblasts into contractile cardiomyocyte-like cells holds promise as a novel therapy for the treatment of this prevalent and morbid disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128331-03
Application #
9463475
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Wong, Renee P
Project Start
2016-04-15
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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