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 #
5R01HL128331-02
Application #
9260926
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
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
$375,758
Indirect Cost
$125,758
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
Vaseghi, Haley; Liu, Jiandong; Qian, Li (2017) Molecular barriers to direct cardiac reprogramming. Protein Cell 8:724-734
Zhou, Yang; Wang, Li; Liu, Ziqing et al. (2017) Comparative Gene Expression Analyses Reveal Distinct Molecular Signatures between Differentially Reprogrammed Cardiomyocytes. Cell Rep 20:3014-3024
Liu, Ziqing; Chen, Olivia; Wall, J Blake Joseph et al. (2017) Systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector. Sci Rep 7:2193
Zhou, Yang; Qian, Li (2016) Advanced Technologies Lead iNto New Reprogramming Routes. Cell Stem Cell 19:286-8
Vaseghi, Haley Ruth; Yin, Chaoying; Zhou, Yang et al. (2016) Generation of an inducible fibroblast cell line for studying direct cardiac reprogramming. Genesis 54:398-406
Qian, Li (2016) Hope for the brokenhearted: Cellular reprogramming improves cardiac function in a mouse model of myocardial infarction. Science 352:1400-1
Liu, Liu; Lei, Ienglam; Karatas, Hacer et al. (2016) Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts. Cell Discov 2:16036
Samsa, Leigh Ann; Ito, Cade Ellis; Brown, Daniel Ross et al. (2016) IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish. PLoS One 11:e0166734
Brown, Daniel R; Samsa, Leigh Ann; Qian, Li et al. (2016) Advances in the Study of Heart Development and Disease Using Zebrafish. J Cardiovasc Dev Dis 3:
Ma, Hong; Liu, Jiandong; Qian, Li (2016) Fat for fostering: Regenerating injured heart using local adipose tissue. EBioMedicine 7:25-6