Congestive heart failure typically occurring as a result of myocardial infarction remains the leading cause of mortality from heart disease. Cardiac stem cell therapy has offered promise in animal and clinical studies, but remains inherently constrained by the logistical challenges of delivering and integrating exogenous cells into a host myocardium. The recent discovery that induced cardiomyocytes (iCMs) could be generated directly from somatic cells offers the exciting possibility of bypassing stem cell staging and, perhaps more importantly, converting scar fibroblasts in situ into iCMs, obviating entirely the challenges of cell implantation into a host myocardium. We and several others have recently demonstrated that the administration of a cardiac transcription factor cocktail (e.g., GATA4, MEF2c and TBX5 [GMT]) results in as much as a 50% increase in ventricular function, reduced fibrosis, and increased iCM populations in small animal myocardial infarction models. Intriguingly, we have also demonstrated that reductions in infarct size appear to far exceed the extent of scar repopulation with iCMs, and that GMT also appears to reduce the population of (scar-producing) myofibroblasts as well as the expression of key scar remodeling cytokines. These data, and our observation that GMT efficacy is enhanced by the angiogenic pre-treatment of myocardial scar with vascular endothelial growth factor (VEGF), suggest the existence of unexplored and non-optimized underlying mechanisms. Given our long-term goal to develop a potentially important new treatment for CHF, we propose to determine whether cellular reprogramming can be applied to improve cardiac infarct remodeling and function by testing the serial hypotheses that: a) inadequate up-regulation of requisite reprogramming genes limits cell transdifferentiation efficiency, which can be optimized beyond current thresholds via the comprehensive application of genomic activation strategies, b) that the density of (contractile) iCMs in infarct zones as well as indirect or paracrine (i.e., anti-fibroti) mechanisms play critical roles in GMT/VEGF mediated infarct remodeling, and c) that cardiac fibroblasts can be made susceptible to reprogramming in a clinically relevant fashion. We will use cutting edge molecular strategies and pre-clinical animal models to execute these aims.

Public Health Relevance

The overall goal of this proposal is to test in vivo cardiac reprogramming as a viable therapeutic strategy after cardiac injury in different animal models. This proposal may help us to develop new methods or tools for treatment for heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL121294-02
Application #
9127324
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schwartz, Lisa
Project Start
2015-09-01
Project End
2019-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Rosengart, Todd K; Patel, Vivek; Sellke, Frank W (2018) Cardiac stem cell trials and the new world of cellular reprogramming: Time to move on. J Thorac Cardiovasc Surg 155:1642-1646
Wang, Hongran; Zhao, Shuying; Barton, Michelle et al. (2018) Reciprocity of Action of Increasing Oct4 and Repressing p53 in Transdifferentiation of Mouse Embryonic Fibroblasts into Cardiac Myocytes. Cell Reprogram 20:27-37
Patel, Vivekkumar; Singh, Vivek P; Pinnamaneni, Jaya Pratap et al. (2018) p63 Silencing induces reprogramming of cardiac fibroblasts into cardiomyocyte-like cells. J Thorac Cardiovasc Surg 156:556-565.e1
Mathison, Megumi; Rosengart, Todd K (2018) Heart regeneration: The endothelial cell comes first. J Thorac Cardiovasc Surg 155:1128-1129
Mathison, Megumi; Singh, Vivek P; Sanagasetti, Deepthi et al. (2017) Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail. J Thorac Cardiovasc Surg 154:1601-1610.e3
Mathison, Megumi; Singh, Vivek P; Chiuchiolo, Maria J et al. (2017) In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: Implications for clinical myocardial regeneration. J Thorac Cardiovasc Surg 153:329-339.e3
Kota, Prashant S; Naguib, Mostafa R; Patel, Vivekkumar et al. (2017) Less may be more: Using small molecules to reprogram human cells into functional cardiomyocytes. J Thorac Cardiovasc Surg 153:128-130
Patel, Vivekkumar; Mathison, Megumi; Singh, Vivek P et al. (2016) Direct Cardiac Cellular Reprogramming for Cardiac Regeneration. Curr Treat Options Cardiovasc Med 18:58
Singh, Vivek P; Mathison, Megumi; Patel, Vivekkumar et al. (2016) MiR-590 Promotes Transdifferentiation of Porcine and Human Fibroblasts Toward a Cardiomyocyte-Like Fate by Directly Repressing Specificity Protein 1. J Am Heart Assoc 5: