Myocardial infarction often induces a period of left ventricular (LV) remodeling. When LV remodeling occurs, an initial period of hemodynamic stability is followed by the development of LV dysfunction that may result in congestive heart failure (CHF). The molecular and cellular basis for the progressive heart failure is the result of the inability of damaged and apoptotic myocytes to be replaced, since cardiac myocytes are thought to be terminally differentiated. Although there are a significant number of reports in recent literature on cellular therapy for myocardial repair using different type of stem cells, the underlying mechanisms of the observed improvement in bioenergetics and cardiac contractile performance in response to the cellular transplantation remain largely unknown. The proposed studies will utilize the pre differentiated myocytes and vascular progenitor cells (CVPC) derived from human induced pluripotent stem cells (hiPSCs) in a porcine model of postinfarction LV remodeling that we have previously demonstrated to be very relevant to human clinical cardiac regenerative therapies. Using the well established pig model of postinfarction LV remodeling and the immuno-suppression by the xenotransplantation protocol, here we will pursue two specific aims (SA) 1: SA1: Examine the physiological, phenotypic, molecular and lineages differentiation of cardiovascular progenitor cells derived from hiPSCs. Studies in this aim evaluate the ability of hiPSC-derived CVPC to engraft into hearts with myocardial infarcts, and differentiate into mature cardiomyocytes, endothelial and smooth muscle. We hypothesize hiPSC-derived CVPC transplantation will improve BZ bioenergetics and contractile function. To test this hypothesis, we will examine the beneficial bioenergetic effects post-cellular treatment that are most prominent in the peri-infarct boarder zone (BZ). BZ stabilization will in turn, limit progressive deterioration of LV chamber function and prevent transition to CHF. To evaluate the hypothesis, in swine hearts with or without transplantation of defined pre-differentiated hiPSC-derived CVPC populations at the time of infarction, high energy phosphate (HEP) contents and PCr/ATP ratios in the BZ and remote zone (RZ) will be compared by chemical shifting 31P magnetic resonance spectroscopy imaging 8 weeks after ligation of the distal left anterior descending coronary artery (LAD). SA 2) Utilize a novel fibrin patch delivery technology, which can covalently bind with define growth factors, we will examine this combined 3D porous biomaterial and cellular therapy will further enhance hCVPC engraftment and maturation, and consequently enhance the regeneration. Together this combined use of novel cell human iPSC-derived CVPC populations, fibrin patch, a large bore high field magnet with a clinically relevant large animal model provides a model that will be readily applicable to patients. The results of these studies may lead to better diagnostic and therapeutic modalities for acute myocardial infarction.

Public Health Relevance

Post-infarction left ventricular remodeling including hypertrophy and chamber dilation occurs to compensate for loss of contractile myocardium. After a period stable hypertrophy myocardial dysfunction can develop and may ultimately lead to overt congestive heart failure (CHF), which is a significant clinical problem. Using a clinically relevant large animal model, the combined use of novel human iPSC-derived populations of cardiac progenitor cells (CPC), fibrin patch, and the large bore high field magnet, these studies will generate findings that will be readily applicable to patients. The results of these studies will lead to better diagnostic and therapeutic modalities for acute myocardial infarction and post infarction LV remodeling. The utilization of novel hiPSC-derived CPCs provides great promise for future therapy of post infarction LV remodeling using human pluripotent stem cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067828-12
Application #
8645678
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Schwartz, Lisa
Project Start
2001-08-24
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
12
Fiscal Year
2014
Total Cost
$421,480
Indirect Cost
$142,354
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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