In hearts with postinfarction LV remodeling, the mechanisms that contribute to the transition from the compensated state to heart failure remain unclear, but may be related to progressive contractile dysfunction of the region of viable myocardium that surrounds the infarct (border zone, BZ). We have recently found that the border zone region of myocardium (BZ) surrounding an infarct has much more severe abnormal bioenergetic characteristics than remote zone myocardium (RZ). It has been reported that cellular therapy improves LV contractile function in hearts with myocardial infarction. We have recently established a population of multipotent adult progenitor cells from swine bone marrow (sMPC) that can proliferate for >100 population doublings, and differentiate at the single cell level into cells with phenotypic and functional characteristics of mesoderm, neuroectoderm, and endoderm lineages. A central hypothesis to be tested in the current proposal is that the sMPC will engraft into hearts with myocardial infarcts, differentiate into cardiomyocytes, endothelium and smooth muscle, and cytokine released from the stem cells induce proliferation and preservation of native myocytes. These beneficial effects will be most prominent in the BZ. BZ stabilization will in turn, limit progressive deterioration of LV chamber function and prevent transition to CHF.
The specific aims of this project are:
SPECIFIC AIM 1. To determine in a pig ischemia and reperfusion model: a) the relationships between elevated systolic LV wall stress, bioenergetic abnormalities and contractile dysfunction in the myocardial ischemic zone (IZ) and BZ and the severity of global LV dysfunction, and b) determine the progression of these abnormalities over an additional 8 week follow-up period.
SPECIFIC AIM 2. To determine whether: A) myocardial transplantation of sMPC into BZ will limit ischemia/reperfusion induced abnormalities in IZ, BZ and global LV function over an 8 week followup period;B) examine possible mechanisms of sMPC benefits including: i) transdifferentiation of sMPC to cardiomyocytes, endothelial and, smooth muscle cells that improve BZ perfusion and function, ii ) a trophic effect: sMPC release cytokines that spare native cardiomyocytes from apoptosis and induce neovascularization;and C) intra-coronary vein infusion of stem cells is more effective that the other routes of delivery.
SPECIFIC AIM 3. To examine whether a mixture of partially pre-differentiated cardiomyocytes and endothelium derived from sMPC delivered within a novel 3D porous PEGylated growth factor enhanced biomaterial patch, will have greater beneficial effects, which are evidenced by significantly increase in the engraftment rate and myocyte regeneration, and further reduction the LV wall stress in BZ and IZ.

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) that is a most significant clinical problem. This proposal will examine whether a PEGylated fibrin patch based stem cell transplantation can provide a new regeneration therapy for heart failure patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095077-04
Application #
8277096
Study Section
Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Buxton, Denis B
Project Start
2009-06-16
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$474,645
Indirect Cost
$163,222
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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Zhang, Sophia; Dutton, James R; Su, Liping et al. (2014) The influence of a spatiotemporal 3D environment on endothelial cell differentiation of human induced pluripotent stem cells. Biomaterials 35:3786-93
Jameel, Mohammad Nurulqadr; Hu, Qingsong; Zhang, Jianyi (2014) Myocytes oxygenation and high energy phosphate levels during hypoxia. PLoS One 9:e101317
Ye, Lei; Chang, Ying-Hua; Xiong, Qiang et al. (2014) Cardiac repair in a porcine model of acute myocardial infarction with human induced pluripotent stem cell-derived cardiovascular cells. Cell Stem Cell 15:750-61
Wendel, Jacqueline S; Ye, Lei; Zhang, Pengyuan et al. (2014) Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model. Tissue Eng Part A 20:1325-35
Ye, Lei; Zhang, Pengyuan; Duval, Sue et al. (2013) Thymosin *4 increases the potency of transplanted mesenchymal stem cells for myocardial repair. Circulation 128:S32-41
Ye, Lei; Swingen, Cory; Zhang, Jianyi (2013) Induced pluripotent stem cells and their potential for basic and clinical sciences. Curr Cardiol Rev 9:63-72
Zhang, Jianyi Jay (2013) Mechanisms of cell therapy for clinical investigations: an urgent need for large-animal models. Circulation 128:92-4
Ye, Lei; Zimmermann, Wolfram-Hubertus; Garry, Daniel J et al. (2013) Patching the heart: cardiac repair from within and outside. Circ Res 113:922-32
Ye, Lei; Zhang, Sophia; Greder, Lucas et al. (2013) Effective cardiac myocyte differentiation of human induced pluripotent stem cells requires VEGF. PLoS One 8:e53764

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