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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-D (02))
Program Officer
Buxton, Denis B
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University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
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Gao, Ling; Gregorich, Zachery R; Zhu, Wuqiang et al. (2018) Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell-Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine. Circulation 137:1712-1730
Zhu, Wuqiang; Zhao, Meng; Mattapally, Saidulu et al. (2018) CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Remuscularization of Injured Ventricle. Circ Res 122:88-96
Zhang, Jianyi; Abel, E Dale (2018) Effective Metabolic Approaches for the Energy Starved Failing Heart: Bioenergetic Resiliency via Redundancy or Something Else? Circ Res 123:329-331
Gao, Ling; Yang, Libang; Wang, Lu et al. (2018) Relationship Between the Efficacy of Cardiac Cell Therapy and the Inhibition of Differentiation of Human iPSC-Derived Nonmyocyte Cardiac Cells Into Myofibroblast-Like Cells. Circ Res 123:1313-1325
Zhu, Wuqiang; Zhang, Eric; Zhao, Meng et al. (2018) Regenerative Potential of Neonatal Porcine Hearts. Circulation :
Chen, Zhongming; Zhu, Wuqiang; Bender, Ingrid et al. (2017) Pathologic Stimulus Determines Lineage Commitment of Cardiac C-kit+ Cells. Circulation 136:2359-2372
Borovjagin, Anton V; Ogle, Brenda M; Berry, Joel L et al. (2017) From Microscale Devices to 3D Printing: Advances in Fabrication of 3D Cardiovascular Tissues. Circ Res 120:150-165
Yang, Libang; Gao, Ling; Nickel, Thomas et al. (2017) Lactate Promotes Synthetic Phenotype in Vascular Smooth Muscle Cells. Circ Res 121:1251-1262
Zhu, Wuqiang; Gao, Ling; Zhang, Jianyi (2017) Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair. J Vis Exp :
Gao, Ling; Kupfer, Molly E; Jung, Jangwook P et al. (2017) Myocardial Tissue Engineering With Cells Derived From Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold. Circ Res 120:1318-1325

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