Although the beneficial effects of cellular therapy in hearts with post myocardial infarction LV remodeling (MI) have been reported recently, there could be additional benefit in applying a prefabricated cardiac muscle tissue equivalent over the surface of myocardial infarct.
We aim to develop a "cardiac muscle patch", formed by entrapping human cardiac myocytes, endothelial cells and smooth muscle cells that derived from human induced pluripotent stem cells (hiPSC) in a 3D porous fibrin biomaterial. A "cardiac muscle patch" could effectively prevent LV infarct scar bulging, reduce the BZ wall stress and improve the myocardial bioenergetics. One of the most significant problems in cardiovascular physiology is how the rate of ATP production and utilization is regulated in the in vivo heart and how the limitation of this rate may contribute to contractile dysfunction in failing hearts. The accurate evaluation of myocardial ATP turnover rates (ADP+Pi ?ATP), has generally not been successful because the level of myocardial free inorganic phosphate (Pi) in the in vivo heart is too low to be measured directly.
We aim to demonstrate a novel double saturation transfer (MRS-MST) method enabling us to calculate the ATP hydrolysis rate without measuring Pi levels, which overcomes the primary barrier in determining the ATP turnover rate in vivo. Although reports of human brain function imaging at high field (>7Tesla, [T]), have generated significant novel findings that advance the field of neuroscience, cardiac MRI and spectroscopy for humans at 7T is nonexistent because of the lack of coil engineering.
The specific aims (SA) are: SA1. To fabricate and characterize the human cardiac muscle patch (hcMP). We will differentiate human induced pluripotent stem cells (hiPSC) into cardiomyocytes (CM), endothelial cells (EC), and smooth muscle cells (SMC);and use these cardiac cells to fabricate an hcMP and characterize the mechanical properties of the hcMP during baseline and in response to pacing. SA2. To examine novel delivery of CM-, EC- and SMC-hiPSC for myocardial repair using an immuno-suppressed swine model of post infarction LV remodeling. We will examine whether the transplantation of a prefabricated hcMP will result in reductions in LV scar bulging and wall stress, and improvements in myocardial bioenergetics and contractile function. We will also compare the electrical stability of hearts with or without C transplantation by using a Loop Recorder to monitor EKGs 24/7 for 8 weeks, and by conducting a PES study. SA3.To examine myocardial bioenergetics in a high field magnet with previously unattainable levels of capability, sensitivity and spatial localization. 3a) To demonstrate a novel NMR MRS-MST technology that can measure the myocardial ATP turnover rate in the in vivo heart. 3b) To develop the first body coil for a 7T/125 CM large-bore magnet that can be used to perform 1H- and 31P- cardiac NMR studies for measurements of myocardial function, perfusion, and ATP turnover rate;The success of this coil will enable these methods to be readily applied in a clinical setting and provide an entirely new and valuable method for monitoring myocardial function, metabolism, and perfusion in the human heart.

Public Health Relevance

We aim to develop a cardiac muscle patch, formed by entrapping human cardiac myocytes, endothelial cells and smooth muscle cells that derived from human induced pluripotent stem cells (hiPSC) in a 3D porous fibrin biomaterial. The accurate evaluation of myocardial ATP turnover rates (ADP+Pi?ATP), has generally not been successful because the level of myocardial free inorganic phosphate (Pi) in the in vivo heart is too low to be measured directly. We aim to demonstrate a novel double saturation transfer (MRS-MST) method enabling us to calculate the ATP hydrolysis rate without measuring Pi levels, which overcomes one of the most significant problems in cardiovascular physiology: measure the rate of ATP turnover in vivo. We will develop new NMR technologies to achieve previously unattainable levels of capability, sensitivity and spatial localization for cardiac imaging and spectroscopy noninvasively in a 7 T large bore magnet. Once this new NMR technology has been tested and validated in our porcine model, the identical method can be readily applied to the clinical situation

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL095077-05A1
Application #
8711999
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
Project Start
2008-12-01
Project End
2018-02-28
Budget Start
2014-03-19
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$486,735
Indirect Cost
$165,969
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
Zhang, Liying; Guo, Jing; Zhang, Pengyuan et al. (2015) Derivation and high engraftment of patient-specific cardiomyocyte sheet using induced pluripotent stem cells generated from adult cardiac fibroblast. Circ Heart Fail 8:156-66
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

Showing the most recent 10 out of 16 publications