All ETDs from UAB

Advisory Committee Chair

Gangjian Qin

Advisory Committee Members

Yuji Nakada

Sumanth D Prabhu

Wuqiang Zhu

Document Type

Dissertation

Date of Award

2022

Degree Name by School

Doctor of Philosophy (PhD) School of Engineering

Abstract

Myocardial infarction (MI) remains one of the major contributors to heart failure, which can lead to death, and there has been a lack of effective treatments so far. Human pluripotent stem cells (hPSCs) have been found to be an encouraging candidate for MI treatment. But it is facing challenge of low engraftment, limited integration of transplanted cells with host myocardium. To enhance the therapeutic efficacy of stem cell therapy of MI treatment, two approaches have been explored: 1)The first approach was to overexpress N-cadherin (CDH2), a cell-cell adhesion molecule, in human induced pluripotent stem cell-derived cardiomyocytes (CDH2-hiPSC-CMs), and examine its effect on hiPSC-CMs function. After transfected with CDH2 containing expression vector, CDH2-hiPSC-CM showed significant faster conduction velocity and increased resistance against hypoxia-induced apoptosis in vitro when compared with hiPSC-CM, suggesting enhanced function and greater survival rate. When CDH2-hiPSC-CMs were injected into the infarcted cardiomyocytes in mouse MI model, survival rate of CDH2-hiPSC-CMs, blood vessel density in border zone of infarction, and more importantly ejection fraction and fractional shortening were all significantly increased when compared with that of controls. These results suggest CDH2 can enhance engraft rate, angiogenesis, and cardiac function. 2) The second approach was to prepare a novel cardiac muscle patch with four types of iii hPSC-derived cardiac cells (4TCC-hCMPs), i.e. hPSC-CMs, hPSC-cardiac fibroblasts, hPSC-smooth muscle cells, and hPSC-arterial endothelial cells. The 4TCC-hCMPs showed significantly increased sarcomere, expression of cell maturation markers including ion-channels and metabolic when compared with three types of hPSCs patch (3TCC-hCMPs, without hPSC-cardiac fibroblasts). These results indicated the maturation of, and electrophysiological function of hPSC-CMs were greatly improved in 4TCChCMPs. In vivo studies showed that transplanted 4TCC-hCMPs held much more viable hPSC-CMs, significantly reduced scar size, and greatly increased ejection fraction and fractional shortening in mouse MI model when compared with that of controls. These results suggest 4TCC-hCMPs can greatly improve engraft rate and cardiac function in MI mouse. These studies suggest that both CDH2-hiPSC-CMs and 4TCC-hCMPs may be potential therapeutic tools to improve the therapeutic effect of stem cell therapy.

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