Advisory Committee Chair
Jianyi Zhang
Advisory Committee Members
Vladimir G Fast
Hind Lal
Gangjian Qin
Jack Rogers
Palaniappan Sethu
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Abstract
Cardiovascular diseases remain the leading cause of death in the United States and the world. Myocardial infarction (MI) happens when there is an occlusion in the blood vessel. Cardiomyocytes (CM) die quickly after MI and are replaced by a fibrotic scar. Since adult mammalian cardiomyocytes have a limited capacity to regenerate, the damages induced by MI usually deteriorate into more severe symptoms such as heart failure. In order to achieve regeneration of the cardiomyocytes, numerous therapies have been proposed, including cellular therapy and CM cell cycle re-entry. During this dissertation study, we focused on improving myocardial infarct repair via cardiac tissue engineering and modified RNA. First of all, we generated human induced pluripotent stem cells (iPSCs) from ventricular and atrial fibroblasts by Sendai virus overexpressing four Yamanaka factors, and then characterized and compared the two iPSCs. Electrophysiology measurements and transcriptional analysis demonstrated that tissue of origin matters to generate iPSC-CMs with better features. However, the sublocation within the cardiac tissue has marginal effects on the differentiation process. Furthermore, we fabricated layer-by-layer (LBL) human cardiac muscle patch (hCMP) with iPSC-derived cardiomyocytes (CMs) and endothelial cells (ECs), and transplantation of the LBL hCMP significantly reduced infarct size, and increased wall thickness and cardiac function. To approach this issue from a different perspective, we also utilized modified mRNA (modRNA) technique to transiently and specifically express cyclin D2 (CCND2), a regulator from G1 to S phase, in cardiomyocytes (CM) to promote CM cell cycle re-entry. Initially, we demonstrated that Cardiomyocyte Specific ModRNA Translation system (CM SMRTs) could result in transient and exclusive translation in cardiomyocytes. Moreover, overexpression of CCND2 with CM SMRTs promoted proliferation in cultured postmitotic CM but not in other cell types. Furthermore, intramyocardial injections of CCND2- CM SMRTs promoted cardiomyocyte proliferation and improved measures of cardiac function, infarct size, and hypertrophy in a mouse MI model. The study of improving myocardial infarct repair via cardiac tissue engineering and modified RNA would provide novel insights in future personalized regenerative medicine treatment of heart failure patients.
Recommended Citation
Wang, Lu, "Improved Myocardial Infarct Repair Via Cardiac Tissue Engineering and Modified RNA" (2023). All ETDs from UAB. 13.
https://digitalcommons.library.uab.edu/etd-collection/13