Bioengineered cardiac patches with decellularized placental scaffold and human induced pluripotent stem cells for myocardial repair

Abstract

Myocardial infarction (MI) is the leading cause of death worldwide. There are limited options clinically available for treatment of MI. The main barrier in developing curative therapeutics is largely from the limited regenerative capacity of adult cardiomyocytes (CMs). Recent advances in human tissue engineering and stem cell technology have provided some promising opportunities in developing novel therapeutics for MI. One of such approaches is the direct cellular transplantation of CMs differentiated from pluripotent stem cells (PSCs) to replace the damaged heart muscles. However, the therapeutic efficiency of this approach is limited due to the poor survival of transplanted CMs in the hostile microenvironment of the ischemic host heart tissue. In this study, we took a design of bioengineered cardiac patch (BCP) as a new strategy for myocardial repair. We engineered a novel BCP by using the extracellular matrix (ECM) from the decellularized placenta as a natural scaffold for CMs derived from human induced PSC (hiPSC). The BCPs were created by seeding human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) onto the decellularized placenta of rat. Extensive biochemical and electrophysiological analyses were performed to obtain the functional properties of these BCPs. The BCPs were then transplanted to the MI heart of rat model induced by permanent left descending coronary artery ligation. Cytokine profiling demonstrated that the decellularized placenta contains multiple growths and angiogenic factors that are crucial for the survival of the hiPSC-CM. Optical mapping analysis showed that the BCPs exhibited organized mechanical contraction and synchronized electrical propagation. The transplanted BCPs significantly improved left ventricular function of the infarcted hearts as determined by measuring maximal positive derivatives of left ventricular pressure, end-systolic pressure-volume relationship, left ventricular ejection fraction, and fractional shortening compared with the MI, MI+DP and MI+CM groups for four weeks follow-up. Histological examination revealed that engraftment of the BCP at the infarct zone decreased infarct size and increased cell retention and neovascularization compared with the MI, MI+DP and MI+CM groups. This thesis highlights a critical design and creation of the functional BCPs based on decellularized placenta and hiPSC-CMs. Transplantation of the BCPs successfully restored the damaged heart function. Thus, the work presented in this thesis provides a novel and promising therapy for treatment of MI.