Engineering nanowired cardiac organoids for cardiac regeneration

Project Summary: Cardiovascular diseases (CVDs) such as myocardial ischemia/reperfusion (I/R) injury lead to extensive cardiomyocyte death and subsequent reduced cardiac function. Due to the human adult heart’s limited regenerative capacity, there is a significant need for exogenous cardiac function restoration post-I/R. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a favorable cell source to restore myocardial function. While promising, the therapeutic potential of hPSC-CM transplantation is hampered by low cell survival and inadequate integration with host myocardium. Thus, our lab has developed nanowired human cardiac organoids composed hPSC-CM, primary human adult cardiac fibroblasts, endothelial cells, stromal cells, and electrically conductive silicon nanowires (e-SiNWs). Our in vivo data shows that organoids are capable of robustly engrafting and providing functional recovery (69% Fractional Shortening recovery) in I/R injured rat hearts, while using 10% of the cell dose (1E6, 1x106 cells/rat) that other hPSC-CM transplantation studies used (1E7, 1x107 cells/rat). Additionally, to alleviate major histocompatibility class (MHC) mismatching to provide a translational platform for hPSC-CM delivery, our lab developed isogenic cardiac organoids, composed of hPSC-CMs, -cardiac fibroblasts (hPSC-cFBs), and -endothelial cells (hPSC-ECs) from a single hiPSC cell line. The goals of this proposal are to 1) investigate the impact of e-SiNW geometry on isogenic organoid function, and 2) demonstrate the therapeutic efficacy of optimized nanowired isogenic cardiac organoids in a rat I/R injury model. The central hypothesis of this proposal is that engineered nanowire surface geometry will enhance interactions between host myocardium and transplanted hPSC-CMs within isogenic cardiac organoids, resulting in efficient engraftment and significant functional recovery. The innovation of this proposal is engineering e-SiNW surface roughness to optimize the efficiency of myocardial engraftment, and thus the functional recovery of I/R-injured hearts. My long-term goal is to leverage translational engineering and informatics to develop a clinically viable cardiac cell therapy heart repair. Accordingly, we will pursue the following two aims: 1) investigate the effects of e-SiNW geometry on isogenic cardiac organoid function, and 2) determine the therapeutic efficacy of optimized nanowired isogenic cardiac organoids to treat I/R-injured rat hearts and investigate e-SiNW graft-host interactions using spatial transcriptomics. The proposed research would provide a translational platform for cardiac repair with efficient engraftment.