Transplantation of human ventricular progenitors significantly reduced infarct volume to 2.5% compared to 7.0% with vehicle and attenuated the decline of cardiac function in a porcine model of chronic ischemic injury.
Do human cardiac progenitors promote heart regeneration and prevent heart failure progression in injured heart models?
Human cardiac progenitors utilize inherent developmental programmes, including CXCL12/CXCR4 chemoattraction and SLIT2/ROBO1 fibroblast repulsion, to counteract injury and promote heart regeneration in preclinical models.
Absolute Event Rate: 2.5% vs 7%
Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.
Poch et al. (2022) studied Myocardial infarction (n=17). Human ventricular progenitors (HVPs) vs. Vehicle was evaluated on Infarct volume (% of LV). Transplantation of human ventricular progenitors significantly reduced infarct volume to 2.5% compared to 7.0% with vehicle and attenuated the decline of cardiac function in a porcine model of chronic ischemic injury.