Spatiotemporal Transcriptomes of Pig Hearts Reveal Midkine-Mediated Vascularization in a Chronic Myocardial Infarcted Model

ABSTRACT Ischemic heart disease is the most prevalent cause of death globally. Regenerative cardiology using stem cell-based therapy is a potential approach to replace infarcted myocardial (MI) heart tissue. We used cardiovascular progenitors (CVPs) derived from human pluripotent embryonic stem cells differentiated to cardiomyocyte progenitors on a laminin 521+221 matrix and transplanted them into acute and chronic MI pig hearts (AMI and CMI). We performed time-series spatial transcriptomics to characterize these human cells at AMI 1- and 2- and at CMI 1-, 4- and 12 weeks post-transplantation. Both models showed high transcriptional reproducibility in the replicates. Furthermore, the human grafts engrafted well, matured, and expressed metabolic, ribosomal, T-tubule, and channel-related genes in the human graft over time. Cell-cell communication analysis revealed Midkine (MDK) signaling as a key pathway that may lead to increased angiogenesis of collaterals in the human graft.