Spatiotemporal transcriptomics of human cardiovascular progenitors in pig hearts identifies Midkine as a positive regulator of neovascularization.

Stem-cell-based cardiac repair holds promise for the infarcted myocardium, yet the in vivo molecular behavior of transplanted cells is poorly understood. Using time series spatial transcriptomics, we profiled human pluripotent stem-cell-derived cardiovascular progenitors engrafted into a pig model. We show that the engrafted cardiovascular progenitors progressively upregulated genes associated with cardiac maturation, oxidative metabolism, calcium handling and fibrosis resolution. Cell-cell communication analysis identified Midkine (MDK), secreted by the human xenograft, as a key regulator of host neovascularization. We validated this using immunohistochemistry, lentiviral MDK overexpression and functional assays that demonstrated enhanced endothelial cell migration and increased CD31+ vascular density in vivo. A publicly available interactive Shiny atlas of spatial and temporal transcriptomic data from myocardial infarction pig hearts with human xenografts is provided. These findings advance mechanistic understanding of stem-cell-mediated cardiac repair and identify MDK as a tractable target for therapeutic angiogenesis in ischemic heart disease.