Multilineage contribution of CD34 cells in cardiac remodeling after ischemia/reperfusion injury.

The ambiguous results of multiple CD34 cell-based therapeutic trials for patients with heart disease have halted the large-scale application of stem/progenitor cell treatment. This study aimed to delineate the biological functions of heterogenous CD34 cell populations and investigate the net effect of CD34 cell intervention on cardiac remodeling. We confirmed, by combining single-cell RNA sequencing on human and mouse ischemic hearts and an inducible Cd34 lineage-tracing mouse model, that Cd34 cells mainly contributed to the commitment of mesenchymal cells, endothelial cells (ECs), and monocytes/macrophages during heart remodeling with distinct pathological functions. The Cd34-lineage-activated mesenchymal cells were responsible for cardiac fibrosis, while CD34Sca-1 was an active precursor and intercellular player that facilitated Cd34-lineage angiogenic EC-induced postinjury vessel development. We found through bone marrow transplantation that bone marrow-derived CD34 cells only accounted for inflammatory response. We confirmed using a Cd34-CreER; R26-DTA mouse model that the depletion of Cd34 cells could alleviate the severity of ventricular fibrosis after ischemia/reperfusion (I/R) injury with improved cardiac function. This study provided a transcriptional and cellular landscape of CD34 cells in normal and ischemic hearts and illustrated that the heterogeneous population of Cd34 cell-derived cells served as crucial contributors to cardiac remodeling and function after the I/R injury, with their capacity to generate diverse cellular lineages.