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 CD34⁺Sca-1^high 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^T2; 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.