Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals.

Hematopoietic stem cells (HSCs) rely on specialized niche cells for their maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. In this study, we identified a subset of protein C receptor-positive (Procr+) endothelial cells (ECs) with progenitor-like properties in bone marrow (BM) which is critical for vascular homeostasis and regeneration after injury. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr also serves as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds heat shock protein A8 (HSPA8) to promote Foxc2 nuclear translocation, thereby upregulating delta-like ligand 4 (Dll4) transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC cross talk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSC notch signaling, coordinating their adipogenic and osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ endothelial progenitor cells (EPCs) in human BM. Human PROCR+ ECs were found to similarly enhance DLL4/Notch3 signaling in MSCs, consequently preserving HSC function, confirming their therapeutic relevance. Our work highlights that Procr+ EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.