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

ABSTRACT: 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.