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 maintenance, yet how these regulators functionally integrate to preserve hematopoiesis remains unknown. Here, we identified a subset of Procr+ endothelial cells (ECs) with progenitor-like properties in bone marrow (BM), which is critical for vascular homeostasis and injury regeneration. Endothelial-specific ablation of Procr severely compromises BM vascular integrity and function. Beyond serving as a stem cell marker, Procr serves dual biological functions as a functional signaling receptor in multicellular communication. Mechanistically, Procr binds HSPA8 to promote Foxc2 nuclear translocation, upregulating Dll4 transcription to sustain Dll4/Notch3 activation in mesenchymal stem cells (MSCs), revealing a Procr/HSPA8/Foxc2/Dll4 axis essential for EC and MSC crosstalk. Through the HSPA8/Foxc2/Dll4/Notch3 axis, Procr+ ECs instruct MSCs Notch signaling, coordinating their adipogenic-osteogenic differentiation to maintain HSC self-renewal and myeloid output. Building on this mechanism, we demonstrated conserved functionality of Procr+ 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 Procr⁺ EPCs sustain vascular integrity and govern MSC-dependent HSC maintenance, offering targeted clinical strategies for niche regeneration.