Procr+ endothelial progenitor cells govern hematopoiesis through fine-tuning mesenchymal stem cell niche signals
Abstract
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.
Article Details
Authors (22)
Chang Xu
Department of Chemistry, Anhui University, 111 Jiulong Road, Hefei 230601, P. R. China
Xue Lv
Shangda Yang
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yanling Lv
Yawei Zheng
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yu-Xiang Wang
Yan Hui
Guohuan Sun
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Xiangnan Zhao
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Lan-yue Ma
4Center for Cell Lineage and Development, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
Honglin Duan
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Linmin Zhang
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Shuangshuang Pu
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Lu Sun
Xialin Li
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Yicheng He
Wenjia Fang
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Meng Yang
Toshio Suda
Qi Chen
Tao Cheng
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Jiangsu Key Laboratory of Advanced Negative Carbon Technologies
Hui Cheng