Piezo1-mediated mechanosensation in bone marrow macrophages promotes vascular niche regeneration after irradiation injury

作者：Xiaomei Zhang, Lijia Hou, Fengjie Li, Weiwei Zhang, Chun Wu, Lixin Xiang, Jiuxuan Li, Luping Zhou, Xiaojie Wang, Yang Xiang, Yanni Xiao, Shengwen Calvin Li, Li Chen, Qian Ran, Zhongjun Li · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.64963 · 被引用次数：60 · 研究领域：Erythrocyte Function and Pathophysiology、Spaceflight effects on biology、Mesenchymal stem cell research

Background: Irradiation disrupts the vascular niche where hematopoietic stem cells (HSCs) reside, causing delayed hematopoietic reconstruction. The subsequent recovery of sinusoidal vessels is key to vascular niche regeneration and a prerequisite for hematopoietic reconstruction. We hypothesize that resident bone marrow macrophages (BM-Ms) are responsible for repairing the HSC niche upon irradiation injury. Methods: We examined the survival and activation of BM-Ms in C57BL/6 mice upon total body irradiation. After BM-M depletion via injected clodronate-containing liposomes and irradiation injury, hematopoietic reconstruction and sinusoidal vascular regeneration were assessed with immunofluorescence and flow cytometry. Then enzyme-linked immunosorbent assay (ELISA) and flow cytometry were performed to analyze the contribution of VEGF-A released by BM-Ms to the vascular restructuring of the HSC niche. VEGF-A-mediated signal transduction was assessed with transcriptome sequencing, flow cytometry, and pharmacology (agonists and antagonists) to determine the molecular mechanisms of Piezo1-mediated responses to structural changes in the HSC niche. Results: The depletion of BM-Ms aggravated the post-irradiation injury, delaying the recovery of sinusoidal endothelial cells and HSCs. A fraction of the BM-M population persisted after irradiation, with residual BM-M exhibiting an activated M2-like phenotype. The expression of VEGF-A, which is essential for sinusoidal regeneration, was u...