Dataset Information

VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche.

ABSTRACT: Haematopoietic stem and progenitor cells (HSPCs) give rise to all blood lineages that support the entire lifespan of vertebrates1. After HSPCs emerge from endothelial cells within the developing dorsal aorta, homing allows the nascent cells to anchor in their niches for further expansion and differentiation2-5. Unique niche microenvironments, composed of various blood vessels as units of microcirculation and other niche components such as stromal cells, regulate this process6-9. However, the detailed architecture of the microenvironment and the mechanism for the regulation of HSPC homing remain unclear. Here, using advanced live imaging and a cell-labelling system, we perform high-resolution analyses of the HSPC homing in caudal haematopoietic tissue of zebrafish (equivalent to the fetal liver in mammals), and reveal the role of the vascular architecture in the regulation of HSPC retention. We identify a VCAM-1+ macrophage-like niche cell population that patrols the inner surface of the venous plexus, interacts with HSPCs in an ITGA4-dependent manner, and directs HSPC retention. These cells, named 'usher cells', together with caudal venous capillaries and plexus, define retention hotspots within the homing microenvironment. Thus, the study provides insights into the mechanism of HSPC homing and reveals the essential role of a VCAM-1+ macrophage population with patrolling behaviour in HSPC retention.

SUBMITTER: Li D

PROVIDER: S-EPMC6492262 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche.

Li Dantong D Xue Wenzhi W Li Mei M Dong Mei M Wang Jianwei J Wang Xianda X Li Xiyue X Chen Kai K Zhang Wenjuan W Wu Shuang S Zhang Yingqi Y Gao Lei L Chen Yujie Y Chen Jianfeng J Zhou Bo O BO Zhou Yi Y Yao Xuebiao X Li Lin L Wu Dianqing D Pan Weijun W

Nature 20181119 7734

Haematopoietic stem and progenitor cells (HSPCs) give rise to all blood lineages that support the entire lifespan of vertebrates1. After HSPCs emerge from endothelial cells within the developing dorsal aorta, homing allows the nascent cells to anchor in their niches for further expansion and differentiation2-5. Unique niche microenvironments, composed of various blood vessels as units of microcirculation and other niche components such as stromal cells, regulate this proces ...[more]

PMID: 30455424

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Project description: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-Mφs) are responsible for repairing the HSC niche upon irradiation injury. Methods: We examined the survival and activation of BM-Mφs in C57BL/6 mice upon total body irradiation. After BM-Mφ 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-Mφs 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-Mφs aggravated the post-irradiation injury, delaying the recovery of sinusoidal endothelial cells and HSCs. A fraction of the BM-Mφ population persisted after irradiation, with residual BM-Mφ exhibiting an activated M2-like phenotype. The expression of VEGF-A, which is essential for sinusoidal regeneration, was upregulated in BM-Mφs post-irradiation, especially CD206+ BM-Mφs. The expression of mechanosensory ion channel Piezo1, a response to mechanical environmental changes induced by bone marrow ablation, was upregulated in BM-Mφs, especially CD206+ BM-Mφs. Piezo1 upregulation was mediated by the effects of irradiation, the activation of Piezo1 itself, and the M2-like polarization induced by the phagocytosis of apoptotic cells. Piezo1 activation was associated with increased expression of VEGF-A and increased accumulation of NFATC1, NFATC2, and HIF-1α. The Piezo1-mediated upregulation in VEGF-A was suppressed by inhibiting the calcineurin/NFAT/HIF-1α signaling pathway. Conclusion: These findings reveal that BM-Mφs play a critical role in promoting vascular niche regeneration by sensing and responding to structural changes after irradiation injury, offering a potential target for therapeutic efforts to enhance hematopoietic reconstruction.

Dataset Information

VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche.

Publications

VCAM-1<sup>+</sup> macrophages guide the homing of HSPCs to a vascular niche.

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