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A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis.

ABSTRACT: Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors^1-6. LEPR⁺ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors^7-12, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin^13,14, distinguishes peri-arteriolar LEPR⁺ cells poised to undergo osteogenesis from peri-sinusoidal LEPR⁺ cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPR⁺osteolectin⁺ cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin⁺ cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin⁺ cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin⁺ cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin⁺ cells depleted osteolectin⁺ cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing.

SUBMITTER: Shen B

PROVIDER: S-EPMC7979521 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis.

Shen Bo B Tasdogan Alpaslan A Ubellacker Jessalyn M JM Zhang Jingzhu J Nosyreva Elena D ED Du Liming L Murphy Malea M MM Hu Shuiqing S Yi Yating Y Kara Nergis N Liu Xin X Guela Shay S Jia Yuemeng Y Ramesh Vijayashree V Embree Claire C Mitchell Evann C EC Zhao Yunduo C YC Ju Lining A LA Hu Zhao Z Crane Genevieve M GM Zhao Zhiyu Z Syeda Ruhma R Morrison Sean J SJ

Nature 20210224 7850

Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors1-6. LEPR+ cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors7-12, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expressi ...[more]

PMID: 33627868

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Project description:BackgroundDuring acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs).MethodsBM vasculature was evaluated in FLT3-ITD+ AML models (MllPTD/WT/Flt3ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and MllPTD/WT/Flt3ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to MllPTD/WT/Flt3ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten.ResultsIn the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection.ConclusionsTreatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation.

Dataset Information

A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis.

Publications

A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis.

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