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Received: 20 April 2020
Accepted: 27 January 2021
Published online: 24 February 2021
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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 expression of an osteogenic growth factor, osteolectin13,14, 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 Sc/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 P1EZO1 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.
Haematopoietic stem cells (HSCs) and restricted progenitors are maintained in specialized microenvironments, or niches, in haematopoietic tissues in which stromal cells synthesize the growth factors that they require15. LEPR+ cells and endothelial cells are the major sources of growth factors for HSC maintenance in adult mouse bone marrow, including SCF1'3'6, C-X-C motif chemokine 12 (CXCL12)2,16 and pleiotrophin5. LEPR+ cells are also a critical source of SCF and 1L-7 for early restricted progenitors, including common lymphoid progenitors (CLPs)4,6. The bone marrow environment changes with age17, contributing to the depletion of lymphoid18 and osteogenic19 progenitors. However, beyond changes in the abundance of some types of blood vessel1719, little is known about how the environment changes or what causes the depletion of lymphoid and osteogenic progenitors during ageing.
HSCs20-22 and erythroid progenitors6 localize adjacent to peri-sinusoidal LEPR+ cells throughout the bone marrow. Single-cell RNA-sequencing (RNA-seq) studies have shown that peri-sinusoidal...