Abstract
Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12). However, how these cells are activated during regeneration and facilitate osteogenesis remains largely unknown. Cell-lineage analysis using Cxcl12-creER mice reveals that quiescent Cxcl12-creER+ perisinusoidal BMSCs differentiate into cortical bone osteoblasts solely during regeneration. A combined single cell RNA-seq analysis demonstrate that these cells convert their identity into a skeletal stem cell-like state in response to injury, associated with upregulation of osteoblast-signature genes and activation of canonical Wnt signaling components along the single-cell trajectory. β-catenin deficiency in these cells indeed causes insufficiency in cortical bone regeneration. Therefore, quiescent Cxcl12-creER+ BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration.
Highlights
Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12)
Cxcl12CE-tdTomato+ cells accounted for only a small portion of Cxcl12-GFPhigh and Leptin receptor (LepR)+ stromal cells in the metaphyseal marrow space or in the endosteal space, suggesting that Cxcl12CE-tdTomato+ cells represent a specific subset of LepR+CXCL12+ stromal cells that are distant from the bone surface
Here, we identified that quiescent Cxcl12-creER+ BMSCs can convert their identity into a precursor cell state similar to skeletal stem cells (SSCs) during injury responses in a manner mediated by canonical Wnt signaling, and substantially contribute to skeletal regeneration
Summary
Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12). How these cells are activated during regeneration and facilitate osteogenesis remains largely unknown. Quiescent Cxcl12-creER+ BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration. Our data reveal that quiescent Cxcl12-creER+ BMSCs transform into precursor cells characterized by a SSC-like state in a manner mediated by canonical Wnt signaling during injury responses, and functionally contribute to skeletal regeneration
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