A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration

Author:

Matsushita YukiORCID,Nagata Mizuki,Kozloff Kenneth M.ORCID,Welch Joshua D.,Mizuhashi Koji,Tokavanich Nicha,Hallett Shawn A.,Link Daniel C.,Nagasawa Takashi,Ono Wanida,Ono NoriakiORCID

Abstract

AbstractBone 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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