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

Yuki Matsushita, Mizuki Nagata, Kenneth M. Kozloff, Joshua D. Welch, Koji Mizuhashi, Nicha Tokavanich, Shawn A. Hallett, Daniel C. Link, Takashi Nagasawa, Wanida Ono and Noriaki Ono ()
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Yuki Matsushita: University of Michigan School of Dentistry
Mizuki Nagata: University of Michigan School of Dentistry
Kenneth M. Kozloff: University of Michigan
Joshua D. Welch: University of Michigan
Koji Mizuhashi: University of Michigan School of Dentistry
Nicha Tokavanich: University of Michigan School of Dentistry
Shawn A. Hallett: University of Michigan School of Dentistry
Daniel C. Link: Washington University School of Medicine, Division of Oncology
Takashi Nagasawa: Osaka University School of Medicine, Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences
Wanida Ono: University of Michigan School of Dentistry
Noriaki Ono: University of Michigan School of Dentistry

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14029-w

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