Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis

Yuki Matsushita, Jialin Liu, Angel Ka Yan Chu, Chiaki Tsutsumi-Arai, Mizuki Nagata, Yuki Arai, Wanida Ono, Kouhei Yamamoto, Thomas L. Saunders, Joshua D. Welch () and Noriaki Ono ()
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Yuki Matsushita: University of Texas Health Science Center at Houston School of Dentistry
Jialin Liu: University of Michigan
Angel Ka Yan Chu: University of Michigan
Chiaki Tsutsumi-Arai: University of Texas Health Science Center at Houston School of Dentistry
Mizuki Nagata: University of Texas Health Science Center at Houston School of Dentistry
Yuki Arai: University of Texas Health Science Center at Houston School of Dentistry
Wanida Ono: University of Texas Health Science Center at Houston School of Dentistry
Kouhei Yamamoto: Tokyo Medical and Dental University
Thomas L. Saunders: University of Michigan Medical School
Joshua D. Welch: University of Michigan
Noriaki Ono: University of Texas Health Science Center at Houston School of Dentistry

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to a stem cell fraction in young stages, which is later replaced by Lepr-cre-marked stromal cells in adult stages. Further, Fgfr3+ endosteal stromal cells give rise to aggressive osteosarcoma-like lesions upon loss of p53 tumor suppressor through unregulated self-renewal and aberrant osteogenic fates. Therefore, Fgfr3+ endosteal SSCs are abundant in young bone marrow and provide a robust source of osteoblasts, contributing to both normal and aberrant osteogenesis.

Date: 2023
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DOI: 10.1038/s41467-023-38034-2

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