Bone Marrow Endosteal Stem Cells Dictate Active Osteogenesis and Aggressive Tumorigenesis

Authors

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
Noriaki Ono

Publication Date

4-25-2023

Journal

Nature Communications

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.

Keywords

Adult, Humans, Aged, Osteogenesis, Bone Marrow, Bone and Bones, Osteoblasts, Stem Cells, Carcinogenesis, Bone Marrow Cells, Cell Differentiation, Bone development, Mesenchymal stem cells, Mesenchymal stem cells

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