Abstract
Bone marrow (BM) is the primary site of postnatal hematopoiesis, yet how it is established during embryogenesis remains poorly understood. BM formation is initiated by the invasion of vascular and mesenchymal cells into a preformed cartilage template, generating the primary ossification center (POC). Here, we identify CD55+CD90+ mesenchymal cells as early regulators of osteoclastogenesis within the POC. These cells share a matrix-degrading transcriptional program with FABP5+ septoclasts that localize to the chondro-osseous interface of developing bone. Fate-mapping analyses reveal that CD55+CD90+ cells transiently give rise to septoclasts during perinatal development, whereas osteoclast-supporting activity is subsequently assumed by LepR+ bone marrow stromal cells (BMSCs). During fracture repair, FABP5+ septoclasts and LepR+ BMSCs are redeployed within the callus, indicating reactivation of a developmental osteogenic program. Together, our findings uncover a conserved mechanism that links skeletal remodeling to the establishment of the BM microenvironment required for hematopoiesis.
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Data availability
Sequencing data that support the findings of this study have been deposited in the Gene Expression Omnibus (GEO): GSE228319 (RNA-seq and scRNA-seq data) [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE228319], GSE315785 (scRNA-seq data) [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE315785], GSE154247 (scRNA-seq data) [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154247]. All other data supporting the findings of this study are available within the paper and its Supplementary Information files. Source data are provided with this paper.
Code availability
Code used for the analyses is available at Zenodo [https://doi.org/10.5281/zenodo.19034907].
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Acknowledgments
We thank members of the Sawa lab: D. Nonaka, M. Watanabe, K. Tanaka, M. Kobayashi, T. Furukawa and M. Ezawa for assistance with experiments; A. Yano for contribution to administrative work related to this project. We thank H. Murota, M. Tanaka and K. Kageyama for embryonic engineering of mice. We also thank members of the Research Promotion Unit of the Medical Institute of Bioregulation, Kyushu University, for supporting mouse experiments. We thank H. Ishikawa, K. Ichikawa and T. Akinaga for help with scRNA-seq experiments. We are grateful to M. Shinohara and T. Saito for insightful comments on this work. This work was funded by KAKENHI (17K15588, 21K08417, JP22J40144, and 25K22772), the Naito Foundation, and the Tokyo Biochemical Research Foundation to E.S. S.S was supported by JST Moonshot R&D (JPMJMS2025), Japan Agency for Medical Research and Development (AMED) PRIME (JP19gm6310005), Naito foundation and Takeda Science Foundation, KAKENHI (JP23K27428), the Joint Research of the Exploratory Research Center on Life and Living Systems (ExCELLS) (program No. 20-316) in the National Institutes of Natural Sciences. This work utilized research equipment shared in the MEXT Project for promoting public utilization of advanced research infrastructure (Program for supporting introduction of the new sharing system), grant Number JPMXS0422300222. This work was supported in part by the MEXT Cooperative Research Project Program, Medical Research Center Initiative for High Depth Omics, and the MEXT Promotion of Development of a Joint Usage/Research System Project: Coalition of Universities for Research Excellence Program (CURE) grant number JPMXP1323015486 for MIB, Kyushu University. The infrastructure of the Omics Science Center Secure Information Analysis System, Medical Institute of Bioregulation at Kyushu University, provides a part of the computational resource.
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E.S. and S.S. designed the project. E.S., S.S., N.N., N.K., M.K.S, Y.K., and Y.M. (Yuka Morioka) performed experiments. E.S., S.S., K.S., and C.K. analyzed the data and prepared figures. K.N., S.S., E.S., M.K.S, Y.K., and T.O. generated novel mouse lines. Y.Y., M.G., M.I., H.A., L.P., and Y.M. (Yuki Matsushita) provided critical mouse lines. M.N. provided experimental material. M.S. and Y.G. provided critical experimental platforms and inputs. E.S. and S.S. wrote the paper. L.P. proofread the manuscript.
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Sumiya, E., Saeki, K., Nakano, K. et al. Medullary cavity expansion is mediated by distinct cell populations during fetal bone development. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71952-5
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DOI: https://doi.org/10.1038/s41467-026-71952-5
