Regional diversity of cranial skeletal stem cells governs bone morphogenetic protein-2 mediated bone regeneration.

Overview

1. Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine,Stanford, CA USA
2. Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan,Ann Arbor, MI USA
3. Molecular and Cellular Biology, University of Illinois at Urbana-Champaign,Urbana, IL USA
4. Department of Neurobiology, Physiology and Behavior, University of California at Davis,Davis, CA USA
5. Department of Radiation Oncology and Medical Physics, School of Medicine, Stanford University,Palo Alto, CA USA

Abstract

Skeletal stem cells (SSCs), originally identified in 2015, are increasingly understood to exhibit significant heterogeneity throughout the body. Cranial SSCs provide a unique model to investigate this diversity because cranial bones arise from both neural crest and mesoderm, unlike mesoderm-derived long bones. Here, we show that cranial SSCs possess anatomically defined transcriptomic and functional heterogeneity. Through comprehensive in vitro and in vivo functional assays combined with targeted gene expression analyses by qPCR, we demonstrate that cranial SSCs exhibit region-specific transcriptional signatures and lineage biases that influence their osteogenic and chondrogenic capacities. Temporal analysis further reveals that SSCs progressively outnumber progenitor cells with age, suggesting that the SSC-to-progenitor ratio may serve as an indicator of skeletal developmental and regenerative potential. Finally, we demonstrate that SSC heterogeneity critically influences bone regeneration in response to Bone Morphogenetic Protein-2 in vitro and in vivo, supporting the need for region-specific optimization of BMP-2-based regenerative therapies.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• bioproject:PRJNA1499731, at NCBI BioProject; found in “Data availability”
• figshare:31968258, at figshare; found in DataCite

Data availability

Raw RNA-sequencing data are available from the NCBI Sequence Read Archive (SRA) under accession PRJNA1499731 (https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1499731). Processed gene expression matrices are available at Figshare (https://doi.org/10.6084/m9.figshare.31968258).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 13 authors, 3 keywords, 10 MeSH terms, 4 funders, 40 references.

Cite

This paper

Takematsu, E., Lachmansingh, R. N., Johnston, K., Hou, S., Bailey, E., Wang, Y., Zhao, L., Hoover, M., Nguyen, H. T. M., Parmar, K. M., Talbott, H., Longaker, M. T., & Chan, C. K. F. (2026). Regional diversity of cranial skeletal stem cells governs bone morphogenetic protein-2 mediated bone regeneration. Nature communications, 17(1), 9479. https://doi.org/10.1038/s41467-026-76286-w

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