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Nature. 2018 Nov;563(7732):514-521. doi: 10.1038/s41586-018-0650-9. Epub 2018 Oct 24.

Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration.

Author information

1
Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
3
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
4
Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, CA, USA.
5
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
6
Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
7
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. howchang@stanford.edu.
8
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. howchang@stanford.edu.
9
Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA. longaker@stanford.edu.
10
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. longaker@stanford.edu.

Abstract

During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which is a process that is used in humans to correct an undersized lower jaw that involves surgically separating the jaw bone, which elicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.

PMID:
30356216
DOI:
10.1038/s41586-018-0650-9

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