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.
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All data to support the conclusions in this manuscript can be found in the figures. All source data for graphs are available in the online version of the paper. Any other data can be requested from the corresponding authors. All ATAC-seq and RNA-seq data can be accessed from the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with accession number GSE104473.
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We thank J. Wysocka for her review of the manuscript and helpful suggestions. We thank the Stanford Functional Genomics Facility, Stanford Cell Sciences Imaging Facility, Lorry Lokey Imaging Facility, and Stanford Shared FACS Facility Cores. We thank D. J. Hunter and D. Atashroo for their respective contributions to the design of the distraction device. This work was supported by the National Institutes of Health (NIH) grants R01DE026730 (to M.T.L. and R.C.R.), U24DE026914 (to M.T.L.) and K08DE024269 (to D.C.W.); the Child Health Research Institute (CHRI) at Stanford University (D.C.W.); The Hagey Laboratory for Pediatric Regenerative Medicine (M.T.L.); the Steinhart/Reed Award (M.T.L); the Gunn–Oliver Fund (M.T.L.); and NIH grant P50-HG007735 and the Scleroderma Research Foundation (H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute.
Nature thanks C. Tabin, L. Gerstenfeld and P. Scacheri for their contribution to the peer review of this work.