Basic and Translational Research
Skeletal Regeneration and Repair
Ransom RC, Foster DS, Salhotra A, Jones RE, Marshall CD, Leavitt T, Murphy MP, Moore AL, Blackshear CP, Brett EA, Wan DC, Longaker MT. Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes. Nat Commun. 2018 Jul 30;9(1):2971. doi: 10.1038/s41467-018-05436-6.
Ransom RC, Carter AC, Salhotra A, Leavitt T, Marecic O, Murphy MP, Lopez ML, Wei Y, Marshall CD, Shen EZ, Jones RE, Sharir A, Klein OD, Chan CKF, Wan DC, Chang HY, Longaker MT. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature. 2018 Oct 24. doi: 10.1038/s41586-018-0650-9.
Distraction osteogenesis (DO) is a powerful method of endogenous bone tissue engineering that has been applied to the craniofacial skeleton with great success. We have previously established a model of mandibular distraction osteogenesis in mice and current efforts are aimed to study the underlying biology governing the DO process. A more thorough understanding of the molecular and cellular responses during this process may allow for new potential strategies of bone formation that could be applied to several other clinical scenarios involving bone deficiency.
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. We have developed 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 used this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Our methodology permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. Using chromatin and transcriptional profiling, we have shown 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. These findings were recently published as an article in Nature.