Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration

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.

Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate

“…We used skeletal progenitor markers to fraction the cells into subpopulations: multipotent progenitor cells, osteo‐ and chondro‐progenitor cells, and stromal progenitor cells, according to previous reports (Supplemental Fig. S5 D ) . ZsG‐positive cells were sorted into all three populations (Supplemental Fig.…”

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

“…In contrast, the transcriptome of NCSCs presents some degree of similarity with the gene expression signatures obtained from bulk RNA-seq of drug-exposed melanoma cultures enriched for induced drug-tolerant cells (IDTCs) (Menon et al 2015) and slow cycling NGFR-high cells (Fallahi-Sichani et al 2017). Intriguingly, the drug-induced NCSC state is reminiscent of a developmentally plastic state induced during jaw regeneration (Ransom et al 2018). This parallel indicates that tumor lesions exploit existing mechanisms at play in normal damaged tissues-such as induction of a stem cell-like state-to resist and recover from therapeutic insults.…”

Biodegradable Magnesium‐Based Implants in Orthopedics—A General Review and Perspectives

“…This technique is named distraction osteogenesis (DO). Even though DO has been applied to effectively treat bone defects for short bones such as the metacarpal and mandible,120 when treating lesions occurring in long bones such as the femur and tibia,121,122 a relatively long period is required to allow new bone tissue fully mineralise and consolidate, with evidence demonstrating that patients need to bear the external fixators for more than 20 months. Concomitant complications such as nail infection, rupture, or loosening of the fixators have largely limited its application.…”