RESUMO
Satellite cells (SCs) reside in a dormant state during tissue homeostasis. The specific paracrine agents and niche cells that maintain SC quiescence remain unknown. We find that Wnt4 produced by the muscle fiber maintains SC quiescence through RhoA. Using cell-specific inducible genetics, we find that a Wnt4-Rho signaling axis constrains SC numbers and activation during tissue homeostasis in adult mice. Wnt4 activates Rho in quiescent SCs to maintain mechanical strain, restrict movement in the niche, and repress YAP. The induction of YAP upon disruption of RhoA is essential for SC activation under homeostasis. In the context of injury, the loss of Wnt4 from the niche accelerates SC activation and muscle repair, whereas overexpression of Wnt4 transitions SCs into a deeper state of quiescence and delays muscle repair. In conclusion, the SC pool undergoes dynamic transitions during early activation with changes in mechano-properties and cytoskeleton signaling preceding cell-cycle entry.
Assuntos
Proliferação de Células/genética , Fibras Musculares Esqueléticas/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Proteína Wnt4/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/fisiologia , Citoesqueleto/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Força Atômica , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , Regeneração/genética , Células Satélites de Músculo Esquelético/citologia , Transdução de Sinais/genética , Nicho de Células-Tronco/genética , Proteína Wnt4/genética , Proteínas de Sinalização YAPRESUMO
The oral mucosa is one of the most rapidly dividing tissues in the body and serves as a barrier to physical and chemical insults from mastication, food, and microorganisms. Breakdown of this barrier can lead to significant morbidity and potentially life-threatening infections for patients. Determining the identity and organization of oral epithelial progenitor cells (OEPCs) is therefore paramount to understanding their roles in homeostasis and disease. Using lineage tracing and label retention experiments, we show that rapidly dividing OEPCs are located broadly within the basal layer of the mucosa throughout the oral cavity. Quantitative clonal analysis demonstrated that OEPCs undergo population-asymmetrical divisions following neutral drift dynamics and that they respond to chemotherapy-induced damage by altering daughter cell fates. Finally, using single-cell RNA-seq, we establish the basal layer population structure and propose a model that defines the organization of cells within the basal layer.