RESUMO
Stem/progenitor cells differentiate into different cell lineages during organ development and morphogenesis. Signaling pathway networks and mechanotransduction are important factors to guide the lineage commitment of stem/progenitor cells during craniofacial tissue morphogenesis. Here, we used tooth root development as a model to explore the roles of FGF signaling and mechanotransduction as well as their interaction in regulating the progenitor cell fate decision. We show that Fgfr1 is expressed in the mesenchymal progenitor cells and their progeny during tooth root development. Loss of Fgfr1 in Gli1+ progenitors leads to hyperproliferation and differentiation, which causes narrowed periodontal ligament (PDL) space with abnormal cementum/bone formation leading to ankylosis. We further show that aberrant activation of WNT signaling and mechanosensitive channel Piezo2 occurs after loss of FGF signaling in Gli1-CreER;Fgfr1fl/fl mice. Overexpression of Piezo2 leads to increased osteoblastic differentiation and decreased Piezo2 leads to downregulation of WNT signaling. Mechanistically, an FGF/PIEZO2/WNT signaling cascade plays a crucial role in modulating the fate of progenitors during root morphogenesis. Downregulation of WNT signaling rescues tooth ankylosis in Fgfr1 mutant mice. Collectively, our findings uncover the mechanism by which FGF signaling regulates the fate decisions of stem/progenitor cells, and the interactions among signaling pathways and mechanotransduction during tooth root development, providing insights for future tooth root regeneration.
Assuntos
Fatores de Crescimento de Fibroblastos , Mecanotransdução Celular , Raiz Dentária , Via de Sinalização Wnt , Animais , Via de Sinalização Wnt/fisiologia , Raiz Dentária/crescimento & desenvolvimento , Raiz Dentária/metabolismo , Raiz Dentária/citologia , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Camundongos , Diferenciação Celular , Células-Tronco/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Canais IônicosRESUMO
Mesenchymal stem cells (MSCs) reside in niches to maintain tissue homeostasis and contribute to repair and regeneration. Although the physiological functions of blood and lymphatic vasculature are well studied, their regulation of MSCs as niche components remains largely unknown. Using adult mouse incisors as a model, we uncover the role of Trp53 in regulating vascular composition through THBS2 to maintain mesenchymal tissue homeostasis. Loss of Trp53 in GLI1+ progeny increases arteries and decreases other vessel types. Platelet-derived growth factors from arteries deposit in the MSC region and interact with PDGFRA and PDGFRB. Significantly, PDGFRA+ and PDGFRB+ cells differentially contribute to defined cell lineages in the adult mouse incisor. Collectively, our results highlight Trp53's importance in regulating the vascular niche for MSCs. They also shed light on how different arterial cells provide unique cues to regulate MSC subpopulations and maintain their heterogeneity. Furthermore, they provide mechanistic insight into MSC-vasculature crosstalk.
Assuntos
Incisivo , Células-Tronco Mesenquimais , Transdução de Sinais , Proteína Supressora de Tumor p53 , Animais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Proteína Supressora de Tumor p53/metabolismo , Incisivo/citologia , Incisivo/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismoRESUMO
ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs' quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.
Assuntos
Proteínas de Ligação a DNA , Células-Tronco Mesenquimais , Proteínas Repressoras , Transdução de Sinais , Animais , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Proliferação de Células , Ativinas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Humanos , Proteína GLI1 em Dedos de ZincoRESUMO
Nerves play important roles in organ development and tissue homeostasis. Stem/progenitor cells differentiate into different cell lineages responsible for building the craniofacial organs. The mechanism by which nerves regulate stem/progenitor cell behavior in organ morphogenesis has not yet been comprehensively explored. Here, we use tooth root development in mouse as a model to investigate how sensory nerves regulate organogenesis. We show that sensory nerve fibers are enriched in the dental papilla at the initiation of tooth root development. Through single cell RNA-sequencing analysis of the trigeminal ganglion and developing molar, we reveal several signaling pathways that connect the sensory nerve with the developing molar, of which FGF signaling appears to be one of the important regulators. Fgfr2 is expressed in the progenitor cells during tooth root development. Loss of FGF signaling leads to shortened roots with compromised proliferation and differentiation of progenitor cells. Furthermore, Hh signaling is impaired in Gli1-CreER;Fgfr2fl/fl mice. Modulation of Hh signaling rescues the tooth root defects in these mice. Collectively, our findings elucidate the nerve-progenitor crosstalk and reveal the molecular mechanism of the FGF-SHH signaling cascade during tooth root morphogenesis.