Neural crest-derived mesenchymal stem cells (MSCs) are known to play an essential function during tooth and skeletal development. PRX1+ cells constitute an important MSC subtype that is implicated in osteogenesis. However, their potential function in tooth development and regeneration remains elusive. In the present study, we first assessed the cell fate of PRX1+ cells during molar development and periodontal ligament (PDL) formation in mice. Furthermore, single-cell RNA sequencing analysis was performed to study the distribution of PRX1+ cells in PDL cells. The behavior of PRX1+ cells during PDL reconstruction was investigated using an allogeneic transplanted tooth model. Although PRX1+ cells are spatial specific and can differentiate into almost all types of mesenchymal cells in first molars, their distribution in third molars is highly limited. The PDL formation is associated with a high number of PRX1+ cells; during transplanted teeth PDL reconstruction, PRX1+ cells from the recipient alveolar bone participate in angiogenesis as pericytes. Overall, PRX1+ cells are a key subtype of dental MSCs involved in the formation of mouse molar and PDL and participate in angiogenesis as pericytes during PDL reconstruction after tooth transplantation.
Primary cilia have a pivotal role in bone development and the dysfunctions of primary cilia cause skeletal ciliopathies. Intraflagellar transport (IFT) proteins are conserved mediators of cilium signaling. IFT sub-complex A is known to regulate retrograde IFT in the cilium. As a core protein of IFT complex A, IFT140 has been shown to have a relationship with serious skeletal ciliopathies caused in humans. However, the effects and mechanisms of IFT140 in bone formation have not been systematically disclosed. To further investigate the potential role of IFT140 in osteogenesis, we established a mouse model by conditional deletion of IFT140 in pre-osteoblasts. The adult knock-out mice exhibited dwarf phenotypes, such as short bone length, less bone mass, and decreased bone mineral apposition rate. In addition, by IFT140 deletion, the expressions of several osteoblastic markers were decreased and loss of bone became severe with aging. These results suggest that cilia gene Ift140 is essential in bone development.
Background: Primary cilia influence cell function and tissue development. Ciliary signaling is mediated by two intraflagellar transport (IFT) protein complexes, IFT-A and IFT-B. The IFT-A complex is responsible for retrograde transport, and IFT140 is a core protein in the A complex. Mutations in IFT140 cause a variety of skeletal disorders. However, the expression and role of IFT140 during bone development remain unclear. In this study, to further explore the potential role of IFT140 in osteogenesis, we used cell lineage tracing and conditional knockout to analyze the distribution and function of IFT140-positive cells during bone formation. Results: In newborn Ift140-creER; R26R tdTomato mice, IFT140-positive cells were mainly located in the medullary cavity and then migrated to and differentiated on the surface of trabecular and cortical bone. In contrast, the number of IFT140-positive cells significantly decreased in the adult stage, and these cells were only located in the bone marrow cavity for a short time. In Osx-cre; Ift140 flox/flox mice, the loss of IFT140 in preosteoblasts caused bone loss in the trabecular bone area at 10 weeks. Conclusion: The results revealed that IFT140-positive cells mainly contribute to the early stage of bone formation.
In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.
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