Project description:Establishment of human teeth relies on coordinated formation of dentin-pulp complex for nurturing and periodontal tissues for anchoring in alveolar bone. The exact cell origin of dentin-pulp complex and periodontal tissues, and the integrative developmental process remain elusive. Here, we identified a bilaminar core of Cd24a+ and Pax9+ stem cells that governs the tooth establishment and persists into adulthood. Specifically, Cd24a+ stem cells gave rise to the dentin-pulp complex while Pax9+ stem cells mainly generated periodontal tissues as well as partial dental pulp. DTA-mediated cell ablation of the Cd24a+/Pax9+ stem cells significantly compromised tooth establishment. Moreover, during development, the Cd24a+/Pax9+ bilaminar core concentrated on the apical region, collectively migrated and contributed to the newly formed dental root, potentially guided by PDGF-B derived from the alveolar bone. Integrated multi-omic analysis and spatial mapping further revealed lineage-associated key signaling pathways in Cd24a+/Pax9+ stem cells and the unique organization of different cell compositions. Finally, the CD24+/PAX9+ bilaminar core was also detected in human teeth at different stages, suggesting it a conserved developmental mechanism. Together, our work identified a unique bilaminar core of bona fide dental stem cells governing tooth establishment and might guide the future regenerative therapy to treat pulpitis, pulp necrosis and periodontal diseases.
Project description:We use the continuously replacing dentition of Lake Malawi cichlid fishes to understand de-novo tooth replacement in adult vertebrates. In this system, each tooth is replaced in a one-for-one fashion every ~50 days. Here, we explore the source of epithelial stem cells for tooth replacement.
Project description:The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying regulatory mechanism remains poorly understood. Here we identified the transcription factor (TF), Specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 governs CT generation and the establishment of trophoblast stem cells (TSCs) and discovered msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to modulate the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a novel regulator of the human trophoblast lineage and implied its regulatory role in placental development and the pathogenies of placental diseases.
Project description:The commitment and differentiation of human placental progenitor cytotrophoblast (CT) cells are crucial for a successful pregnancy, but the underlying regulatory mechanism remains poorly understood. Here we identified the transcription factor (TF), Specificity protein 6 (SP6), as a human species-specific trophoblast lineage TF expressed in human placental CT cells. Using pluripotent stem cells as a model, we demonstrated that SP6 governs CT generation and the establishment of trophoblast stem cells (TSCs) and discovered msh homeobox 2 (MSX2) as the downstream effector in these events. Mechanistically, we showed that SP6 interacts with histone acetyltransferase P300 to modulate the landscape of H3K27ac at targeted regulatory elements, thereby favoring transcriptional activation and facilitating CT cell fate decisions and TSC maintenance. Our results established SP6 as a novel regulator of the human trophoblast lineage and implied its regulatory role in placental development and the pathogenies of placental diseases.
Project description:Specificity protein 6 governs human cytotrophoblast fate decisions and trophoblast stem cell establishment by targeting MSX2 regulatory elements
Project description:Throughout the various stages of tooth development, reciprocal epithelial-mesenchymal interactions are the driving force, for instance crucially involved in the differentiation of mature enamel-forming ameloblasts and dentin-producing odontoblasts. Here we established mouse tooth ‘assembloids’, comprised of tooth organoid-derived dental epithelial cells (from mouse molars and incisors) cultured together with molar dental pulp stem cells (DPSCs), to mimic these developmental interactions. Assembloids from both tooth types were grown both in basal- and differentiation-inducing conditions. Single cell transcriptomics analysis was applied to in detail characterize and validate the newly developed mouse tooth assembloid model and evaluate the induced differentiation processes.