ScRNA-Seq Reveals a Distinct Osteogenic Progenitor of Alveolar Bone

The metabolism and remodeling of alveolar bone are the most active among the whole skeletal system, which is related to the biological characteristics and heterogeneity of the bone mesenchymal stromal cells (MSCs). However, there is a lack of systematic description of the heterogeneity of MSC-derived osteoblastic lineage cells as well as their distinct osteogenic differentiation trajectory of alveolar bone. In this study, we constructed a single-cell atlas of the mouse alveolar bone cells through single-cell RNA sequencing (scRNA-seq). Remarkably, by comparing the cell compositions between the alveolar bone and long bone, we uncovered a previously undescribed cell population that exhibits a high expression of protocadherin Fat4 (Fat4⁺ cells) and is specifically enriched around alveolar bone marrow cavities. ScRNA-seq analysis indicated that Fat4⁺ cells may initiate a distinct osteogenic differentiation trajectory in the alveolar bone. By isolating and cultivating Fat4⁺ cells in vitro, we demonstrated that they possess colony-forming, osteogenic, and adipogenic capabilities. Moreover, FAT4 knockdown could significantly inhibit the osteogenic differentiation of alveolar bone MSCs. Furthermore, we revealed that the Fat4⁺ cells exhibit a core transcriptional signature consisting of several key transcription factors, such as SOX6, which are involved in osteogenesis, and further demonstrated that SOX6 is required for the efficient osteogenic differentiation of the Fat4⁺ cells. Collectively, our high-resolution single-cell atlas of the alveolar bone reveals a distinct osteogenic progenitor that may contribute to the unique physiological characteristics of alveolar bone.