The periosteum plays a critical role in bone repair and is significantly influenced by the surrounding immune microenvironment. In this study, we employed 10× single-cell RNA sequencing to create a detailed cellular atlas of the swine cranial periosteum, highlighting the cellular dynamics and interactions essential for cranial bone injury repair. We noted that such injuries lead to an increase in M2 macrophages, which are key in modulating the periosteum’s immune response and driving the bone regeneration process. These macrophages actively recruit periosteal stromal cells (PSCs) by secreting Neuregulin 1 (NRG1), a crucial factor in initiating bone regeneration. This recruitment process emphasizes the critical role of PSCs in effective bone repair, positioning them as primary targets for therapeutic interventions. Our results indicate that enhancing the interaction between M2 macrophages and PSCs could significantly improve the outcomes of treatments aimed at cranial bone repair and regeneration.

Epigenetic regulation provides new insights into the mechanisms of osteogenic differentiation and identifies potential targets for treating bone-related diseases. However, the specific regulatory networks and mechanisms involved still need further investigation. In this study, we identify PRMT7 as a novel epigenetic regulator of mesenchymal stem cells (MSCs) osteogenic commitment. Conditional knockout of Prmt7 in mice reveals a significant impairment in osteogenesis and bone regeneration, specifically in females, affecting both femurs and mandibles, with no noticeable effect in males. Mechanistically, PRMT7 modulates MSCs osteogenic differentiation by activating PTEN. Specifically, PRMT7 enhances PTEN transcription by increasing H3R2me1 levels at the PTEN promoter. Additionally, PRMT7 interacts with the PTEN protein and stabilizes nuclear PTEN, revealing an unprecedented pathway. Notably, overexpression of PTEN alleviates the osteogenic deficits observed in Prmt7-deficient mice. This research establishes PRMT7 as a potential therapeutic target for promoting bone formation/regeneration and offers novel molecular insights into the PRMT7–PTEN regulatory axis, underscoring its significance in bone biology and regenerative medicine.