Sun Zhixuan, Chen Yujie, Ding Pengbing, Wang Zheng, Lin Zhiyu, Zhou Binyi, Hu Fengyi, Lu Enhang, Xiang Haibo, Yang Xin, Zhang Peiyang, Zhao Zhenmin
Department of Plastic Surgery, Peking University Third Hospital, Beijing, 100191, China.
Department of Plastic Surgery, Peking University People's Hospital, Beijing, 100044, China.
Stem Cell Res Ther. 2025 Jul 1;16(1):330. doi: 10.1186/s13287-025-04458-4.
Midfacial hypoplasia is a common craniofacial deformity. Trans-sutural distraction osteogenesis (TSDO), which applies mechanical force to stimulate bone formation at the zygomaticomaxillary sutures (ZMS), has emerged as an effective therapeutic strategy. However, the underlying mechanisms of TSDO-induced osteogenesis remain unclear, resulting in prolonged treatment durations and limited clinical application.
A TSDO model was established in 4-week-old C57BL/6 mice and neutrophil-depleted mice to investigate the role of neutrophils in bone regeneration at the ZMS. Single-cell RNA sequencing was used to characterize neutrophil dynamics and heterogeneity during TSDO, and intercellular signaling pathways were identified through CellChat analysis. Additionally, in vitro stretching experiments using differentiated HL-60 cells were performed to assess the mechanosensitive behavior of neutrophils.
In the TSDO model, mechanical distraction significantly increased neutrophil infiltration in the ZMS and surrounding bone marrow. Neutrophil depletion impaired distraction-induced bone formation. Single-cell sequencing revealed that the Jun neutrophil subset (Jun-Neu) facilitated the osteogenic differentiation of suture-derived stem cells (SuSCs) via secretion of oncostatin M (OSM). In vitro, mechanical stretching (10%, 0.5 Hz) activated the phosphoinositide 3-kinase (PI3K)-AKT pathway in neutrophils, enhancing OSM release and promoting the osteogenic differentiation of SuSCs.
This study identifies a mechanical force-neutrophil-bone regeneration axis in TSDO, highlighting the critical role of Jun-Neu-derived OSM in promoting osteogenesis. These findings provide theoretical insights for optimizing TSDO-based clinical strategies.
面中部发育不全是一种常见的颅面畸形。经缝牵引成骨术（TSDO）通过施加机械力刺激颧上颌缝（ZMS）处的骨形成，已成为一种有效的治疗策略。然而，TSDO诱导成骨的潜在机制仍不清楚，导致治疗时间延长且临床应用受限。
在4周龄的C57BL/6小鼠和中性粒细胞耗竭的小鼠中建立TSDO模型，以研究中性粒细胞在ZMS骨再生中的作用。使用单细胞RNA测序来表征TSDO过程中中性粒细胞的动态变化和异质性，并通过CellChat分析确定细胞间信号通路。此外，使用分化的HL-60细胞进行体外拉伸实验，以评估中性粒细胞的机械敏感行为。
在TSDO模型中，机械牵张显著增加了ZMS和周围骨髓中的中性粒细胞浸润。中性粒细胞耗竭会损害牵张诱导的骨形成。单细胞测序显示，Jun中性粒细胞亚群（Jun-Neu）通过分泌制瘤素M（OSM）促进缝线来源干细胞（SuSCs）的成骨分化。在体外，机械拉伸（10%，0.5Hz）激活了中性粒细胞中的磷酸肌醇3激酶（PI3K）-AKT通路，增强了OSM释放并促进了SuSCs的成骨分化。
本研究确定了TSDO中的机械力-中性粒细胞-骨再生轴，突出了Jun-Neu来源的OSM在促进成骨中的关键作用。这些发现为优化基于TSDO的临床策略提供了理论见解。
