Chen Jie, Zhao Yiwei, Zeng Chongmai, Tian Guoli, Feng Zhicai, Cao Yang
Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, 510055, China.
Stem Cell Res Ther. 2025 Jun 17;16(1):309. doi: 10.1186/s13287-025-04380-9.
Craniomaxillofacial sutures play a critical role in craniomaxillofacial development through continuous bone reconstruction and regeneration, processes modulated by mechanical tension. Bone suture stem cells (SuSCs) are central to these functions. Distraction osteogenesis, which promotes craniomaxillofacial suture growth, is a common therapeutic approach for craniofacial deformities. However, the underlying mechanisms by which mechanical forces drive suture and bone remodeling remain poorly understood, posing significant clinical challenges.
To investigate these mechanisms, we established a rapid maxillary expansion (RME) model in mice to widen the midpalatal suture. Single-cell RNA sequencing (scRNA-seq) was employed to identify subsets of SuSCs responsive to mechanical tension and analyze their differentiation potential under varying conditions. Further functional studies were conducted to explore the role of DALR anticodon binding domain containing 3 (Dalrd3) and its associated tRNA 3-methylcytosine (m3C) modification in SuSCs under mechanical tension.
Our study identified a subset of SuSCs with multidirectional differentiation potential that shifted from a chondrogenic to an osteogenic trajectory in response to mechanical tension. Mechanical tension also upregulated Dalrd3 expression and its associated tRNA m3C modification in activated SuSCs. Knockdown of Dalrd3 in SuSCs significantly impaired osteogenic differentiation, proliferation, migratory capacity, and translational activity within the bone morphogenetic protein (BMP) signaling pathway. Furthermore, Dalrd3 knockdown suppressed the translational activity of inhibitor of DNA binding 3 (Id3), a key BMP-induced mediator of osteoblastogenesis. Restoring Id3 expression in Dalrd3-deficient SuSCs rescued their osteogenic, proliferative, and migratory functions.
These findings reveal a translational regulatory mechanism in SuSCs activated by mechanical tension and underscore the pivotal role of Dalrd3 in suture remodeling and bone formation. The insights provided by this study have the potential to guide targeted therapeutic strategies for optimizing distraction osteogenesis and other treatments for craniofacial deformities.
颅颌面骨缝通过持续的骨重建和再生在颅颌面发育中发挥关键作用，这些过程受机械张力调节。骨缝干细胞（SuSCs）是这些功能的核心。牵张成骨可促进颅颌面骨缝生长，是治疗颅面畸形的常用方法。然而，机械力驱动骨缝和骨重塑的潜在机制仍知之甚少，这带来了重大的临床挑战。
为了研究这些机制，我们在小鼠中建立了快速上颌扩展（RME）模型以扩宽腭中缝。采用单细胞RNA测序（scRNA-seq）来识别对机械张力有反应的SuSCs亚群，并分析它们在不同条件下的分化潜能。进行了进一步的功能研究，以探讨含DALR反密码子结合结构域3（Dalrd3）及其相关的tRNA 3-甲基胞嘧啶（m3C）修饰在机械张力下SuSCs中的作用。
我们的研究鉴定出了具有多向分化潜能的SuSCs亚群，其响应机械张力从软骨生成轨迹转变为成骨轨迹。机械张力还上调了活化的SuSCs中Dalrd3的表达及其相关的tRNA m3C修饰。在SuSCs中敲低Dalrd3会显著损害成骨分化、增殖、迁移能力以及骨形态发生蛋白（BMP）信号通路中的翻译活性。此外，Dalrd3敲低抑制了DNA结合抑制剂3（Id3）的翻译活性，Id3是BMP诱导的成骨细胞生成的关键介质。在Dalrd3缺陷的SuSCs中恢复Id3表达可挽救其成骨、增殖和迁移功能。
这些发现揭示了机械张力激活的SuSCs中的一种翻译调控机制，并强调了Dalrd3在骨缝重塑和骨形成中的关键作用。本研究提供的见解有可能指导优化牵张成骨和其他颅面畸形治疗方法的靶向治疗策略。
