Human skeletal development and regeneration are shaped by functional diversity of stem cells across skeletal sites

人类骨骼的发育与再生受不同骨骼部位干细胞功能多样性的调控

Cell Stem Cell. 2025 May 1;32(5):811-823.e11. doi: 10.1016/j.stem.2025.02.013.

摘要：骨骼是人体结构和组成最多样化的器官系统之一，这种多样性取决于独特的细胞动态特性。本研究整合了从十个骨骼部位前瞻性分离的人类骨骼干细胞（hSSCs：CD45⁻CD235a⁻TIE2⁻CD31⁻CD146⁻PDPN⁺CD73⁺CD164⁺）用于功能实验验证及单细胞RNA测序（scRNA-seq）分析，鉴定了发育过程中hSSCs的成软骨、成骨、基质与成纤维亚型，并揭示了其与骨骼表型的关联。研究绘制了不同骨骼部位hSSCs亚型的独特组成图谱，并证明了它们在体内独特的克隆动力学。研究发现，与年龄相关的骨形成变化和再生障碍源于hSSC池中的病理性成纤维转变。通过布尔算法，揭示了决定hSSCs生成特定骨骼组织能力差异的基因调控网络。重要的是，hSSC谱系动力学具有药理学可塑性，这为治疗衰老和骨骼疾病中异常的hSSC多样性提供了新策略。

【Abstract】

The skeleton is one of the most structurally and compositionally diverse organ systems in the human body, depending on unique cellular dynamisms. Here, we integrate prospective isolation of human skeletal stem cells (hSSCs; CD45^-CD235a^-TIE2^-CD31^-CD146^-PDPN⁺CD73⁺CD164⁺) from ten skeletal sites with functional assays and single-cell RNA sequencing (scRNA-seq) analysis to identify chondrogenic, osteogenic, stromal, and fibrogenic subtypes of hSSCs during development and their linkage to skeletal phenotypes. We map the distinct composition of hSSC subtypes across multiple skeletal sites and demonstrate their unique in vivo clonal dynamics. We find that age-related changes in bone formation and regeneration disorders stem from a pathological fibroblastic shift in the hSSC pool. Utilizing a Boolean algorithm, we uncover gene regulatory networks that dictate differences in the ability of hSSCs to generate specific skeletal tissues. Importantly, hSSC lineage dynamics are pharmacologically malleable, providing a new strategy to treat aberrant hSSC diversity central to aging and skeletal maladies.

编译：田雨、谢杨丽

陆军特色医学中心、重庆大坪医院