Ambrosi Thomas H, Taheri Sahar, Chen Kun, Sinha Rahul, Wang Yuting, Hunt Ethan J, Goodnough L Henry, Murphy Matthew P, Steininger Holly M, Hoover Malachia Y, Felix Franco, Weldon Kelly C, Koepke Lauren S, Sokol Jan, Liu Daniel Dan, Zhao Liming, Conley Stephanie D, Lu Wan-Jin, Morri Maurizio, Neff Norma F, Van Rysselberghe Noelle L, Wheeler Erika E, Wang Yongheng, Leach J Kent, Saiz Augustine, Wang Aijun, Yang George P, Goodman Stuart, Bishop Julius A, Gardner Michael J, Wan Derrick C, Weissman Irving L, Longaker Michael T, Sahoo Debashis, Chan Charles K F
Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA 95817, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Computer Science and Engineering, Jacob's School of Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Stem Cell. 2025 May 1;32(5):811-823.e11. doi: 10.1016/j.stem.2025.02.013. Epub 2025 Mar 20.
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; CD45CD235aTIE2CD31CD146PDPNCD73CD164) 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.
骨骼是人体中结构和组成最为多样的器官系统之一，这取决于独特的细胞动态变化。在此，我们将从十个骨骼部位对人类骨骼干细胞（hSSCs；CD45CD235aTIE2CD31CD146PDPNCD73CD164）进行前瞻性分离，与功能分析和单细胞RNA测序（scRNA-seq）分析相结合，以确定发育过程中hSSCs的软骨生成、成骨、基质和纤维生成亚型，以及它们与骨骼表型的联系。我们绘制了多个骨骼部位hSSC亚型的不同组成，并展示了它们在体内独特的克隆动态。我们发现，骨形成和再生障碍中与年龄相关的变化源于hSSC库中的病理性成纤维细胞转变。利用布尔算法，我们揭示了决定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谱系动态在药理学上具有可塑性，这为治疗衰老和骨骼疾病中核心的异常hSSC多样性提供了一种新策略。
