Bone fracture is one of the most common clinical injuries, with a significant proportion of patients, especially the elderly, at risk of poor healing or even nonunion, leading to additional surgery and morbidity. Skeletal stem cells (SSCs) are not a homogeneous population, and although they express similar surface markers, different cell types serve as site-specified SSCs contributing to bone development, bone maintenance and fracture repair.
Periosteum is enriched with SSCs that labeled by Ctsk. Unlike other SSCs that form bone through an initial cartilage template as endochondral ossification, Ctsk-lineage periosteal SSCs (P-SSCs) form bone directly through intramembranous ossification. However, P-SSCs can mediate endochondral ossification after fracture, raising the question whether there are distinct subpopulations of P-SSCs that are separately responsible for fracture repair and steady-state bone formation.
In a study published in Cell Research, the team led by Prof. ZOU Weiguo from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, in collaboration with Prof. LE Rongrong from Tongji University, profiled the composition of periosteal cells and identified a resting subpopulation of P-SSCs that labeled by Angptl7.
Based on Angptl7-mScarlet and Angptl7-CreER mouse models, the researchers demonstrated that Angptl7-lineage cells are specifically present in the periosteum with rare contribution to steady-state bone formation, although they possess the capacity for in vitro colony formation and trilineage differentiation.
In addition, Angptl7-lineage P-SSCs have a clear and indispensable contribution to post-injury endochondral ossification. Based on lineage depletion and conditional knock-out mouse models, the researchers found that Angptl7-lineage cells are indispensable for mediating bone fracture healing process. Long-term lineage tracing assays also showed that Angptl7-lineage cells can regenerate the entire bone architecture, including the whole periosteum, cortex, endosteum, and even the bone marrow stroma. By multi-omics approaches, the researchers uncovered an activated inflammatory-responding stage of Angptl7-lineage P-SSCs after fracture.
Inflammatory signals, such as TNF-α, can trigger the activation of Angptl7-lineage P-SSCs by up-regulating NF-κB signaling pathway, which subsequently promotes the expression of Cxcl5 in activated Angptl7-lineage cells.
Together, this study advances the understanding of the cell basis for bone maintenance and fracture repair. The Angptl7-related mouse models defined absolute specificity of lineage tracing experiments for fracture-repairing P-SSCs. The genetic models and datasets established here will also benefit future studies for decoding the mechanisms underlying clinical fracture non-union events.
Reference: https://doi.org/10.1038/s41422-025-01202-8
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