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<p>Aging profoundly impacts bone homeostasis and regeneration, yet the cellular and molecular mechanisms underlying periosteal aging remain poorly understood. Using single-cell RNA sequencing, we profiled the periosteum of 3-, 9-, and 18-month-old mice, which revealed age-related shifts in progenitor, neutrophil, and macrophage subpopulations. Aging reduced mesenchymal cell populations and impaired osteogenic potential, may contribute to periosteal homeostasis. Periosteal progenitor subsets exhibited distinct aging trajectories: <i>Dpt</i>⁺ fibrous-layer cells undergoing early senescence, while <i>Postn</i>⁺ progenitors showed osteogenic decline. Aging also shifted immune profiles, increasing inflammatory <i>Cd38</i><sup>hi</sup> macrophages and dysfunctional <i>Nlrp3</i><sup>hi</sup> neutrophils, further disrupting bone homeostasis. Notably, aged progenitor cells upregulated CSF1 and CXCL signaling, driving macrophage and neutrophil infiltration, exacerbating bone loss. Our findings provide a comprehensive periosteal aging atlas, revealing aging-associated alterations in progenitor-immune crosstalk that may influence bone tissue dynamics, and offering insights into potential targets for age-related skeletal conditions.</p>

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Single-cell mapping reveals age-related alterations in periosteal progenitor cells and immune microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Lei Zhao,
  • Chao Wu,
  • Keran Chen,
  • Zhaoning Xu,
  • Yu You,
  • Peiru Zhao,
  • Di Zhu,
  • Meiling Su,
  • Jian Luo,
  • Yiyun Wang

摘要

Aging profoundly impacts bone homeostasis and regeneration, yet the cellular and molecular mechanisms underlying periosteal aging remain poorly understood. Using single-cell RNA sequencing, we profiled the periosteum of 3-, 9-, and 18-month-old mice, which revealed age-related shifts in progenitor, neutrophil, and macrophage subpopulations. Aging reduced mesenchymal cell populations and impaired osteogenic potential, may contribute to periosteal homeostasis. Periosteal progenitor subsets exhibited distinct aging trajectories: Dpt⁺ fibrous-layer cells undergoing early senescence, while Postn⁺ progenitors showed osteogenic decline. Aging also shifted immune profiles, increasing inflammatory Cd38hi macrophages and dysfunctional Nlrp3hi neutrophils, further disrupting bone homeostasis. Notably, aged progenitor cells upregulated CSF1 and CXCL signaling, driving macrophage and neutrophil infiltration, exacerbating bone loss. Our findings provide a comprehensive periosteal aging atlas, revealing aging-associated alterations in progenitor-immune crosstalk that may influence bone tissue dynamics, and offering insights into potential targets for age-related skeletal conditions.