Age-related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in old mice

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-06-02 DOI:10.1111/acel.14212
Daniel Clark, Sloane Brazina, Ted Miclau, Sangmin Park, Christine L. Hsieh, Mary Nakamura, Ralph Marcucio
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Abstract

Fracture healing complications increase with age, with higher rates of delayed unions and nonunions and an associated increase in morbidity and mortality in older adults. Macrophages have a dynamic role in fracture healing, and we have previously demonstrated that age-related changes in macrophages are associated with attenuated fracture repair in old mice. Here, we provide a single cell characterization of the immune cells involved in the early phase of fracture healing. We show that there were multiple transcriptionally distinct macrophage subpopulations present simultaneously within the healing tissue. Fracture healing was attenuated in old mice compared to young, and macrophages from the fracture callus of old mice demonstrated a pro-inflammatory phenotype compared to young. Interestingly, Trem2 expression was decreased in old macrophages compared to young. Young mice lacking Trem2 demonstrated attenuated fracture healing and inflammatory dysregulation similar to old mice. Trem2 dysregulation has previously been implicated in other age-related diseases, but its role in fracture healing is unknown. This work provides a robust characterization of the macrophage subpopulations involved in fracture healing, and further reveals the important role of Trem2 in fracture healing and may be a potential driver of age-related inflammatory dysregulation. Future work may further examine macrophages and Trem2 as potential therapeutic targets for management of fracture repair in older adults.

Abstract Image

Abstract Image

与年龄相关的巨噬细胞亚群变化和 TREM2 失调是老年小鼠骨折愈合能力减弱的特征。
骨折愈合并发症会随着年龄的增长而增加,老年人骨折愈合延迟和不愈合的比例较高,发病率和死亡率也随之增加。巨噬细胞在骨折愈合过程中发挥着动态作用,我们之前已经证明,巨噬细胞与年龄相关的变化与老年小鼠骨折修复能力减弱有关。在这里,我们对参与骨折愈合早期阶段的免疫细胞进行了单细胞鉴定。我们发现在愈合组织中同时存在多个转录不同的巨噬细胞亚群。与年轻小鼠相比,年老小鼠的骨折愈合能力减弱,而且与年轻小鼠相比,来自年老小鼠骨折胼胝体的巨噬细胞表现出一种促炎表型。有趣的是,与幼年小鼠相比,老年小鼠巨噬细胞中 Trem2 的表达量减少。缺乏 Trem2 的年轻小鼠表现出与老年小鼠相似的骨折愈合减弱和炎症失调。Trem2 的失调以前曾与其他年龄相关疾病有关,但它在骨折愈合中的作用尚不清楚。这项研究有力地描述了参与骨折愈合的巨噬细胞亚群的特征,进一步揭示了 Trem2 在骨折愈合中的重要作用,并可能是与年龄相关的炎症失调的潜在驱动因素。未来的工作可能会进一步研究巨噬细胞和 Trem2,将其作为治疗老年人骨折修复的潜在靶点。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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