Center for Craniofacial Regeneration, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, USA.
Department of Periodontics and Preventive Dentistry, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, USA.
Aging Cell. 2024 Sep;23(9):e14212. doi: 10.1111/acel.14212. Epub 2024 Jun 2.
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.
骨折愈合并发症随年龄增长而增加，老年人的延迟愈合和不愈合发生率更高，发病率和死亡率也随之增加。巨噬细胞在骨折愈合中具有动态作用，我们之前的研究表明，与老年小鼠相比，巨噬细胞的年龄相关变化与减弱的骨折修复有关。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特征描述。结果表明，在愈合组织中同时存在多个转录上不同的巨噬细胞亚群。与年轻小鼠相比，老年小鼠的骨折愈合减弱，并且来自老年小鼠骨折骨痂的巨噬细胞表现出促炎表型。有趣的是，与年轻巨噬细胞相比，老年巨噬细胞中的 Trem2 表达降低。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 失调先前与其他与年龄相关的疾病有关，但它在骨折愈合中的作用尚不清楚。这项工作对参与骨折愈合的巨噬细胞亚群进行了强有力的描述，进一步揭示了 Trem2 在骨折愈合中的重要作用，并且可能是与年龄相关的炎症失调的潜在驱动因素。未来的研究可能会进一步研究巨噬细胞和 Trem2 作为治疗靶点，以管理老年人的骨折修复。
