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Age-related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in
Daniel Clark1,2, Sloane Brazina3, Ted Miclau4
1Center for Craniofacial Regeneration, University of Pittsburgh School of Dental Medicine, Pittsburgh, Pennsylvania, USA.
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.
Insights
Aging impairs fracture healing due to inflammatory macrophages. Decreased Trem2 expression in older mice contributes to this, highlighting Trem2 as a potential therapeutic target for fracture repair.
Area of Science:
- Immunology
- Regenerative Medicine
- Gerontology
Background:
- Fracture healing complications, including delayed unions and nonunions, are more prevalent in older adults.
- Macrophages play a critical role in fracture repair, but age-related changes can attenuate this process.
- Previous studies suggest age-related macrophage alterations are linked to impaired fracture healing in mice.
Purpose of the Study:
- To perform a single-cell characterization of immune cells during the early phase of fracture healing.
- To investigate the role of Trem2 (Triggering Receptor Expressed on Myeloid Cells 2) in age-related fracture healing deficits.
- To identify potential therapeutic targets for improving fracture repair in older adults.
Main Methods:
- Single-cell RNA sequencing to characterize immune cells in the fracture callus.
- Comparative analysis of fracture healing in young and old mice.
- Genetic manipulation of Trem2 in young mice to assess its functional role.
Main Results:
- Multiple distinct macrophage subpopulations were identified within the healing fracture tissue.
- Older mice exhibited attenuated fracture healing with a pro-inflammatory macrophage phenotype compared to young mice.
- Trem2 expression was reduced in macrophages from old mice, and its absence in young mice mimicked age-related healing impairments and inflammatory dysregulation.
Conclusions:
- Fracture healing involves diverse macrophage subpopulations, with age-related changes leading to a pro-inflammatory state.
- Decreased Trem2 expression is a key factor in age-related fracture healing attenuation and inflammatory dysregulation.
- Macrophages and Trem2 represent promising therapeutic targets for enhancing fracture repair in the elderly.
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