Resumen
Macrophages are important for repair of injured tissues, but their role in healing after surgical repair of musculoskeletal tissues is not well understood. We used single-cell RNA sequencing (RNA-seq), flow cytometry, and transcriptomics to characterize functional phenotypes of macrophages in a mouse anterior cruciate ligament reconstruction (ACLR) model that involves bone injury followed by a healing phase of bone and fibrovascular interface tissue formation that results in bone-to-tendon attachment. We identified a novel “surgery-induced” highly inflammatory CD9+ IL1+ macrophage population that expresses neutrophil-related genes, peaks 1 day after surgery, and slowly resolves while transitioning to a more homeostatic phenotype. In contrast, CX3CR1+ CCR2+ macrophages accumulated more slowly and unexpectedly expressed an interferon signature, which can suppress bone formation. Deletion of Ccr2 resulted in an increased amount of bone in the surgical bone tunnel at the tendon interface, suggestive of improved healing. The “surgery-induced macrophages” identify a new cell type in the early phase of inflammation related to bone injury, which in other tissues is dominated by blood-derived neutrophils. The complex patterns of macrophage and inflammatory pathway activation after ACLR set the stage for developing therapeutic strategies to target specific cell populations and inflammatory pathways to improve surgical outcomes.
| Idioma original | English |
|---|---|
| Número de artículo | e10635 |
| Publicación | JBMR Plus |
| Volumen | 6 |
| N.º | 7 |
| DOI | |
| Estado | Published - jul. 2022 |
Financiación
This work was supported by grants from the N.I.H. (LBI), and by support for the Rosensweig Genomics Center from The Tow Foundation. We thank Ugur Ayturk (HSS) for helpful discussions and David Oliver (David Z. Rosensweig Genomics Center, HSS) for advice and assistance with scRNAseq and multiparameter flow cytometric analysis, the Weill Cornell Medicine Genomics Core Facility for next generation sequencing, and Weill Cornell Medicine–HSS Flow Cytometry Core Facility for flow cytometry support. This work was supported by grants from the N.I.H. (LBI), and by support for the Rosensweig Genomics Center from The Tow Foundation. We thank Ugur Ayturk (HSS) for helpful discussions and David Oliver (David Z. Rosensweig Genomics Center, HSS) for advice and assistance with scRNAseq and multiparameter flow cytometric analysis, the Weill Cornell Medicine Genomics Core Facility for next generation sequencing, and Weill Cornell Medicine–HSS Flow Cytometry Core Facility for flow cytometry support. Authors’ roles: TF designed and performed most of the cellular and molecular experiments, performed bioinformatic analysis, prepared the figures, and wrote the manuscript. SW and CC performed surgeries with assistance from YN, YL, DC, and XD, and provided intellectual input. W.M. contributed experiments, RB analyzed flow cytometry data, TP performed histological analysis, and US performed bioinformatic analysis. KHPM conceptualized the study, designed and oversaw the experiments, and wrote the manuscript. SR provided expertise and intellectual input and oversaw the surgical experiments. LBI conceptualized and oversaw the study, interpreted data, and edited the manuscript. All authors reviewed and provided input on the manuscript.
| Financiadores | Número del financiador |
|---|---|
| N.I.H. | |
| Rosensweig Genomics Center | |
| Weill Cornell Medicine Genomics Core Facility | |
| Weill Cornell Medical College | |
| Tow Foundation |
ASJC Scopus Subject Areas
- Endocrinology, Diabetes and Metabolism
- Orthopedics and Sports Medicine
ODS de las Naciones Unidas
Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible
