Wound Healing Society

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Fibrosis Around Implants Is Driven By Three Unique Subgroups Of Macrophages
Britta A. Kuehlmann, Clark A. Bonham, Geoffrey C. Gurtner.
Stanford, Stanford, CA, USA.

Background- Implants are used to restore and maintain bodily function in response to a wide variety of diseases. The body’s immune system attempts to destroy these foreign bodies through the foreign body response (FBR) and fibrotic tissue forms around the implant. These capsules cause complications and often require corrective surgery.
Methods- We have attempted to discover the major cellular constituents that drive fibrotic development. Using a novel murine model, we placed small silicone implants in Bl6-mice. After 90 days, we harvested the fibrotic tissue surrounding the implants and isolated the cells. Cells were subjected to fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR) and single cell RNA sequencing to determine their genetic profiles and function.
Results- FACS yielded distinct cell populations within the fibrotic tissue, with CD45+/ CD11b+ macrophages being among the most prevalent. They appeared to be depositing collagen. We subjected the tissue at day 90 to single cell RNA-sequencing without FACS separation. Macrophages were found to be the predominant cell type in the capsule, with three subsets identified. All subsets expressed Cd45, Cd11b and Cd14. The first macrophage subset uniquely expressed Cd36 known to promote fibrogenic pathways. Subgroup 1 is characterized by a highly inflammatory genetic profile, regulating cell signal production associated with acute inflammation. The second macrophage subset distinctly expressed Cd209, which is essential to recognizing foreign bodies and inciting an inflammatory response. Macrophages in group 2 display genes that contribute to acute inflammation. Subgroups 1 and 2 both expressed Adgre1, which encodes F4/80.The third macrophage subset maintained a genetic profile based on its expression of Ccr2. The 3 subgroups seem to contribute to the induction of inflammation through pro-fibrotic and phagocytic activity and signaling.
Conclusions- According to current literature, fibroblasts are the source of collagen deposition in the FBR. We found three macrophage subgroups that drive fibrosis and deposit collagen. Our findings have promising therapeutic implications for the treatment of skin fibrosis.

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