Collagen-Producing Macrophages Contribute To Fibrosis
Britta A. Kuehlmann, Clark A. Bonham, Geoffrey C. Gurtner.
Stanford University, Stanford, CA, USA.
BACKGROUND- Implants stimulate collagen deposition resulting in a fibrotic capsule. The most common complication following breast implants is capsular fibrosis (CF). We analyze fibrotic human samples, and use animal models to clarify the mechanisms underlying this fibrotic process.
METHODS- We have established the largest tissue bank worldwide for breast capsular tissues. This registry provides the opportunity to analyze mechanisms underlying fibrosis. Using RNA analysis with a 2,559-gene probeset, the gene expression from 40 patients was analyzed. 20 human samples expressing the mildest form of CF (Baker I) were compared to 20 human specimens of the most severe form of CF (Baker IV). To recreate CF within an animal model, implants were placed in Bl6-mice. We used vav-reporter-mice for lineage tracking. Cells from the capsule were isolated and characterized by FACS, qPCR and single cell RNA sequencing to determine the genetic profiles of those most responsible for fibrotic development.
RESULTS- 1,543 genes were upregulated and 1,016 were downregulated in Baker IV vs Baker I. Genes regulating macrophage activation and macrophages surface marker expression were among the most highly expressed in Baker IV. Lineage tracking identified the presence of cells with distinct characteristics of macrophages, confirming their existence within the chronology of CF. In the murine capsules of Bl6-mice we found the predominant cells were myeloid cells, not fibroblasts. Using FACS, we confirmed that these macrophages produce ECM at the protein level with >80% of macrophages expressing collagen 1.
CONCLUSIONS- For the first time, we demonstrate that collagen-depositing macrophages are responsible for fibrosis around implants by analyzing patient samples and murine models. Our findings have promising implications for the treatment of capsular fibrosis.
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