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Overcoming Foreign Body Response In Breast Reconstruction By Modulation Of Fibroblast Subpopulations
Michelle Griffin, MD PhD, Arash Momeni, MD, Derrick Wan, MD, Michael Longaker, MD MBA.
Stanford Hospital, Stanford, CA, USA.
PURPOSE:Foreign body response (FBR) to breast implants remains a major clinical challenge. While fibroblasts are known drivers of fibrosis, the roles of distinct fibroblast subpopulations and their signaling pathways in implant-associated FBR are not well defined. Moreover, the influence of local tissue environment—subcutaneous versus muscle—on FBR has not been systematically explored.
METHODS:In a murine model, 8-mm silicone discs were implanted subcutaneously in the dorsal region of 12-week-old, B6-mice. Peri-implant tissue was harvested at postoperative-day-28. Histology, immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and single-cell ATAC sequencing (scATAC-seq) were used to characterize fibrotic fibroblasts. The fibrotic capsule adjacent to subcutaneous tissue (“subcutaneous capsule”) was compared with that adjacent to muscle (“muscle capsule”). Parallel analyses were performed on matched human FBR capsules from subcutaneous and muscle-contact regions (n=6), using scRNA-seq and spatial protein profiling.
RESULTS: In both mouse and human, subcutaneous capsules were significantly thicker (p < 0.0001;n = 6) and exhibited greater collagen deposition (p = 0.0016;n = 6) than muscle capsules (
FigA-B). scRNA-seq revealed enrichment of mechanically sensitive YAP⁺, thrombospondin-1 (THBS1)⁺ fibroblasts within human and mosue subcutaneous capsules
(FigC). Genetic deletion of THBS1 or pharmacologic THBS1 inhibition in mice abrogated the exaggerated subcutaneous FBR, reducing fibrosis to levels comparable with muscle capsules (
FigD).
CONCLUSION:Our findings identify THBS1⁺ mechanically sensitive fibroblasts as key mediators of FBR-associated fibrosis in both mouse and human breast FBR. These data highlight the critical role of tissue microenvironment in modulating FBR and position THBS1 inhibition as a promising therapeutic strategy to mitigate fibrotic complications of breast implants.
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