Targeting Wnt11 and collagen-depositing macrophages to reduce fibrosis around implants
Kuehlmann B.1,2, Bonham C.A.1, Gurtner G.C.1, Prantl L.2
1Stanford University, Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford, Vereinigte Staaten von Amerika, 2University Hospital Regensburg and Caritas Hospital St. Josef, University Center for Plastic, Reconstructive, Aesthetic and Hand Surgery, Regensburg, Deutschland
Introduction: Fibrosis is a common outcome following surgical implantation of biomedical devices, which are a mainstay of modern medicine. Implants elicit a foreign body response resulting in collagen-deposition and fibrotic encapsulation but a better understanding of the pathophysiology is required for new therapeutics to be developed to optimize patient outcome.
Methods: Using a murine model to simulate the generation of capsular fibrosis (CF) around implants, we compared its development within Wnt11 KO mice to that of regular Bl/6 mice by placing miniature silicone implants subcutaneously. Cells from the capsules were characterized by FACS, single cell qPCR and RNA sequencing to determine the genetic profiles of those most responsible for fibrotic development. Further, SEM, TEM, 3D-confocal imaging and several stains.
Results: We found a significant decrease in fibrotic deposition in the capsules of our Wnt11 KO mice. Additionally, we found the predominant cells across different time-points were myeloid cells and not fibroblasts. We confirmed that these cells were macrophages able to produce ECM by subjecting them to FACS analysis. We found over 80% of the macrophages expressing collagen1.
Conclusion: Our findings exhibit that Wnt signaling&Wnt11 are essential to the progression of CF and suggest that Wnt11 inhibition can be applicable to therapeutics going forward. Additionally, we found a majority of macrophages expressing collagen1, denoting their impact as key mediators within fibrotic capsules as collagen-depositing macrophages. Our findings have widespread clinical implications for the treatment of fibrosis and allow us to develop solutions to therapeutically treat fibrosis.