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Engrailed-positive Fibroblasts: The Primary Cell Type Present In Fibrotic Capsules During Foreign Body Response
Jennifer B. Parker, BSc, Michelle Griffin, MB BCh, MRCS, PhD, Amanda F. Spielman, BSc, MPH, Nicholas J. Guardino, BSc, Asha C. Cotterell, BSc, MSc, Derrick C. Wan, MD, Michael T. Longaker, MD, MBA.
Stanford University, Stanford, CA, USA.

PURPOSE: Scar formation is a typical component of the wound-healing process. Recently, our group established that En1 positive fibroblasts (EPFs) predominate in wounds and are derived from a subpopulation of En1 negative fibroblasts via mechanotransduction signalling. Meanwhile, foreign body response (FBR), wherein a fibrotic capsule forms around an implanted structure, is a common surgical implant complication. Though believed to have some mechanistic overlap with normal wound healing, much remains to be discovered about the specific mechanism by which this occurs.
METHODS: En1Cre transgenic driver mice were crossed with R26mTmG reporter mice, generating En1Cre; Rosa26mTmG (En1+) mice. In these mice, cells that express En1 also express GFP, while all other cells express RFP. Silicone discs were surgically implanted below the subcutaneous layer of En1+ mice dorsi, and fibrotic capsules surrounding the implants were harvested at POD30 (acute foreign body response) and 90 (chronic foreign body response). As many cell types are engaged in foreign body response, including fibroblast, macrophages, and neutrophils, we sought to identify which cell types were expressed by En1 positive cells, and to further characterize the cell types involved in fibrotic capsule formation using immunohistochemistry and FACS analysis.
RESULTS: Fibrotic capsules that formed around silicone implants in En1+ mice showed a higher number of En1-positive cells at POD 30 and 90 when compared to unwounded skin (*P<0.05, n=6). In unwounded skin, very few GFP+ cells were present. Immunohistochemistry staining revealed that GFP+ cells within the fibrotic capsules expressed pro-fibrotic markers such as Col-I, a-SMA, and Col-III. FACS analysis confirmed this observation. These cells were also negative for CD41 and CD45, endothelial and immune cell markers, respectively. These data indicate that En1-positive cells seen within fibrotic capsules were primarily of fibroblast origin.
CONCLUSION: As with normal wound healing, where EPFs are the primary cell type within a healing scar, our findings strongly suggest that En1 plays a key role in fibrotic capsule formation, and that these capsules are predominantly made up of EPFs. Further understanding of the specific molecular cues and lineage dynamics that drive fibrotic capsule formation during FBR may provide important insights into developing novel strategies targeting FBR.
Figure 1: Murine Foreign Response Model


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