Macrophages Acquire Fibroblast Characteristics in a Rat Model of Proliferative Vitreoretinopathy

Abstract

Purpose: Our aim was to establish a rat model of proliferative vitreoretinopathy (PVR) induced by macrophages and investigate whether macrophages can be a cell origin of fibroblast-like cells present in PVR. Methods: One eye of each rat received an intravitreal injection of macrophages. Clinical examination was performed to evaluate the development of PVR. Histological study was carried out to observe the pathological progression. Immunohistochemical staining with vimentin (VIM), glial fibrillary acidic protein (GFAP), α-smooth-muscle actin (α-SM actin), cytokeratin (CK) and CD68 characterized the cell types within the PVR membranes. The distribution, morphological change of prelabeled macrophages, as well as their colocalization with CD68, VIM, GFAP, α-SM actin and CK, were observed on days 3, 14 and 28 after injection. Results: In response to intravitreal injection of macrophages, 90% of the experimental rats developed PVR from postoperative day 7. The histological progression of PVR was characterized by the sequential appearance of inflammatory cell invasion, fibroblast proliferation and scar formation. The dominating cells comprising the proliferative membranes at the advanced stage were fibroblasts. Injected macrophages retained round shape and positive staining with CD68 on day 3. On day 28, they acquired elongated/spindle shape combined with intense staining of VIM but absence of CD68, GFAP, α-SM actin and CK, and became the primary constituent of fibrocellular membranes. Conclusions: Macrophages effectively and reproducibly induce the development of proliferative fibrocellular membranes in rats. In this PVR model, macrophages acquire fibroblast-like cell phenotype and contribute to fibrocellular membranes directly, suggesting that macrophages may be a cell origin of fibroblast-like cells involved in PVR.

FGF2-induced Ras/Erk MAPK signalling maintains lymphatic endothelial cell identity by up-regulating endothelial cell-specific gene expression and suppressing TGFβ signalling via Smad2

“…However, macrophages have been reported to incorporate into the endothelial layer of lymphatic vessels and occasionally transdifferentiate into LEC-like cells and/or aSMA-positive fibroblast-like cells during wound healing and proliferative eye diseases (Lin et al, 2011;Maruyama et al, 2007;Maruyama et al, 2005). Therefore, it remains to be elucidated whether aSMA-positive LECs arise during lymphedematous conditions.…”

Animal Models of Proliferative Vitreoretinopathy and Their Use in Pharmaceutical Investigations

“…A number of cells, including RPE, leukocytes, macrophage, glial cells, fibroblast-like cells, and others, are implicated in the development of PVR [39]. They not only constitute the pro liferative membrane but also serve as a source of growth factors.…”

“…Therefore, many animal models are designed to introduce exogenous cells into the vitreous cavity. Cell types include autologous or homologous fibroblast cells including dermal [40, 41], conjunctival [16, 19], corneal [42] and choroidal fibroblast [21], autologous, homologous or heterologous RPE cells [43-45], and activated macrophages [39, 46]. Evidence suggests that the primary factor in the development of traction RD and membrane formation are platelet-derived factors [1].…”

β-Catenin–regulated myeloid cell adhesion and migration determine wound healing

“…Macrophages are thought to have the capacity to attain cytological features similar to those in mesenchymal cells (36)(37)(38)(39)(40)(41). Such a phenotype might be related to their migratory capacity, as is the case in tumor cells during migration (8,32,42).…”