Myo/Nog Cells Give Rise to Myofibroblasts During Epiretinal Membrane Formation in a Mouse Model of Proliferative Vitreoretinopathy

Abstract

Purpose Myo/Nog cells are the source of myofibroblasts in the lens and synthesize muscle proteins in human epiretinal membranes (ERMs). In the current study, we examined the response of Myo/Nog cells during ERM formation in a mouse model of proliferative vitreoretinopathy (PVR). Methods PVR was induced by intravitreal injections of gas and ARPE-19 cells. PVR grade was scored by fundus imaging, optical coherence tomography, and histology. Double label immunofluorescence localization was performed to quantify Myo/Nog cells, myofibroblasts, and leukocytes. Results Myo/Nog cells, identified by co-labeling with antibodies to brain-specific angiogenesis inhibitor 1 (BAI1) and Noggin, increased throughout the eye with induction of PVR and disease progression. They were present on the inner surface of the retina in grades 1/2 PVR and were the largest subpopulation of cells in grades 3 to 6 ERMs. All α-SMA-positive (+) cells and all but one striated myosin+ cell expressed BAI1 in grades 1 to 6 PVR. Folds and areas of retinal detachment were overlain by Myo/Nog cells containing muscle proteins. Low numbers of CD18, CD68, and CD45+ leukocytes were detected throughout the eye. Small subpopulations of BAI1+ cells expressed leukocyte markers. ARPE-19 cells were found in the vitreous but were rare in ERMs. Pigmented cells lacking Myo/Nog and muscle cell markers were present in ERMs and abundant within the retina by grade 5/6. Conclusions Myo/Nog cells differentiate into myofibroblasts that appear to contract and produce retinal folds and detachment. Targeting BAI1 for Myo/Nog cell depletion may be a pharmacological approach to preventing and treating PVR.

Myo/Nog Cells: The Jekylls and Hydes of the Lens

“…lineage [70]. We concluded that the death of human RPE cells was the likely stimulus for proliferation and migration of Myo/Nog cells and their engulfment of cell corpses [70], as occurs in other tissues, including the lens [68].…”

“…The next phase of our exploration of Myo/Nog cells involved characterizing their behaviors in normal and diseased tissues of adult mammals. Similar to the chick embryo, Myo/Nog cells are present in low numbers in all adult tissues and organs analyzed thus far, from mice to humans [ 16 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Within the eye, Myo/Nog cells are residents of the lens, cornea, ciliary body, retina and choroid [ 16 , 62 , 63 , 66 , 67 , 68 , 70 , 71 , 72 ] ( Figure 4 ).…”

“…Similar to the chick embryo, Myo/Nog cells are present in low numbers in all adult tissues and organs analyzed thus far, from mice to humans [ 16 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Within the eye, Myo/Nog cells are residents of the lens, cornea, ciliary body, retina and choroid [ 16 , 62 , 63 , 66 , 67 , 68 , 70 , 71 , 72 ] ( Figure 4 ). They also are present on the zonules of Zinn migrating towards the lens from the ciliary body [ 64 ] ( Figure 4 F).…”

“…Myo/Nog cells also phagocytose beads injected into the anterior chamber to induce glaucoma in mice , tattoo ink in human skin and dead cells in the retina [ 68 , 70 ]. Antibodies to markers of the monocyte lineage, ionized calcium binding adaptor molecule 1 (Iba1) and F4/80, did not bind to Myo/Nog cells in the skin, eyes or brain [ 16 , 61 , 68 , 72 ].…”

“…Antibodies to markers of the monocyte lineage, ionized calcium binding adaptor molecule 1 (Iba1) and F4/80, did not bind to Myo/Nog cells in the skin, eyes or brain [ 16 , 61 , 68 , 72 ]. However, CD68, which is expressed in microglia, macrophages, other leukocytes, fibroblasts and endothelial cells [ 90 , 91 ], was found in a small subpopulation of BAI1+/Noggin+ cells in a mouse model of proliferative vitreoretinopathy (PVR) in a study described below [ 70 ]. This was not surprising because both CD68 and BAI1 are receptors for phosphatidylserine (PS) present in the outer leaflet of the plasma membrane of apoptotic cells [ 19 , 20 , 92 , 93 ].…”