More than a decade ago, we observed an accumulation of numerous Nkx2.2-positive cells in the IPL of NMDA (
N-methyl-
d-aspartate)-damaged retinas (
Fig. 4; Fischer and Reh, unpublished observations, 2001). This finding was unexpected, and the identity of these cells was uncertain. Thus, we shelved these data without having a reasonable interpretation. These cells were again observed several years later, while we were investigating the effects of insulin and IGF1 on cell-signaling and Müller glia, and we decided to pay more attention to their accumulation within the IPL. We observed accumulations of Nkx2.2/transitin-positive cells scattered across the IPL of treated retinas.
32,33 Based on their morphology and position within the retina, we believed that these cells were microglialike cells. However, the cells were negative for the microglial markers CD45, RCA1, and lysosomal membrane glycoprotein.
32 Based on the phenotype and location within the retina, we termed these cells nonastrocytic inner retinal glial (NIRG) cells.
32 NIRG cells are distinctly different from Müller glia and oligodendrocytes; these cells were positive for Sox2, Sox9, Nkx2.2, vimentin and transitin, but were negative for other well-established glial markers, including glutamine synthetase, Pax2, GFAP, S100β, 2M6 (Top
AP), and transferin-binding protein.
32 We propose that the NIRG cells are not a type of astrocyte, because they are negative for both GFAP and Pax2, they are not associated with blood vessels (unlike most astrocytes in mammalian retinas), and they do not upregulate GFAP in response to damage.
32,57 In all species examined, retinal astrocytes express GFAP and Pax2, and GFAP expression is dramatically increased in damaged tissues.
57,58 Although NIRG-like cells were not observed in the retinas of mice or guinea pigs, they have been found in the retinas of dogs and monkeys,
59 suggesting the presence of similar cells in the eyes of humans.