Retinal cell death dependent reactive proliferative gliosis in the mouse retina

Abstract

Neurodegeneration is a common starting point of reactive gliosis, which may have beneficial and detrimental consequences. It remains incompletely understood how distinctive pathologies and cell death processes differentially regulate glial responses. Müller glia (MG) in the retina are a prime model: Neurons are regenerated in some species, but in mammals there may be proliferative disorders and scarring. Here, we investigated the relationship between retinal damage and MG proliferation, which are both induced in a reproducible and temporal order in organotypic culture of EGF-treated mouse retina: Hypothermia pretreatment during eye dissection reduced neuronal cell death and MG proliferation; stab wounds increased both. Combined (but not separate) application of defined cell death signaling pathway inhibitors diminished neuronal cell death and maintained MG mitotically quiescent. The level of neuronal cell death determined MG activity, indicated by extracellular signal-regulated kinase (ERK) phosphorylation, and proliferation, both of which were abolished by EGFR inhibition. Our data suggest that retinal cell death, possibly either by programmed apoptosis or necrosis, primes MG to be able to transduce the EGFR–ERK activity required for cell proliferation. These results imply that cell death signaling pathways are potential targets for future therapies to prevent the proliferative gliosis frequently associated with certain neurodegenerative conditions.

EGFR inhibitor, AG1478, inhibits inflammatory infiltration and angiogenesis in mice with diabetic retinopathy

“…In the retina, EGFR is highly expressed in several retinal cells, including retinal pigment epithelium (RPE) and Müller cells . Additionally, EGFR appears to crucially regulate epithelial mesenchymal migration and proliferation of RPE and Müller cells . These findings implicate EGFR in regulation of retinal function in DR.…”

Ferrochelatase regulates retinal neovascularization

“…In OIR experiments, at various time points, pups were euthanized by decapitation, and the eyes were enucleated and fixed in 4% PFA for 2 hours at room temperature. The retinal flatmounts were prepared and immunostained as per a previously published protocol (45). Briefly, after removal of the optic nerve, the anterior eye parts and lens from the mouse eyes, neural retina was carefully dissected from the RPE-choroidsclera complex and transferred to a glass slide.…”

Regenerative medicine in the retina: from stem cells to cell replacement therapy

“…Although retinal structure and metabolism is highly conserved among mammals, and the eye has an active immune privilege mechanism, the functional integration of xenotransplants into rodent retinas is not comparable to syngeneic and allogeneic transplants in patients. Furthermore, retinal immune privilege should not be overstated when considering transplantation into a neurodegenerative environment, within which ongoing gliosis, 159 inflammation and immune infiltration can change the microenvironment significantly from what is being observed within healthy hosts. 160 …”