Harnessing the Neuroprotective Behaviors of Müller Glia for Retinal Repair

Abstract

Progressive and irreversible vision loss in mature and aging adults creates a health and economic burden, worldwide. Despite the advancements of many contemporary therapies to restore vision, few approaches have considered the innate benefits of gliosis, the endogenous processes of retinal repair that precede vision loss. Retinal gliosis is fundamentally driven by Müller glia (MG) and is characterized by three primary cellular mechanisms: hypertrophy, proliferation, and migration. In early stages of gliosis, these processes have neuroprotective potential to halt the progression of disease and encourage synaptic activity among neurons. Later stages, however, can lead to glial scarring, which is a hallmark of disease progression and blindness. As a result, the neuroprotective abilities of MG have remained incompletely explored and poorly integrated into current treatment regimens. Bioengineering studies of the intrinsic behaviors of MG hold promise to exploit glial reparative ability, while repressing neuro-disruptive MG responses. In particular, recent in vitro systems have become primary models to analyze individual gliotic processes and provide a stepping stone for in vivo strategies. This review highlights recent studies of MG gliosis seeking to harness MG neuroprotective ability for regeneration using contemporary biotechnologies. We emphasize the importance of studying gliosis as a reparative mechanism, rather than disregarding it as an unfortunate clinical prognosis in diseased retina.

Identifying Hmga2 preserving visual function by promoting a shift of Müller glia cell fate in mice with acute retinal injury

“…MG proliferation may contribute to establishing glial scar, or be an indicator of cellular de-differentiation for MG reprogramming [ 10 , 16 ]. We utilized EdU labeling to monitor proliferative MG in vivo during retinal injury process.…”

“…MG migration always takes place at the late stage of gliosis development [ 10 , 32 ]. From 3 to 14 dpi, we observed that some MG moved into the ONL which were also EdU positive, and the amount of migrated MG was gradually increased (Fig.…”

“…At the late stages of retinal injury, MG suffered gliosis fate as opposed to reprogramming fate, nevertheless [ 9 ]. MG gliosis is characterized by glial hypertrophy, the up-regulation of intermediate filament proteins, particularly glial fibrillary acidic protein (GFAP) and Vimentin, proliferation and migration [ 10 , 11 ]. Retinal injury finally triggers MG to establish a glial scar to fill retinal breaks and to replace degenerated neurons, prevents neuronal cell migration, axonal regrowth, and limits endogenous regeneration [ 12 – 14 ].…”

BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps

“…This may be a phenomenon that is intrinsic to RGCs, but at this time we cannot rule out that this process is influenced by surrounding cells, such as supporting macro- and microglia that are responding to the damaged environment. Such responses could be the generation of trophic factors, clearance mechanisms of damaged RGC compartments, and the efforts to maintain ion homeostasis and synaptic function ( 74 , 75 , 76 ).…”

MicroRNA-152-3p and MicroRNA-196a-5p Are Downregulated When Müller Cells Are Promoted by Components of the Internal Limiting Membrane: Implications for Macular Hole Healing

“…Additionally, reactive Müller cells are capable of re-entering the cell cycle in preparation for proliferation [41]. In response to retinal injuries, Müller cells undergo three primary gliotic changes-hypertrophy, proliferation, and migration-to protect the remaining healthy tissue [42]. A temporal window exists before gliosis transitions into a chronic scar, during which directing Müller cells in gliotic tissue to dedifferentiate into progenitor cells and regenerate retinal neurons, as observed in lower vertebrates, may be plausible.…”