Are Müller glial cells gatekeepers of neuroprotection and regeneration in age-related macular degeneration? Unraveling their roles in pathophysiology and therapeutic innovation

Age-related macular degeneration (AMD) is traditionally conceptualized as a disorder of the retinal pigment epithelium (RPE)-photoreceptor axis; however, this paradigm incompletely explains early disease dynamics and therapeutic failure in geographic atrophy (GA). This review aims to reframe AMD progression through a Müller glial cell-centered framework that integrates cellular homeostasis, structural transitions, and stage-dependent therapeutic implications. Emerging transcriptomic, histologic, and functional evidence demonstrates that Müller glial cells actively participate in AMD pathobiology, including complement regulation, metabolic coupling, redox control, and inflammatory signaling. In early AMD, Müller glial cells exhibit adaptive responses that preserve retinal integrity despite increasing metabolic and extracellular stress. Progressive accumulation of basal laminar deposits and extracellular remodeling may impose diffusion constraints and inflammatory burden, thereby promoting glial reprogramming. A critical transition occurs with descent of the external limiting membrane (ELM), which corresponds to the loss of photoreceptor support, disruption of retinal compartmentalization, and onset of irreversible degeneration. Beyond this threshold, Müller glial cells undergo structural remodeling and contribute to the formation of subretinal glial membranes, reflecting a shift from homeostatic support to containment. This framework proposes a biologically testable staging axis from preserved Müller glial cell function to progressive dysfunction, aligning disease progression with therapeutic windows. Pre-ELM stages are characterized by retained plasticity and suitability for neuroprotective and metabolic interventions, whereas post-ELM stages require strategies focused on stabilization and limiting degeneration. Importantly, most current clinical trials do not explicitly incorporate Müller glial cell state or ELM integrity as stratification variables, potentially contributing to insensitive or diluted outcome assessment. In conclusion, Müller glial cells may function as central integrators of retinal homeostasis and disease progression in AMD. Integrating glial biology with structural biomarkers may enable stage-specific precision therapies and improve clinical trial design.