Reprogramming Mammal Müller Glial Cells for Retinal Neuroregeneration

Müller glia (MG) are the predominant nonneuronal cells of the vertebrate retina, playing an integral role in retinal homeostasis and photopic signal transmission. In lower vertebrates, MG retain robust regenerative potential, acting as a source of neuronal progenitors following injury. In contrast, mammalian MG primarily respond to damage with gliosis, a process that provides initial neuroprotection but ultimately restricts their neurogenic capacity. This limitation is especially consequential in humans, where genetic disorders and age-related diseases, such as diabetic retinopathy, glaucoma, and macular degeneration, lead to retinal neuron death and irreversible visual loss. One promising therapeutic strategy is to reprogram MG in vivo into stem-like progenitor cells capable of replacing lost neurons, with the expectation that these new cells can form functional synaptic circuits, replace lost neurons, and restore retinal function. Recent studies have reviewed the integrated regulatory network, encompassing signaling pathways, including Notch, Wnt/β-catenin, mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphatidylinositol 3-kinase/AKT, SMADs, and Hippo-YAP, alongside key transcription factors and epigenetic mechanisms, which collectively govern MG cell cycle re-entry and neurogenesis in mammals. This review synthesizes current knowledge of this integrated regulatory network, mainly focusing on the role of signaling pathways in MG regeneration, highlighting strategies to harness the intrinsic neurogenic potential of MG for retinal repair, underlining their promise as cellular targets for curing degenerative retinal diseases from intrinsic cellular sources.