Muller Glia: A Promising Target for Therapeutic Regeneration

In the past 10 years, there has been a paradigm shift in our understanding of brain development and approaches to treat degenerative diseases, including those that affect the retina. The latest knowledge includes (1) the discovery that the adult brain harbors proliferating progenitors and that neurons are born throughout life, particularly in the subventricular zone (SVZ) of the lateral ventricle and the subgranular layer (SGL) of the dentate gyrus of the hippocampus(1) and (2) the observation that glia perform dual functions, providing homeostatic support and serving as the source of stem cells in the embryonic brain and the adult SVZ and SGL.(2) In contrast to the SVZ and SGL, active neurogenesis has not been detected in adult mammalian retina. However, neurogenic changes have been observed in injured retina, and the source of injury-induced neurogenesis is traced to Muller glia, the sole glial cells generated by multipotential retinal progenitors. Recent evidence that a subset of Muller glia possesses an evolutionarily conserved stem cell potential has posited these cells as a viable target for replacing degenerating neurons in diseases such as age-related macular degeneration, retinitis pigmentosa, and glaucoma, where vision loss is due to the degeneration of specific types of neurons. This approach has the potential to effectively address significant barriers, such as the lack of a renewable source of cells that are nonimmunogenic and nonteratogenic, which currently makes ex vivo cell therapy approach impractical. This review describes the recent progress made in our understanding of the stem cell properties and regenerative potential of Muller glia and includes a discussion of (1) the development of Muller glia; (2) the neurogenic potential of Muller glia across species; (3) the characterization of Muller glia as stem cells; (4) the facile activation of Muller glia; and (5) the molecular mechanisms underlying the stemness (i.e., stem-like properties) of Muller glia. This information is critical in making potential therapeutic approaches effective, efficient, predictable, and safe. This review does not include the homeostatic functions of Muller glia; readers are referred to an excellent review on the topic by Bringmann et al.(3)