Reprogramming Glia into Neurons Becomes Less Effective with Advancing Age
The research community is in the early stages of development of therapies for age-related neurodegeneration based on reprogramming the supporting glial cells of the brain to provoke transformation into neurons. A supply of new neurons can restore lost function, integrating into existing neural circuits. As noted here, however, much of this research and development has been conducted in young mice. In old mice, a combination of chronic inflammation and changes in glial cells acts to reduce the efficiency of reprogramming. Attempts to build therapies based on generating new neurons from glial cells will have to address these issues.
Reprogramming resident glia into neurons holds great therapeutic promise for neurodegenerative diseases across the central nervous system, yet these strategies have been developed largely in young animals. Because aging is the primary risk factor for neurodegeneration, whether glia-to-neuron reprogramming remains effective in aged tissue is a critical unanswered question. Here, using the retina as an accessible part of the central nervous system, we show that aging is a major barrier to glia-to-neuron reprogramming in vivo.
Across three transcription factor-based strategies, aged Müller glia exhibit consistently reduced neurogenesis. Single-cell transcriptomics reveal that aged glia fail to activate progenitor programs and instead adopt reactive and inflammatory states. Concurrently, the aged retina mounts an exacerbated neuroimmune response to injury. Immunomodulation with dexamethasone partially restores neurogenesis. Thus, aging imposes both glial-intrinsic and microenvironmental barriers to neuronal regeneration that can be partially overcome by immunomodulation.