Regeneration of retinal ganglion cell-like cells and reconstruction of visual neural circuits in mice with glaucoma

Glaucoma is an irreversible blinding eye disease characterized by apoptosis of mature neurons-retinal ganglion cells (RGCs), visual field defect and vision loss. Regeneration of RGCs and reconstruction of the neural connections between the retina and the brain is considered an effective strategy to promote visual restoration in patients with glaucoma. However, there are currently no effective methods for regenerating RGCs to restore vision in clinical practice. Microglia are a type of glial cells that regulate the immune response in the retina and central nervous system (CNS), whether they have pluripotency and be reversed into RGCs remains unclear and challenging. This study revealed that the ectopic expression of multiple genes (Brn3b, Sox2, Cbln1, and NP1, referred to as BSCN) in microglia can promote their conversion into RGC-like cells by microglia fate lineage tracing in vivo. The regenerated RGC-like cells project axons to the distant brain and reconstruct the visual neural circuit, restoring the impaired vision in adult mice with acute glaucoma induced by retinal ischemia-reperfusion (I/R) injury. Furthermore, the regenerated RGC-like cells could survive stably for up to one year, and the same regeneration strategy was performed in older mice with acute glaucoma, which confirmed the effectiveness of the BSCN reprogramming to regenerate RGC-like cells. In summary, we have identified the microglia as a new type of reprogramming seed cells, and four key genes were found to be involved in regenerating RGC-like cells to restore vision. These findings highlight a new strategy of RGC-like cell regeneration and provide a theoretical basis for treatment of glaucoma in the future.