ASCL1 induces neurogenesis in human Müller glia

• Published in: Stem cell reports Vol. 18; no. 12; pp. 2400 - 2417
• Main Authors: Wohlschlegel, Juliette, Finkbeiner, Connor, Hoffer, Dawn, Kierney, Faith, Prieve, Aric, Murry, Alexandria D., Haugan, Alexandra K., Ortuño-Lizarán, Isabel, Rieke, Fred, Golden, Sam A., Reh, Thomas A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.12.2023; Elsevier
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Cell Proliferation - physiology; Ependymoglial Cells - metabolism; Humans; Mammals - metabolism; Mice; Neurogenesis - physiology; Neuroglia - metabolism; Neurons - metabolism; Retina - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2023.10.021

In mammals, loss of retinal cells due to disease or trauma is an irreversible process that can lead to blindness. Interestingly, regeneration of retinal neurons is a well established process in some non-mammalian vertebrates and is driven by the Müller glia (MG), which are able to re-enter the cell cycle and reprogram into neurogenic progenitors upon retinal injury or disease. Progress has been made to restore this mechanism in mammals to promote retinal regeneration: MG can be stimulated to generate new neurons in vivo in the adult mouse retina after the over-expression of the pro-neural transcription factor Ascl1. In this study, we applied the same strategy to reprogram human MG derived from fetal retina and retinal organoids into neurons. Combining single cell RNA sequencing, single cell ATAC sequencing, immunofluorescence, and electrophysiology we demonstrate that human MG can be reprogrammed into neurogenic cells in vitro. •MG develop in the PF as early as fetal day 59, earlier than previously known•Human MG can be derived from fetal retina or retinal organoids and grown as dissociated cells•Expression of the pro-neural TF ASCL1 can reprogram human MG to a neurogenic state•Neurons derived from human MG resemble immature amacrine and ganglion cells Loss of neurons in the human retina is an irreversible process. Using human MG cultures, we demonstrated that over-expression of the pro-neural factor ASCL1 in vitro can stimulate the production of immature amacrine and ganglion cells. Our data provide a proof of principle of intrinsic retinal regeneration in the human retina.