Pharmacologic fibroblast reprogramming into photoreceptors restores vision

• Published in: Nature (London) Vol. 581; no. 7806; pp. 83 - 88
• Main Authors: Mahato, Biraj, Kaya, Koray Dogan, Fan, Yan, Sumien, Nathalie, Shetty, Ritu A., Zhang, Wei, Davis, Delaney, Mock, Thomas, Batabyal, Subrata, Ni, Aiguo, Mohanty, Samarendra, Han, Zongchao, Farjo, Rafal, Forster, Michael J., Swaroop, Anand, Chavala, Sai H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2020; Nature Publishing Group
• Subjects: 13; 13/107; 631/532; 631/532/2435; Analysis; Animals; ASCL1 protein; Axin Protein - metabolism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Blindness; Care and treatment; Cellular Reprogramming - drug effects; Chemical properties; Control; Degeneration; Diabetic retinopathy; Disease Models, Animal; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Flow Cytometry; Gene expression; Humanities and Social Sciences; Light; Methods; Mice; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; multidisciplinary; NF-kappa B - metabolism; NF-κB protein; Nuclear reprogramming; Oxygen; Pharmacology, Experimental; Phosphodiesterase; Photoreception; Photoreceptors; Protein Transport - drug effects; Reactive oxygen species; Reactive Oxygen Species - metabolism; Restoration; Retinal Degeneration - pathology; Retinal Degeneration - therapy; Retinal diseases; Retinal Rod Photoreceptor Cells - cytology; Retinal Rod Photoreceptor Cells - drug effects; Retinal Rod Photoreceptor Cells - transplantation; Science; Science (multidisciplinary); Signal Transduction - drug effects; Stem cells; Transcription factors; Translocation; Transplantation; Vision; Vision, Ocular - drug effects; Vision, Ocular - physiology; Visual perception; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2201-4

Photoreceptor loss is the final common endpoint in most retinopathies that lead to irreversible blindness, and there are no effective treatments to restore vision 1 , 2 . Chemical reprogramming of fibroblasts offers an opportunity to reverse vision loss; however, the generation of sensory neuronal subtypes such as photoreceptors remains a challenge. Here we report that the administration of a set of five small molecules can chemically induce the transformation of fibroblasts into rod photoreceptor-like cells. The transplantation of these chemically induced photoreceptor-like cells (CiPCs) into the subretinal space of rod degeneration mice (homozygous for rd1 , also known as Pde6b ) leads to partial restoration of the pupil reflex and visual function. We show that mitonuclear communication is a key determining factor for the reprogramming of fibroblasts into CiPCs. Specifically, treatment with these five compounds leads to the translocation of AXIN2 to the mitochondria, which results in the production of reactive oxygen species, the activation of NF-κB and the upregulation of  Ascl1 . We anticipate that CiPCs could have therapeutic potential for restoring vision. A set of five small molecules can induce the transformation of fibroblasts into rod photoreceptor-like cells, which can partially restore pupil reflex and visual function when transplanted into a rod degeneration mouse model.