Pharmacologic fibroblast reprogramming into photoreceptors restores vision

Biraj Mahato, Koray Dogan Kaya, Yan Fan, Nathalie Sumien, Ritu A. Shetty, Wei Zhang, Delaney Davis, Thomas Mock, Subrata Batabyal, Aiguo Ni, Samarendra Mohanty, Zongchao Han, Rafal Farjo, Michael J. Forster, Anand Swaroop, Sai H. Chavala

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Photoreceptor loss is the final common endpoint in most retinopathies that lead to irreversible blindness, and there are no effective treatments to restore vision1,2. 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.

Original languageEnglish
Pages (from-to)83-88
Number of pages6
JournalNature
Volume581
Issue number7806
DOIs
StatePublished - 7 May 2020

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    Mahato, B., Kaya, K. D., Fan, Y., Sumien, N., Shetty, R. A., Zhang, W., Davis, D., Mock, T., Batabyal, S., Ni, A., Mohanty, S., Han, Z., Farjo, R., Forster, M. J., Swaroop, A., & Chavala, S. H. (2020). Pharmacologic fibroblast reprogramming into photoreceptors restores vision. Nature, 581(7806), 83-88. https://doi.org/10.1038/s41586-020-2201-4