Open AccessPharmacologic fibroblast reprogramming into photoreceptors restores vision
Author(s) -
Biraj Mahato,
Koray Dogan Kaya,
Yan Fan,
Nathalie Sumien,
Ritu A. Shetty,
Wei Zhang,
Delaney L Davis,
Thomas Möck,
Subrata Batabyal,
Aiguo Ni,
Samarendra Mohanty,
Zongchao Han,
Rafal Farjo,
Michael J. Forster,
Anand Swaroop,
Sai H. Chavala
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2201-4
Subject(s) - reprogramming , microbiology and biotechnology , retinitis pigmentosa , transplantation , downregulation and upregulation , biology , retinal degeneration , induced pluripotent stem cell , retina , neuroscience , chemistry , embryonic stem cell , cell , medicine , biochemistry , gene
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.