Pharmacologic fibroblast reprogramming into photoreceptors restores vision
| Autor: | Subrata Batabyal, Thomas Thomas Mock, Michael J. Forster, Aiguo Ni, Yan Fan, Delaney L Davis, Zongchao Han, Anand Swaroop, Nathalie Sumien, Wei Zhang, Ritu A. Shetty, Samarendra K. Mohanty, Rafal Farjo, Koray Dogan Kaya, Sai H. Chavala, Biraj Mahato |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
genetic structures Vision Disorders Mitochondrion Article 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Axin Protein PDE6B Retinal Rod Photoreceptor Cells medicine Basic Helix-Loop-Helix Transcription Factors Humans Animals Fibroblast Vision Ocular Multidisciplinary Chemistry Retinal Degeneration NF-kappa B Fibroblasts Cellular Reprogramming Flow Cytometry eye diseases Cell biology Mitochondria Transplantation Disease Models Animal Protein Transport 030104 developmental biology medicine.anatomical_structure Reflex sense organs Stem cell Reactive Oxygen Species Reprogramming 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | N Engl J Med Nature |
| ISSN: | 1476-4687 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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