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Pharmacologic fibroblast reprogramming into photoreceptors restores vision
- Source :
- N Engl J Med, Nature
- Publication Year :
- 2018
-
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. 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14764687
- Volume :
- 581
- Issue :
- 7806
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....30a0d21334b59c13cad38639f8533313