Global Transcriptional and Epigenetic Reconfiguration during Chemical Reprogramming of Human Retinal Pigment Epithelial Cells into Photoreceptor-like Cells

Retinal degenerative diseases are frequently caused by the loss of retinal neural cells such as photoreceptors. Cell replacement is regarded as one of the most promising therapies. Multiple types of stem and somatic cells have been tested for photoreceptor conversion. However, current induction effi...

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Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2022-10, Vol.11 (19), p.3146
Main Authors: Deng, Xiaoqian, Lee, Ryan, Lim, Sin Yee, Zhong, Zheng, Wang, Jing, Liu, Yizhi, Fan, Guoping
Format: Article
Language:English
Subjects:
Analysis
Antibodies
Care and treatment
chemical reprogramming
Degenerative diseases
Diagnosis
DNA methylation sequencing
Efficiency
Epigenetics
Fetuses
Fibroblasts
Genetic aspects
Glutamic acid receptors
Growth factors
Health aspects
human retinal pigment epithelial cells
Mesenchyme
Methylation
Molecular modelling
photoreceptor-like cells
Photoreceptors
Receptor mechanisms
Retina
Retinal degeneration
Retinal diseases
Retinal pigment epithelium
RNA sequencing
single-cell RNA sequencing
Somatic cells
Stem cells
Transplantation
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Summary:Retinal degenerative diseases are frequently caused by the loss of retinal neural cells such as photoreceptors. Cell replacement is regarded as one of the most promising therapies. Multiple types of stem and somatic cells have been tested for photoreceptor conversion. However, current induction efficiencies are still low and the molecular mechanisms underlying reprogramming remain to be clarified. In this work, by combining treatment with small molecules, we directly reprogrammed human fetal retinal pigment epithelial (RPE) cells into chemically induced photoreceptor-like cells (CiPCs) in vitro. Bulk and single-cell RNA sequencing, as well as methylation sequencing, were performed to understand the transcriptional and epigenetic changes during CiPCs conversion. A multi-omics analysis showed that the direct reprogramming process partly resembled events of early retina development. We also found that the efficiency of CiPCs conversion from RPE is much better than that from human dermal fibroblasts (HDF). The small molecules effectively induced RPE cells into CiPCs via suppression of the epithelial-to-mesenchymal transition (EMT). Among the signaling pathways involved in CiPCs conversion, glutamate receptor activation is prominent. In summary, RPE cells can be efficiently reprogrammed into photoreceptor-like cells through defined pharmacological modulations, providing a useful cell source for photoreceptor generation in cell replacement therapy for retinal degenerative diseases.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11193146