Dataset Information

Fullerol rescues the light-induced retinal damage by modulating Muller glia cell fate.

ABSTRACT: Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation remain unclear. Therefore, we established a MG lineage-tracing mouse model of light-induced retinal damage to examine the therapeutic effects of fullerol. Fullerol exhibited superior protection against light-induced retinal injury compared to glutathione (GSH) and reduced oxidative stress levels, inhibited gliosis by suppressing the TGF-β pathway, and enhanced the de-differentiation of MG cells. RNA sequencing revealed that transcription candidate pathways, including Nrf2 and Wnt10a pathways, were involved in fullerol-induced neuroprotection. Fullerol-mediated transcriptional changes were validated by qPCR, Western blotting, and immunostaining using mouse retinas and human-derived Müller cell lines MIO-M1 cells, confirming that fullerol possibly modulated the Nrf2, Wnt10a, and TGF-β pathways in MG, which suppressed gliosis and promoted the de-differentiation of MG in light-induced retinal degeneration, indicating its potential in treating retinal diseases.

SUBMITTER: Cha Z

PROVIDER: S-EPMC10570010 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Fullerol rescues the light-induced retinal damage by modulating Müller glia cell fate.

Cha Zhe Z Yin Zhiyuan Z A Luodan L Ge Lingling L Yang Junling J Huang Xiaona X Gao Hui H Chen Xia X Feng Zhou Z Mo Lingyue L He Juncai J Zhu Shuang S Zhao Maoru M Tao Zui Z Gu Zhanjun Z Xu Haiwei H

Redox biology 20231005

Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation rem ...[more]

PMID: 37816275

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Project description:BackgroundUnlike in lower vertebrates, Müller glia (MG) in adult mammalian retinas lack the ability to reprogram into neurons after retinal injury or degeneration and exhibit reactive gliosis instead. Whether a transition in MG cell fate from gliosis to reprogramming would help preserve photoreceptors is still under exploration.MethodsA mouse model of retinitis pigmentosa (RP) was established using MG cell lineage tracing mice by intraperitoneal injection of sodium iodate (SI). The critical time point for the fate determination of MG gliosis was determined through immunohistochemical staining methods. Then, bulk-RNA and single-cell RNA seq techniques were used to elucidate the changes in RNA transcription of the retina and MG at that time point, and new genes that may determine the fate transition of MG were screened. Finally, the selected gene was specifically overexpressed in MG cells through adeno-associated viruses (AAV) in the mouse RP model. Bulk-RNA seq technique, immunohistochemical staining methods, and visual function testing were used to elucidate and validate the mechanism of new genes function on MG cell fate transition and retinal function.ResultsHere, we found the critical time point for MG gliosis fate determination was 3 days post SI injection. Hmga2 was screened out as a candidate regulator for the cell fate transition of MG. After retinal injury caused by SI, the Hmga2 protein is temporarily and lowly expressed in MG cells. Overexpression of Hmga2 in MG down-regulated glial cell related genes and up-regulated photoreceptor related genes. Besides, overexpressing Hmga2 exclusively to MG reduced MG gliosis, made MG obtain cone's marker, and retained visual function in mice with acute retinal injury.ConclusionOur results suggested the unique reprogramming properties of Hmga2 in regulating the fate transition of MG and neuroprotective effects on the retina with acute injury. This work uncovers the reprogramming ability of epigenetic factors in MG.

Project description:Rationale: Müller glia (MG) play a key role in maintaining homeostasis of the retinal microenvironment. In zebrafish, MG reprogram into retinal progenitors and repair the injured retina, while this MG regenerative capability is suppressed in mammals. It has been revealed that microglia in zebrafish contribute to MG reprogramming, whereas those in mammals are over-activated during retinal injury or degeneration, causing chronic inflammation, acceleration of photoreceptor apoptosis, and gliosis of MG. Therefore, how to modulate the phenotype of microglia to enhance MG reprogramming rather than gliosis is critical. Methods: PLX3397, a colony-stimulating factor 1 receptor inhibitor, was applied to deplete microglia in the retinas of retinal degeneration 10 (rd10) mice, and withdrawal of PLX3397 was used to induce the repopulated microglia (Rep-MiG). The protective roles of the Rep-MiG on the degenerative retina were assessed using a light/dark transition test, and scotopic electroretinogram recordings. Immunofluorescence, western blot, transcriptomic sequencing, and bioinformatics analysis were performed to investigate the effects and mechanisms of microglia on MG reprogramming. Results: Following PLX3397 withdrawal, Rep-MiG replenished the entire retina with a ramified morphology and significantly improved the retinal outer nuclear layer structure, the electroretinography response, and the visual behavior of rd10 mice. Coincidentally, MG were activated, de-differentiated, and showed properties of retina progenitors in a spatial correlation with Rep-MiG. Morphological and transcriptomic analyses revealed Rep-MiG significantly enhanced protease inhibitor activity and suppressed extracellular matrix (ECM) levels during retinal degeneration. Conclusions: It suggested that Rep-MiG with the homeostasis characteristic stimulated the progenitor cell-like properties of MG, probably through regulating ECM remodeling, which protected photoreceptors and improved visual function of rd10 mice. It might be a potential protocol to reprogram MG and delay mammal retinal degeneration.

Dataset Information

Fullerol rescues the light-induced retinal damage by modulating Muller glia cell fate.

Publications

Fullerol rescues the light-induced retinal damage by modulating Müller glia cell fate.

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