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Induction of a Müller glial-specific protective pathway safeguards the retina from diabetes induced damage

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posted on 2024-10-24, 16:08 authored by Cheng-Hui Lin, Man-Ru Wu, Bogdan Tanasa, Praveen Prakhar, Boxiong Deng, Alexander E. Davis, Liang Li, Alexander Xia, Yang Shan, Patrice E. Fort, Sui Wang

Abstract

Diabetes can lead to cell-type-specific responses in the retina, including vascular lesions, glial dysfunction and neurodegeneration, all of which contribute to retinopathy. However, the molecular mechanisms underlying these cell type-specific responses, and the cell types that are sensitive to diabetes have not been fully elucidated. Employing single cell transcriptomics, we profiled the transcriptional changes induced by diabetes in different retinal cell types in rat models as the disease progressed. Rod photoreceptors, a subtype of amacrine interneurons, and Müller glia exhibited rapid responses to diabetes at the transcript levels. Genes associated with ion regulation were upregulated in all three cell types, suggesting a common response to diabetes. Furthermore, focused studies revealed that while Müller glia initially increased the expression of genes playing protective roles, they cannot sustain this beneficial effect. We explored one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), and observed that depleting Zfp36 in rat Müller glial cells in vivo using AAV-based tools exacerbated diabetes-induced phenotypes, including glial reactivation, neurodegeneration, and vascular defects. Over-expression of Zfp36 slowed the development of these phenotypes. This work unveiled retinal cell types that are sensitive to diabetes and demonstrated that Müller glial cells can mount protective responses through Zfp36.







Article Highlights

1. In this study, we sought to unveil the molecular mechanisms underlying the diabetes-induced cell-type-specific responses, with the hope of advancing our understanding of diabetic retinopathy and informing therapeutic strategies.

2. Single cell transcriptomics revealed that retinal rod photoreceptors, A17 amacrine cells and Müller glia are sensitive to diabetes at the transcript levels.

3. Retinal Müller glial cells upregulate potential protective genes in response to diabetes but failed to sustain this beneficial effect.

4. Enhanced Zfp36 expression in retinal Müller glial cells alleviates diabetes-induced damage in the retina.

Funding

American Diabetes Association 1-16-INI-16

U.S. Department of Health and Human Services > National Institutes of Health > National Eye Institute 1R01EY03258501 1R01EY033527 1R01EY03379201 1R21EY035465

NIH x P30EY007003 P30EY026877

Research to Prevent Blindness

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