Unveiling the cellular and molecular mechanisms of diabetic retinopathy with human retinal organoids

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F25%3A00083333" target="_blank" >RIV/65269705:_____/25:00083333 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/25:00143121

Výsledek na webu

<a href="https://www.nature.com/articles/s41419-025-08244-1" target="_blank" >https://www.nature.com/articles/s41419-025-08244-1</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41419-025-08244-1" target="_blank" >10.1038/s41419-025-08244-1</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Unveiling the cellular and molecular mechanisms of diabetic retinopathy with human retinal organoids

Popis výsledku v původním jazyce

Diabetic retinopathy (DR) is a leading cause of vision impairment worldwide, driven by chronic hyperglycaemia and its complex metabolic consequences. While animal models have been widely used to study DR, they often fail to replicate the physiology of the human retina. Here, we employed human retinal organoids to investigate the effects of incremental hyperglycaemic stress-a modest increase from a standard high-glucose baseline (17.5 mM) to 25 mM D-glucose-across different stages of retinal differentiation. Early-stage organoids demonstrated resilience to high-glucose levels, maintaining normal morphology, viability, and gene expression. In contrast, late-stage organoids exhibited marked photoreceptor vulnerability, including downregulation of outer segment (OS)-specific genes, shortened OSs, increased oxidative stress, astrocyte activation, and significantly higher levels of apoptosis. Transcriptomic analysis revealed substantial changes in pathways related to vision, including the G protein-coupled receptor signalling pathway, response to light stimulus, and visual perception. While photoreceptors were particularly vulnerable, other retinal cell types, including bipolar cells, ganglion cells, and M &amp; uuml;ller glia, showed greater resilience. Additionally, glial activation, evidenced by increased expression of astrocyte markers, suggested an adaptive response to hyperglycaemia. To validate our findings, we compared our dataset with publicly available transcriptomic datasets from human retinas with DR, confirming key overlaps in pathways related to photoreceptor dysfunction, gliogenesis, and oxidative stress responses. While this non-vascularised model does not replicate the onset of DR from physiological glucose levels, it provides a human-specific platform for dissecting the molecular mechanisms of neurodegeneration associated with incremental hyperglycaemic stress.

Název v anglickém jazyce

Unveiling the cellular and molecular mechanisms of diabetic retinopathy with human retinal organoids

Popis výsledku anglicky

Diabetic retinopathy (DR) is a leading cause of vision impairment worldwide, driven by chronic hyperglycaemia and its complex metabolic consequences. While animal models have been widely used to study DR, they often fail to replicate the physiology of the human retina. Here, we employed human retinal organoids to investigate the effects of incremental hyperglycaemic stress-a modest increase from a standard high-glucose baseline (17.5 mM) to 25 mM D-glucose-across different stages of retinal differentiation. Early-stage organoids demonstrated resilience to high-glucose levels, maintaining normal morphology, viability, and gene expression. In contrast, late-stage organoids exhibited marked photoreceptor vulnerability, including downregulation of outer segment (OS)-specific genes, shortened OSs, increased oxidative stress, astrocyte activation, and significantly higher levels of apoptosis. Transcriptomic analysis revealed substantial changes in pathways related to vision, including the G protein-coupled receptor signalling pathway, response to light stimulus, and visual perception. While photoreceptors were particularly vulnerable, other retinal cell types, including bipolar cells, ganglion cells, and M &amp; uuml;ller glia, showed greater resilience. Additionally, glial activation, evidenced by increased expression of astrocyte markers, suggested an adaptive response to hyperglycaemia. To validate our findings, we compared our dataset with publicly available transcriptomic datasets from human retinas with DR, confirming key overlaps in pathways related to photoreceptor dysfunction, gliogenesis, and oxidative stress responses. While this non-vascularised model does not replicate the onset of DR from physiological glucose levels, it provides a human-specific platform for dissecting the molecular mechanisms of neurodegeneration associated with incremental hyperglycaemic stress.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10601 - Cell biology

Projekt

<a href="/cs/project/NU22-07-00380" target="_blank" >NU22-07-00380: Aplikace retinálních buněk a organoidů ve funkční diagnostice a léčbě ztráty zraku u Bardet-Biedlova syndromu</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cell Death &amp; Disease

ISSN

2041-4889

e-ISSN

2041-4889

Svazek periodika

16

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

892

Kód UT WoS článku

001642805500002

EID výsledku v databázi Scopus

2-s2.0-105025377523