enrichment-retinal-endothelial-cells-mller-glia-enable-comprehensive

Enrichment of Retinal Endothelial Cells and M&#252;ller Glia Enable Comprehensive scRNA-Seq Profiling of the Blood-Retinal Barrier

Obtaining high-quality single-cell suspensions from neural tissues such as the murine retina remains technically challenging due to cellular fragility, ...

University of Freiburg

Aberrant angiogenesis is a hallmark of cardiovascular and retinal neovascular disease. The STAT3 signaling pathway represents a potential pharmacological target for these diseases due to its impact on angiogenesis. Surprisingly, some STAT3 activators, such as the IL-6 cytokine family member oncostatin M (OSM), enhance angiogenesis, whereas others, such as ciliary neurotropic factor (CNTF), reduce it. This study aimed to clarify these conflicting effects. In contrast to the anti-angiogenic cytokine CNTF, the pro-angiogenic cytokine OSM was able to activate intracellular signaling pathways beyond the STAT3 pathway, including the ERK and AKT pathways. These differences translated into transcriptomic and metabolic shifts. siRNA-mediated STAT3 knockdown experiments showed a decrease in VEGF-induced endothelial migration and sprouting, enhancing the pro-angiogenic drive of OSM and switching the CNTF response from anti-angiogenic to pro-angiogenic. These effects correlated with a transcriptomic shift representing enhanced STAT1 and ERK activity following STAT3 knockdown, including a compensatory prolonged phosphorylated STAT1 activity. In conclusion, the angiogenic effect of STAT3 appears to be determined by cytokine-induced STAT3 specificity and simultaneous activity of other intracellular signaling pathways, whereas the STAT3 pathway, predominantly recognized for its pro-angiogenic phenotypes, reveals novel anti-angiogenic potential.

STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis.

The IL-6 cytokine family, with its crucial and pleiotropic intracellular signaling pathway STAT3, is a promising target for treating vasoproliferative retinal diseases. Previous research has shown that IL-6 cis-signaling (via membrane-bound receptors) and trans-signaling (via soluble receptors) can have distinct effects on target cells, leading to their application in various disease treatments. While IL-6 has been extensively studied, less is known about the angiogenic effects of IL-11, another member of the IL-6 family, in the retina. Therefore, the aim of this study was to characterize the effects of IL-11 on retinal angiogenesis.

Characterization of the angiomodulatory effects of Interleukin 11 cis- and trans-signaling in the retina.

Despite great advances in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. While resident vitreous macrophages called hyalocytes have been implicated in the pathophysiology of vitreoretinal proliferative disease previously, little is known about their exact role in PDR. In this study, we address molecular and cellular alterations in the vitreous of PDR patients as a means towards assessing the potential contribution of hyalocytes to disease pathogenesis.

The multifaceted role of vitreous hyalocytes: Orchestrating inflammation, angiomodulation and erythrophagocytosis in proliferative diabetic retinopathy.

Externalized Inflammasomes in Visceral Fat Sustain Obesity-Related Inflammation.

Vascular endothelial growth factor (VEGF) is regarded as the essential promoter of vitreoretinal vascular diseases that threaten eyesight, such as proliferative diabetic retinopathy (PDR). Therefore, VEGF is the primary therapeutic target in these diseases, but not all patients respond adequately to VEGF inhibition. This raises the question if other factors contribute to disease modulation. PDR evolves in an interplay of pathological processes including inflammation, barrier integrity loss, aberrant angiogenesis, and metabolic dysregulation. Interleukin-6 (IL-6), recognized for its pro-inflammatory properties, was the focus of this study.

Article	Year
STAT3 signaling induced by the IL-6 family of cytokines modulates angiogenesis. Journal of cell science\| PubMed ID: 36458801	2023
Characterization of the angiomodulatory effects of Interleukin 11 cis- and trans-signaling in the retina. Journal of neuroinflammation\| PubMed ID: 39294742	2024
The multifaceted role of vitreous hyalocytes: Orchestrating inflammation, angiomodulation and erythrophagocytosis in proliferative diabetic retinopathy. Journal of neuroinflammation\| PubMed ID: 39543723	2024
Externalized Inflammasomes in Visceral Fat Sustain Obesity-Related Inflammation. Circulation research\| PubMed ID: 41200821	2025
IL-6 trans-signaling: an overlooked driver of retinal neovascularization? Angiogenesis\| PubMed ID: 41417254	2025

Malte Jung

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