Dataset Information

Vegf signaling between Muller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration.

ABSTRACT: In the zebrafish retina, Müller glia (MG) can regenerate retinal neurons lost to injury or disease. Even though zebrafish MG share structure and function with those of mammals, only in zebrafish do MG function as retinal stem cells. Previous studies suggest dying neurons, microglia/macrophage, and T cells contribute to MG's regenerative response [White et al., Proc. Natl. Acad. Sci. U.S.A. 114, E3719 (2017); Hui et al., Dev. Cell 43, 659 (2017)]. Although MG end-feet abut vascular endothelial (VE) cells to form the blood-retina barrier, a role for VE cells in retina regeneration has not been explored. Here, we report that MG-derived Vegfaa and Pgfa engage Flt1 and Kdrl receptors on VE cells to regulate MG gene expression, Notch signaling, proliferation, and neuronal regeneration. Remarkably, vegfaa and pgfa expression is regulated by microglia/macrophages, while Notch signaling in MG is regulated by a Vegf-dll4 signaling system in VE cells. Thus, our studies link microglia/macrophage, MG, and VE cells in a multicomponent signaling pathway that controls MG reprogramming and proliferation.

SUBMITTER: Mitra S

PROVIDER: S-EPMC9897474 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Vegf signaling between Müller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration.

Mitra Soumitra S Devi Sulochana S Lee Mi-Sun MS Jui Jonathan J Sahu Aresh A Goldman Daniel D

Proceedings of the National Academy of Sciences of the United States of America 20221205 50

In the zebrafish retina, Müller glia (MG) can regenerate retinal neurons lost to injury or disease. Even though zebrafish MG share structure and function with those of mammals, only in zebrafish do MG function as retinal stem cells. Previous studies suggest dying neurons, microglia/macrophage, and T cells contribute to MG's regenerative response [White et al., Proc. Natl. Acad. Sci. U.S.A. 114, E3719 (2017); Hui et al., Dev. Cell 43, 659 (2017)]. Although MG end-feet ...[more]

PMID: 36469778

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Project description:Upon retinal injury, zebrafish Müller glia (MG) transition from a quiescent supportive cell to a progenitor cell (MGPC). This event is accompanied by the induction of key transcription and pluripotency factors. Because somatic cell reprogramming during iPSC generation is accompanied by changes in DNA methylation, especially in pluripotency factor gene promoters, we were interested in determining if DNA methylation changes also underlie MG reprogramming following retinal injury. Consistent with this idea, we found that genes encoding components of the DNA methylation/demethylation machinery were induced in MGPCs and that manipulating MGPC DNA methylation with 5-aza-2’-deoxycytidine altered their properties. A comprehensive analysis of the DNA methylation landscape as MG reprogram to MGPCs revealed that demethylation predominates at early times, while levels of de novo methylation increase at later times. We found that these changes in DNA methylation were largely independent of Apobec2 protein expression. A correlation between promoter DNA demethylation and injury-dependent gene induction was noted. In contrast to iPSC formation, we found that pluripotency factor gene promoters were already hypomethylated in quiescent MG and remained unchanged in MGPCs. Interestingly, these pluripotency factor promoters were also found to be hypomethylated in mouse MG. Our data identify a dynamic DNA methylation landscape as zebrafish MG transition to a MGPC and suggest that DNA methylation changes will complement other regulatory mechanisms to ensure gene expression programs controlling MG reprogramming are appropriately activated during retina regeneration. Reduced representation bisulfite sequencing (MspI,~40-220bp size fraction) of zebrafish MG before and after injury. This dataset includes 4 replicated samples: The MG samples report the genomic methylation of a quiescent state. The 4dpi MGPC sampes report the methylation of a dedifferentiated, proliferating progenitor. The 2dpi morpholino samples report the genomic methylation of a dedifferentiated MGPC following a conrtol or Apobec2a,2b knockdown.

Dataset Information

Vegf signaling between Muller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration.

Publications

Vegf signaling between Müller glia and vascular endothelial cells is regulated by immune cells and stimulates retina regeneration.

Similar Datasets

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