Inhibiting the activation of MAPK (ERK1/2) in stressed Müller cells prevents photoreceptor degeneration
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE205370 | GEO | 2022/10/05
REPOSITORIES: GEO
Similar Datasets
Project description:This study has applied proteomic methodologies to compare protein expression profiles of gliotic and normal human retina as well as established human Müller stem cell lines. It is hoped that this investigation may provide insight into mechanisms of gliosis and also aid studies focusing on endogenous regeneration of the retina following disease or injury
2018-09-06 | PXD008485 | Pride
Project description:Müller cells are the main macroglial cells of the retina exerting a wealth of functions to maintain retinal homoeostasis. Upon pathological changes in the retina, they become gliotic with both protective and detrimental consequences. Accumulating data also provide evidence for a pivotal role of Müller cells in the pathogenesis of diabetic retinopathy (DR). While microglial cells, the resident immune cells of the retina are considered as main players in inflammatory processes associated with DR, the implication of activated Müller cells in chronic retinal inflammation remains to be elucidated. In order to assess the signaling capacity of Müller cells and their role in retinal inflammation, we performed in-depth proteomic analysis of Müller cell proteomes and secretomes after stimulation with INFγ, TNFα, IL-4, IL-6, IL-10, TGFβ1, TGFβ2 and TGFβ3. We used both, primary porcine Müller cells and the human Müller cell line MIO-M1 for our hypothesis generating approach. Our results point towards an intense signaling capacity of Müller cells, which reacted in a highly discriminating manner upon treatment with different cytokines. Stimulation of Müller cells results in a primarily pro-inflammatory phenotype with secretion of cytokines and components of the complement system. Furthermore, we observed evidence for mitochondrial dysfunction, implying oxidative stress after treatment with the various cytokines. Finally, both MIO-M1 cells and primary porcine Müller cells showed several characteristics of atypical antigen-presenting cells, as they are capable of inducing MHC class I and MHC class II with co-stimulatory molecules. In line with this, they express proteins associated with formation and maturation of phagosomes. Thus, our findings underline the importance of Müller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation underlying the pathogenesis of diabetic retinopathy.
2022-02-16 | PXD028390 | Pride
Project description:Rat Retinal Müller cells from diabetic rats (diabetes duration 6 months) compared to Rat Retinal Müller cells from healthy rats. Diabetes was induced by streptozotozine. Diabetic rats were treated with small doses of insulin to prevent catabolism. Keywords: ordered
2004-11-17 | E-GEOD-1979 | biostudies-arrayexpress
Project description:Here we have characterized the MoA of Erk inhibitors in terms of Erk1/2 signalling, gene expression and antiproliferative efficacy in BRAF and RAS mutant cell lines.
2020-10-08 | E-MTAB-7959 | biostudies-arrayexpress
Project description:Non-mammalian vertebrates have a robust ability to regenerate injured retinal neurons from Müller glia cells (MG) that activate the proneural factor Achaete-scute homolog 1 (Ascl1/Mash1) and de-differentiate into progenitors cells. In contrast, mammalian MG have a limited regenerative response and fail to upregulate Ascl1 after injury. To test whether Ascl1 could restore a neurogenic potential to mammalian MG, we over-expressed Ascl1 in dissociated mouse MG cultures and intact retinal explants. Ascl1-infected MG upregulate retinal progenitor-specific genes, while downregulating glial genes. Furthermore, Ascl1 remodeled the chromatin at its targets from a repressive to active configuration. MG-derived progenitors differentiated into cells that exhibited neuronal morphologies, expressed retinal subtype-specific neuronal markers, and displayed neuron-like physiological responses. These results indicate that a single transcription factor, Ascl1, can produce a neurogenic state in mature Muller glia. Expresssion profiling was used to determine the genes that were changed after Ascl1 infection of P12 cultured Müller glia compared with those present in P0 progenitors and P7-P21 Müller glia Retinas were dissociated and FAC-sorted from Hes5-GFP mice at P0, P7, P10, P14 or P21 and submitted for profiling. WT Retinas were dissociated at P12, grown for 1 week in culture, and infected with lentiviruses expressing Ascl1 or GFP for four days. Total RNA was extracted and submitted for profiling.
2013-04-06 | E-GEOD-45835 | biostudies-arrayexpress
Project description:As any other radial glia in the central nervous system, Müller glia derive from the same neuroepithelial precursors, perform similar functions and exhibit neurogenic properties as radial glia in the brain. Müller glial cells retain progenitor-like characteristics in the adult human eye, and can partially restore visual function upon intravitreal transplantation into animal models of glaucoma. Recently, it has been demonstrated that intracellular communication is possible via the secretion of nano-sized membrane-bound extracellular vesicles (EV), which contain bioactive molecules like microRNA (miRNA) and proteins that induce phenotypic changes when internalised by recipient cells. We conducted high-throughput sequencing to profile the microRNA signature of EV populations secreted by Müller glia in culture, and used bioinformatic tools to evaluate their potential role in the neuroprotective signalling attributed to these cells. Sequencing of miRNA within Müller EV suggested enrichment with species associated with stem cells such as miR-21 and miR-16, as well as with miRNA previously found to play a role in diverse Müller cell functions in the retina: miR-9, miR-125b and the let-7 family. A total of 51 miRNA were found to be differentially enriched in EV compared to whole cells from which EV originated. Bioinformatic analyses also indicated preferential enrichment of species demonstrated to regulate genes involved in cell proliferation and survival, including PTEN the master inhibitor of the PI3K/AKT pathway. The results suggest that the release by Müller cells of miRNA-enriched EV abundant in species that regulate anti-apoptotic signalling networks, is likely to represent a significant proportion of the neuroprotective effect observed after transplantation of these cells into animal models of retinal ganglion cell (RGC)-depletion. Future work will seek to evaluate the modulation of putative genes, as well as the activation of these pathways in in vitro and in vivo models following the internalisation of Müller-EV by target retinal neurons.
2024-01-03 | GSE245286 | GEO
Project description:Loss of neurons in the neural retina is a leading cause of vision loss. Retinal regeneration in zebrafish is attributed to Müller glia, which are activated, adopt a stem cell-like state, proliferate, and generate new neurons. Despite the same endogenous Müller glia being present in all vertebrates including humans, Müller glia activation in mammals leads to glial scarring instead of neurogenesis. Therefore, understanding Müller glia cellular states and molecular processes during zebrafish regeneration may allow us to improve mammalian regeneration. Since only a subset of Müller glia activate following neuron loss, we asked whether a specialised subset of Müller glia might be genetically primed for activation. Single-cell RNA sequencing (sc-RNAseq) from integrated zebrafish Müller glia samples reveals heterogeneity of gene expression across the quiescent Müller glia pool with 4 main clusters emerging, two of which are genetically similar. Labelling for key differentially expressed markers identified that these main clusters correlated with glia spatially distributed across dorsal, central and ventral retina. Using a genetically driven, chemically induced nitroreductase approach, three distinct photoreceptor types were ablated: the long (Lws2), short wavelength-sensitive (Sws2) and rod (Xops) photoreceptors, which also differ in their abundance. As expected, histological analysis of the three injuries and sc-RNAseq data for the two cone photoreceptor ablations identified common genetic program involved in the transition of Müller glia quiescence to activation, and differential responses to injury related to either injury extent or subtype of photoreceptor targeted. Interestingly, despite differences in the distributed across the retina, biased activation of Müller glia was observed in dorsal and central regions. Gene ontology analysis revealed that these injury-responsive dorsal and central Müller glia express genes related to dorsal/ventral pattern formation, growth factor activity, and regulation of developmental process. Müller glia upregulated genes related to homeostasis as well as certain AP-1 and injury-responsive transcription factors, followed by expression of genes involved in cell cycle, chromatin remodeling, and microtubule organisation. Prior to cell cycle entry, Müller glia show a transient upregulation of genes involved in gliogenesis, and Notch signalling. These findings enhance our understanding of heterogeneous states of quiescent Müller glia, and how these differences relate to activation and regeneration potential following neural ablation. A comparison of the distinct quiescent Müller glia with glia states in mammals will reveal key molecular pathways that could be targeted for improved mammalian neural regeneration.
2023-08-21 | GSE218107 | GEO
Project description:ERK/MAPK pathway is one of the highly activated and a crucial player in gastric cancer proliferation and progression. To delineate the complex transcription program associated with ERK/MAPK pathway, PD98059 a known ERK/MAPK inhibitor was treated in AGS, one of the ERK/MAPK signaling pathway over expressed gastric cancer cell line. The resultant changes in genome-wide mRNA expression pattern between control and PD98059 treated was profiled using Human Gene 1.0 ST arrays.
2021-12-11 | GSE163545 | GEO
Project description:Müller cells are the primary glia of the neural retina and play crucial roles in maintaining the structural and functional homeostasis of the retina. Müller cells also possess certain levels of retinal regeneration capacity, especially in lower vertebrates. In this study, we deep sequenced the transcriptomes and methylomes of mouse Müller cells and early retinal progenitor cells (RPCs), as well as Müller cells from injured retinas and aged retinas, which will help to reveal molecular mechanisms governing Müller cells development, physiological functions and regeneration activities.
2019-11-12 | GSE124532 | GEO
Project description:Objective: Homeostasis of intestinal stem cells (ISCs) is maintained by external niche signals and complicated intrinsic signaling networks. Mitogen-activated protein kinase (MAPK) cascades play pivotal roles in stem cell self-renewal and differentiation, but the functions and underlying molecular mechanisms are not fully understood. Design: We performed studies with mice deletion of Erk1/2 genes in intestinal epithelial cells at embryonic stages or a control mice. Intestinal tissues were collected and analyzed by histology, gene expression profiling, immunohistochemistry, immunfluorescence, western blotting and organoid culture. Organoids were treated with specific inhibitors for Ras or Akt activity. Mice were treated by intraperitoneal injection of rapamycin to inhibit mTOR signaling. Results: We found that deletion of Erk1/2 genes resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 strongly impaired secretory cell differentiation and enterocyte maturation with aberrant Wnt signaling activation. Erk1/2 depletion resulted in loss of feedback regulation leading to Ras/Raf cascade activation. Ras then transactivated Akt activity to stimulate mTOR and phosphorylate β-catenin on Ser552. Suppression of Ras or Akt activity through specific inhibitors significantly repressed Akt downstream signaling and restored cell proliferation and differentiation phenotypes ex vivo. Moreover, inhibition of mTOR signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged mutant mouse life span. Conclusions Our study demonstrates an unexplored critical role of ERK/MAPK pathway negative feedback regulation of Akt/mTOR in intestine development and homeostasis, suggesting a complicated regulatory network in ISC function.
2020-08-10 | GSE134249 | GEO