scholarly journals The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Federica Maria Conedera ◽  
Ana Maria Quintela Pousa ◽  
Nadia Mercader ◽  
Markus Tschopp ◽  
Volker Enzmann
Keyword(s):  
Vision Loss ◽  
Transforming Growth Factor ◽  
Müller Cells ◽  
Transforming Growth Factor Β ◽  
Glial Scar ◽  
Reactive Gliosis ◽  
Muller Cells ◽  
Hypertrophic Response ◽  
Epithelial Phenotype ◽  
Induced Changes

Abstract Background Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals, where they undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound healing, including both scar formation and regeneration. However, targeting TGFβ may affect other physiological mechanisms, owing its pleiotropic nature. The regulation of various cellular activities by TGFβ relies on its interaction with other pathways including Notch. Here, we explore the interplay of TGFβ with Notch and how this regulates MC response to injury in zebrafish and mice. Furthermore, we aimed to characterize potential similarities between murine and human MCs during chronic reactive gliosis. Methods Focal damage to photoreceptors was induced with a 532 nm diode laser in TgBAC (gfap:gfap-GFP) zebrafish (ZF) and B6-Tg (Rlbp1-GFP) mice. Transcriptomics, immunofluorescence, and flow cytometry were employed for a comparative analysis of MC response to laser-induced injury between ZF and mouse. The laser-induced injury was paired with pharmacological treatments to inhibit either Notch (DAPT) or TGFβ (Pirfenidone) or TGFβ/Notch interplay (SIS3). To determine if the murine laser-induced injury model translates to the human system, we compared the ensuing MC response to human donors with early retinal degeneration. Results Investigations into injury-induced changes in murine MCs revealed TGFβ/Notch interplay during reactive gliosis. We found that TGFβ1/2 and Notch1/2 interact via Smad3 to reprogram murine MCs towards an epithelial lineage and ultimately to form a glial scar. Similar to what we observed in mice, we confirmed the epithelial phenotype of human Müller cells during gliotic response. Conclusion The study indicates a pivotal role for TGFβ/Notch interplay in tuning MC stemness during injury response and provides novel insights into the remodeling mechanism during retinal degenerative diseases. Graphical abstract

scholarly journals The TGFβ/Notch axis facilitates Müller cell-to-epithelial transition to ultimately form a chronic glial scar

2020 ◽  
Author(s):  
Federica Maria Conedera ◽  
Ana Maria Quintela Pousa ◽  
Nadia Mercader ◽  
Markus Tschopp ◽  
Volker Enzmann
Keyword(s):  
Vision Loss ◽  
Transforming Growth Factor ◽  
Müller Cells ◽  
Transforming Growth Factor Β ◽  
Glial Scar ◽  
Reactive Gliosis ◽  
Muller Cells ◽  
Hypertrophic Response ◽  
Epithelial Phenotype ◽  
Induced Changes

Abstract Background Contrasting with zebrafish, retinal regeneration from Müller cells (MCs) is largely limited in mammals. There, MCs undergo reactive gliosis that consist of a hypertrophic response and ultimately results in vision loss. Transforming growth factor β (TGFβ) is essential for wound healing, including both scar formation and regeneration. However, targeting TGFβ may affect other physiological mechanisms, owing its pleiotropic nature. The regulation of various cellular activities by TGFβ relies on its interaction with other pathways including Notch. Here, we explore the interplay of TGFβ with Notch and how this regulates MC response to injury in zebrafish and mice. Furthermore, we aimed to characterize potential similarities between murine and human MCs during chronic reactive gliosis. Methods Focal damage to photoreceptors was induced with a 532 nm diode laser in TgBAC (gfap:gfap-GFP) zebrafish (ZF) and B6-Tg (Rlbp1-GFP) mice. Transcriptomics, immunofluorescence, and flow cytometry were employed for a comparative analysis of MC response to laser-induced injury between ZF and mouse. The laser-induced injury was paired with pharmacological treatments to inhibit either Notch (DAPT) or TGFβ (Pirfenidone) or TGFβ/Notch interplay (SIS3). To determine if the murine laser-induced injury model translates to the human system, we compared the related MC response to human donors with early retinal degeneration. Results Investigations into injury-induced changes in murine MCs revealed TGFβ/Notch interplay during reactive gliosis. We found that TGFβ1/2 and Notch1/2 interact via Smad3 to reprogram murine MCs towards an epithelial lineage and ultimately to form a glial scar. Similar to what we observed in mice, we confirmed the epithelial phenotype of human Müller cells during gliotic response. Conclusion This study indicates a pivotal role for TGFβ/Notch interplay in tuning MC stemness during injury response and provides novel insights into the remodeling mechanism during retinal degenerative diseases.

scholarly journals Endothelin2 Induces Expression of Genes Associated with Reactive Gliosis in Retinal Müller Cells

2014 ◽  
Vol 40 (11) ◽  
pp. 1181-1184 ◽  
Author(s):  
Vijay P. Sarthy ◽  
Hari Sawkar ◽  
V. Joseph Dudley
Keyword(s):  
Müller Cells ◽  
Reactive Gliosis ◽  
Muller Cells ◽  
Expression Of Genes

scholarly journals Norepinephrine-Induced Changes in Cardiac Transforming Growth Factor-β Isoform Expression Pattern of Female and Male Rats

Hypertension ◽  
2004 ◽  
Vol 44 (4) ◽  
pp. 410-418 ◽  
Author(s):  
Wilfried Briest ◽  
Lars Homagk ◽  
Beate Raβler ◽  
Barbara Ziegelhöffer-Mihalovicová ◽  
Henning Meier ◽  
...  
Keyword(s):  
Growth Factor ◽  
Expression Pattern ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Male Rats ◽  
Isoform Expression ◽  
Induced Changes

scholarly journals TNFα drives the proliferation and inflammatory response, but not regenerative potential of Müller cells in the mouse retina

2019 ◽  
Author(s):  
Lianglaing Niu ◽  
Yuan Fang ◽  
Xiaoqian Yao ◽  
Yi Zhang ◽  
Jihong Wu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Progenitor Cell ◽  
Müller Cells ◽  
Müller Cell ◽  
Janus Kinase ◽  
Reactive Gliosis ◽  
Muller Cells ◽  
Mapk Pathways ◽  
Retinal Injury ◽  
Muller Cell

Abstract Background Mouse Müller cells, considered dormant retinal progenitors, respond to retinal injury by undergoing reactive gliosis rather than displaying regenerative responses. Tumor necrosis factor alpha (TNFα) is a key cytokine induced after injury, and implicated in mediating inflammatory and regenerative responses. However, the molecular events driving reactive gliosis and regenerative responses in Müller cells, and the role of TNFα in these processes, remain unclear. In this study, we investigated the effects of TNFα on Müller cell responses following injury. Methods To investigate the involvement of TNFα in retinal injury, adult C57BL/6J mice were subjected to treatment with light (5,000 lux) for 14 consecutive days; induction of TNFα was confirmed by quantitative polymerase chain reaction (qPCR). TNFα effects on Müller-cell proliferation were evaluated via 5-ethynyl-2’-deoxyuridine (EdU) incorporation in culture. TNFα-mediated gene profile changes were examined using Affymetrix microarray, and gene ontology analysis was carried out to define the molecular pathways involved. Gene- and protein-expression changes were further verified by qPCR, western blot, and enzyme linked immunosorbent assay (ELISA). Results We showed that TNFα induced Müller cell proliferation and the expression of inflammatory and proliferation-related genes, including NFKBIA, Leukemia inhibitory factor, Interleukin-6, Janus kinase (Jak) 1, Jak2, Signal transducer and activator of transcription (Stat) 1, Stat2, Mitogen-Activated Protein Kinase (MAPK) 7, and MAP4K4. Blockade of Jak/Stat and MAPK pathways attenuated TNFα-induced Müller cell proliferation. Moreover, we detected TNFα drove A1 phenotype-reactive gliosis, while Wnt attenuated TNFα-mediated induction of A1 phenotype and promoted an A2-like phenotype. Conclusion In Müller cells, TNFα triggered primarily inflammatory and reactive gliosis by activating Jak/Stat and MAPK-pathways without inducing progenitor cell/regeneration-related genes. Wnt signaling suppressed inflammation, and induced proliferation and expression of progenitor-cell genes in Müller cells. These results suggest that reactive gliosis and regenerative responses in Müller cells are regulated by independent mechanisms. Our study provides new insights into regulation of inflammatory and regenerative responses of Müller cells in the injured retina

Maturation-induced changes in L-aspartate receptors from muller cells

1992 ◽  
Vol 21 ◽  
pp. B19
Author(s):  
A.M. López-Colomé ◽  
M. Romo-de-Vivar
Keyword(s):  
Müller Cells ◽  
Muller Cells ◽  
Induced Changes

scholarly journals Dissection of N-, O- and glycosphingolipid glycosylation changes in PaTu-S pancreatic adenocarcinoma cells upon TGF-β challenge

2021 ◽  
Author(s):  
Jing Zhang ◽  
Zejian Zhang ◽  
Stephanie Holst ◽  
Constantin BlÖchl ◽  
Katarina Madunic ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Ductal Adenocarcinoma ◽  
Independent Manner ◽  
Pancreatic Cancer Cells ◽  
Smad2 Phosphorylation ◽  
Adenocarcinoma Cells ◽  
Epithelial Marker ◽  
Induced Changes

Pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and high mortality. Transforming growth factor-β (TGF-β) plays a key role in tumor progression, which is often associated with aberrant glycosylation. How PDAC cells respond to TGF-β and the role of glycosylation therein is, however, not well known. Here, we investigated the TGF-β-mediated response and glycosylation changes in SMAD4-deficient PaTu-8955S (PaTu-S) cell line. PaTu-S cells responded to TGF-β by upregulating SMAD2 phosphorylation and target gene expression. TGF-β induced expression of the mesenchymal marker N-cadherin, but did not significantly affect epithelial marker E-cadherin expression. The differences of N-glycans, O-glycans and glycosphingolipid (GSL) glycans in PaTu-S cells with TGF-β stimulation were examined. TGF-β treatment primarily induced N-glycome aberrations involving elevated levels of branching, core fucosylation, and sialylation in PaTu-S cells, in line with TGF-β-induced changes in the expression of glycosylation-related genes. In addition, we observed differences in O- and GSL-glycosylation profiles after TGF-β treatment, including lower levels of sialylated Tn antigen, and neoexpression of globosides. Furthermore, SOX4 expression was upregulated upon TGF-β stimulation, and its depletion blocked the TGF-β-induced N-glycomic changes. Thus, our study provides a mechanism by which TGF-β-induced N-glycosylation changes in SOX4 dependent and SMAD4 independent manner in pancreatic cancer cells. Our results open up avenues to study the relevance of glycosylation in TGF-β signaling in SMAD4 inactivated PDAC.

Sign in / Sign up

Export Citation Format

Share Document