Wnt/β-catenin signaling activation induces differentiation in human limbal epithelial stem cells cultured ex vivo
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234403 | GEO | 2023/06/26
REPOSITORIES: GEO
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Project description:Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of intracellular Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β‐catenin pathway Wnt intracellular mediators, SFRP2, DVL2, GSK3β and β‐catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real‐Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK‐3β, DVL2 and β‐catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK‐3β, DVL2, β‐catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.
2021-09-09 | PXD020783 | Pride
Project description:Endothelial cells (ECs) in the central nervous system (CNS) acquire specialized barrier properties in response to extrinsic signals, with Wnt/β-catenin signaling coordinating multiple aspects of endothelial barrier function. We used human pluripotent stem cell (hPSC)-derived endothelial progenitor cells to profile the EC response to Wnt activation using multiple strategies, including the small molecule GSK-3 inhibitor CHIR 99021, and the CNS-derived ligands Wnt7a and Wnt7b.
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Project description:Strong activation of the oncogenic Wnt/beta-catenin pathway is a main mechanism of resistance to FOXO3a-induced apoptosis promoted by PI3K and AKT inhibitors in colorectal cancer (CRC). Reducing Wnt/beta-catenin activity would sensitize colorectal tumors to these inhibitors. However, no Wnt/beta-catenin signaling inhibitor has proven clinical potential yet. Recently, inhibitors that block tankyrases were shown to reduce colon cancer cell proliferation by decreasing nuclear beta-catenin. We aim to identify determinants of response to these novel Wnt-inhibitors. Therefore, we treated in vivo three different patient-derived xenograft models (PDX; P2, P5 and P30) growing subcutaneously in NOD SCID mice with the novel tankyrase inhibitor NVP-TNKS656.
2015-08-10 | E-MTAB-2446 | biostudies-arrayexpress
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Project description:Wnt/β-catenin signaling is a highly organized biochemical cascade that triggers a gene expression program in the signal-receiving cell. The Wnt/β-catenin-driven transcriptional response is involved in virtually all cellular processes during development, homeostasis, and its deregulation causes human disease. However, outstanding questions remain unanswered. Here, we combined RNA sequencing with CUT&RUN-LoV-U against β-catenin to assess the correlation between β-catenin recruitment to target loci and its effect on target gene expression. To this end, we performed a bulk RNA sequencing analysis on human embryonic stem cells (hESCs) treated with the the GSK3 inhibitor/Wnt activator CHIR99021 (10 mM) for 3 days, and compared them to untreated hESCs. We then correlated the observed gene expression changes with β-catenin binding events identified from a separate experiment (see “Related Accession Number”). We observed that β-catenin binding is associated with both activation and repression of cell-specific gene expression programs, underscoring how Wnt/b-catenin drives complex cell behaviors.
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