Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA341511 | ENA |
REPOSITORIES: ENA
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Project description:We previously showed that the combination of markers LNGFR+ and THY-1+ can be used selectively to isolate human mesenchymal stem cells (hMSCs) in bone marrow and several tissues. However, the molecular mechanisms regulating stemness of hMSCs remain to be elucidated. In this study, we found that Frizzled 5 (FZD5) and Receptor tyrosine kinase-like orphan receptor 2 (ROR2) were highly enriched in LNGFR+THY-1+ derived clones that retain a high potential for proliferation (rapidly expanding clones; RECs). WNT5A, the ligand of FZD5, causes FZD5 and ROR2 to co-localize and activates non-canonical Wnt pathway in RECs. Moreover, FZD5 knockdown attenuated proliferation and caused senescence. In contrast, FZD5 overexpression delayed senescence. These results indicate that intrinsic activation of non-canonical Wnt signaling via FZD5 and ROR2 modulates stemness and senescence of RECs. Thus, control of non-canonical Wnt signaling would enable us to regulate hMSC quality and to enhance the efficacy of cell-replacement therapy using hMSCs.
2016-09-02 | GSE86369 | GEO
Project description:Wnt ligands oligomerize Frizzled (Fzd) and Lrp5/6 receptors to control the specification and activity of stem cells in many species. How Wnt is selectively activated in different stem cell populations, often within the same organ, is not understood. In lung alveoli, wherein Wnt-dependent epithelial and stromal progenitors are intermingled, we show that distinct Wnt receptors are expressed by epithelial (Fzd5/6), endothelial (Fzd4), and stromal (Fzd1) cells. Moreover, Fzd5 was uniquely required for alveolar epithelial stem cell activity. However, by developing an expanded repertoire of Fzd-Lrp agonists (FLAgs), we could activate canonical Wnt signaling in alveolar epithelial stem cells via either Fzd5 or, unexpectedly, non-canonical Fzd6. Fzd5 and Fzd6 FLAgs stimulated supra-physiological alveolar epithelial stem cell activity in mice following lung injury, but only Fzd6 FLAg promoted an alveolar fate in airway-derived progenitors. Therefore, we identify a potential strategy for promoting regeneration without exacerbating fibrosis during lung injury.
2023-06-16 | GSE208770 | GEO
Project description:WNT activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human trophoblast stem (TS) cells, activation of canonical WNT signaling is a key to maintenance of the TS cell stem state. NOTUM, a negative regulator of canonical WNT signaling, was prominently expressed in first trimester EVT cells developing in situ and upregulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for human TS cell differentiation to EVT cells. Canonical WNT signaling is essential for maintaining human trophoblast cell stemness and prevention of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for EVT cell differentiation.
2024-03-06 | GSE206034 | GEO
Project description:WNT activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human trophoblast stem (TS) cells, activation of canonical WNT signaling is a key to maintenance of the TS cell stem state. NOTUM, a negative regulator of canonical WNT signaling, was prominently expressed in first trimester EVT cells developing in situ and upregulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for human TS cell differentiation to EVT cells. Canonical WNT signaling is essential for maintaining human trophoblast cell stemness and prevention of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for EVT cell differentiation.
2024-03-06 | GSE206035 | GEO
Project description:Cellular heterogeneity in breast cancer encompasses many features, yet an understanding of the coexistence and regulation of various tumor cell subpopulations remains a significant challenge in cancer biology. In the current study, we approached tumor cell heterogeneity from the perspective of Wnt pathway biology to address how different modes of Wnt signaling shape the behaviors of diverse cell populations within a heterogeneous tumor landscape. Using a syngeneic TP53 null mouse model of breast cancer, we identified distinctions in the topology of canonical Wnt b-catenin dependent signaling activity and noncanonical b-catenin independent Ror2-mediated Wnt signaling across subtypes and within tumor cell subpopulations in vivo. We further discovered an antagonistic role for Ror2 in regulating canonical Wnt/b-catenin activity in vivo, where lentiviral shRNA depletion of Ror2 expression augmented canonical Wnt/b-catenin signaling activity across multiple basal-like models. Depletion of Ror2 expression yielded distinct phenotypic outcomes and divergent alterations in gene expression programs among different tumors, despite all sharing basal-like features. Notably, we uncovered cell state plasticity and adhesion dynamics regulated by Ror2, where Ras Homology Family Member A (RhoA) and Rho-Associated Coiled-Coil Kinase 1 (ROCK1) activity downstream of Dishevelled-2 (Dvl2) were implicated. Collectively, these studies illustrate the integration and collaboration of Wnt pathways in basal-like breast cancer, where Ror2 provides a spatiotemporal function to regulate the balance of Wnt signaling and cellular heterogeneity during tumor progression.
2017-01-23 | GSE93815 | GEO
Project description:We show that Ror2 mediated non-canonical Wnt signaling in the dental mesenchyme plays a critical role in cell proliferation and thereby regulates root development size in mouse molars. Furthermore, Cdc42 acts as a potential downstream mediator of Ror2 signaling in root formation.
2020-11-13 | GSE161395 | GEO
Project description:The rapid regeneration of the small intestinal epithelium is sustained by crypt intestinal stem cells (ISCs). Wnt/b-catenin signaling is essential for intestinal crypt homeostasis and maintenance of Lgr5+ ISC, and yet no single or combinatorial knockout of Frizzled (FZD) genes, representing Wnt receptors, has phenocopied the severe intestinal epithelial effects of Wnt signaling blockade. The elusive identification of specific Frizzled (Fzd) receptor(s) underlying homeostatic proliferation and ISC function would greatly inform therapeutic mucosal repair strategies. In prior pharmacologic studies, bioengineered antagonists that block Wnt binding to both FZD5 and FZD8 receptors induced lethal crypt and villus loss, implicating FZD5 and/or FZD8 as essential for ISCs maintenance. Here, the potential function of Fzd5 in during intestinal homeostasis was examined by epithelial-specific Fzd5 ko, which rapidly elicited lethal pan-intestinal crypt and villus loss, and by Lgr5-specific Fzd5 cKO, which strongly reduced Lgr5+ ISC while inducing their premature differentiation. In parallel, Fzd5 cKO potently repressed Wnt target gene expression, with phenotypic rescue by constitutive activation of b-catenin in vivo and confirmation upon in vitro organoid culture. Fzd5 cKO but not Fzd8 cKO in organoids ablated responsiveness to dual specificity bioengineered FZD5/FZD8-selective Wnt surrogate agonists, which reversed DSS-induced colitis phenotypes in both wild-type and Fzd8 cKO mice. Overall, our results implicate the FZD5 receptor as an essential regulator of crypt homeostasis, Lgr5+ ISCs and intestinal response to bioengineered Wnt surrogate agonists.
2024-10-18 | GSE233260 | GEO
Project description:Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome. Examination of Bcl9/9l-knockout versus wild-type transcriptome in murine AOM-DSS tumors, APC-Kras tumors and healthy colocyte extracts.
2015-11-08 | E-GEOD-60837 | biostudies-arrayexpress
Project description:Canonical Wnt signaling in endothelial cells (ECs) is required for vascularization of the central nervous system (CNS) and for formation and maintenance of barrier properties unique to CNS vasculature. Gpr124 is an orphan member of the adhesion G-protein-coupled receptor family that is expressed in ECs and is essential for CNS angiogenesis and barrier formation via an unknown mechanism. Using canonical Wnt signaling assays in cell culture and genetic loss- and gain-of-function experiments in mice, we show that Gpr124 functions as a co-activator of Wnt7a- and Wnt7b-stimulated canonical Wnt signaling via a Frizzled receptor and Lrp co-receptor, and that Gpr124-stimulated signaling functions in concert with Norrin/Frizzled4 signaling to control CNS vascular development. These experiments identify Gpr124 as a ligand-specific co-activator of canonical Wnt signaling. Total mRNA from HEK-293/STF cells was subjected to RNAseq
2014-08-20 | E-GEOD-60529 | biostudies-arrayexpress
Project description:Breast cancer is the most common cancer in women with more than two million new cases diagnosed in 2018. Patients frequently develop metastases in the course of their disease which limit survival due to the lack of a curative treatment. One signaling pathway that is frequently involved in cancer initiation and progression is the WNT pathway. Breast cancer has been associated with activation of the WNT signaling pathway, although the underlying molecular mechanisms are still unclear. Here, we found the WNT receptor ROR2 to be highly expressed in aggressive breast tumors and associated with worse metastasis-free survival. In this study we addressed this question and demonstrated for the first time that WNT11 is a novel ligand for ROR2 in humans. WNT11 binds to the CRD of ROR2 and mediates WNT/PCP signaling via the RHO/ROCK pathway that confers an aggressive phenotype to breast cancer cells. ROR2 and WNT11 are both highly expressed in human brain metastases and linked with short patient survival.
2022-02-21 | GSE161865 | GEO