scholarly journals Canonical Wnt signalling is activated during BEC-to-hepatocyte conversion in vivo and modulates liver epithelial cell plasticity in hepatic organoids

2020 ◽  
Author(s):  
Eider Valle-Encinas ◽  
Niya Aleksieva ◽  
Carmen Velasco Martinez ◽  
Michael Dawes ◽  
Matthew Zverev ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Progenitor Cell ◽  
Wnt Pathway ◽  
Hepatocyte Proliferation ◽  
Limiting Factor ◽  
Cell Plasticity ◽  
Wnt Ligands ◽  
Severe Liver Damage ◽  
Canonical Wnt

SummaryWhile it is recognized that the Wnt/ß-catenin pathway orchestrates hepatocyte proliferation in both homeostasis and injury, little is known about the importance of β-catenin in biliary epithelial cell (BEC) plasticity. In this study, the dynamics of activation of the canonical Wnt pathway were investigated during BEC-to-hepatocyte conversion using as a model methionine/choline deficient (MCD)-injured livers where hepatocyte proliferation was compromised by the overexpression of p21. In this model, activation of β-catenin was found an event associated with BEC reprogramming. Using ductal organoids to model BECs transitioning into hepatocytes, we found that activation of the Wnt/ß-catenin pathway in these cells promoted partial escape from a biliary fate and triggered the acquisition of progenitor cell features. Our data furthermore support that BECs are source of Wnt ligands and that Rspo proteins potentially act as the limiting factor controlling the activation of β-catenin activation and BEC reprogramming during severe liver damage.

scholarly journals R-Spondin Family Members Regulate the Wnt Pathway by a Common Mechanism

2008 ◽  
Vol 19 (6) ◽  
pp. 2588-2596 ◽  
Author(s):  
Kyung-Ah Kim ◽  
Marie Wagle ◽  
Karolyn Tran ◽  
Xiaoming Zhan ◽  
Melissa A. Dixon ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Expression Patterns ◽  
Family Members ◽  
Wnt Signaling Pathway ◽  
Direct Consequence ◽  
Common Mechanism ◽  
Wnt Ligands ◽  
Canonical Wnt

The R-Spondin (RSpo) family of secreted proteins is implicated in the activation of the Wnt signaling pathway. Despite the high structural homology between the four members, expression patterns and phenotypes in knockout mice have demonstrated striking differences. Here we dissected and compared the molecular and cellular function of all RSpo family members. Although all four RSpo proteins activate the canonical Wnt pathway, RSpo2 and 3 are more potent than RSpo1, whereas RSpo4 is relatively inactive. All RSpo members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSpo proteins are general regulators of canonical Wnt signaling. Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association. Analysis of RSpo deletion mutants indicates that the cysteine-rich furin domains are sufficient and essential for the amplification of Wnt signaling and inhibition of DKK1, suggesting that Wnt amplification by RSpo proteins may be a direct consequence of DKK1 inhibition. Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo.

scholarly journals Loss of FLCN inhibits canonical WNT signaling via TFE3

2019 ◽  
Vol 28 (19) ◽  
pp. 3270-3281 ◽  
Author(s):  
John C Kennedy ◽  
Damir Khabibullin ◽  
Thomas Hougard ◽  
Julie Nijmeh ◽  
Wei Shi ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Lower Lobe ◽  
Fetal Lung ◽  
Lung Fibroblasts ◽  
Pulmonary Cysts ◽  
Wnt Ligands ◽  
Neonatal Lung ◽  
Canonical Wnt ◽  
Human Fetal Lung ◽  
Bhd Syndrome

Abstract Lower lobe predominant pulmonary cysts occur in up to 90% of patients with Birt–Hogg–Dubé (BHD) syndrome, but the key pathologic cell type and signaling events driving this distinct phenotype remain elusive. Through examination of the LungMAP database, we found that folliculin (FLCN) is highly expressed in neonatal lung mesenchymal cells. Using RNA-Seq, we found that inactivation of Flcn in mouse embryonic fibroblasts leads to changes in multiple Wnt ligands, including a 2.8-fold decrease in Wnt2. This was associated with decreased TCF/LEF activity, a readout of canonical WNT activity, after treatment with a GSK3-α/β inhibitor. Similarly, FLCN deficiency in HEK293T cells decreased WNT pathway activity by 76% post-GSK3-α/β inhibition. Inactivation of FLCN in human fetal lung fibroblasts (MRC-5) led to ~ 100-fold decrease in Wnt2 expression and a 33-fold decrease in Wnt7b expression—two ligands known to be necessary for lung development. Furthermore, canonical WNT activity was decreased by 60%. Classic WNT targets such as AXIN2 and BMP4, and WNT enhanceosome members including TCF4, LEF1 and BCL9 were also decreased after GSK3-α/β inhibition. FLCN-deficient MRC-5 cells failed to upregulate LEF1 in response to GSK3-α/β inhibition. Finally, we found that a constitutively active β-catenin could only partially rescue the decreased WNT activity phenotype seen in FLCN-deficient cells, whereas silencing the transcription factor TFE3 completely reversed this phenotype. In summary, our data establish FLCN as a critical regulator of the WNT pathway via TFE3 and suggest that FLCN-dependent defects in WNT pathway developmental cues may contribute to lung cyst pathogenesis in BHD.

scholarly journals Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e101894 ◽  
Author(s):  
Fan Hu ◽  
Li Xu ◽  
Zhi-Hua Liu ◽  
Meng-Meng Ge ◽  
Di-Yun Ruan ◽  
...  
Keyword(s):  
Lead Exposure ◽  
Wnt Pathway ◽  
Canonical Wnt Pathway ◽  
Canonical Wnt

scholarly journals Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation

2003 ◽  
Vol 162 (5) ◽  
pp. 899-908 ◽  
Author(s):  
Lilia Topol ◽  
Xueyuan Jiang ◽  
Hosoon Choi ◽  
Lisa Garrett-Beal ◽  
Peter J. Carolan ◽  
...  
Keyword(s):  
Limb Development ◽  
Wnt Pathway ◽  
Biological Systems ◽  
Signaling Molecules ◽  
Tumor Formation ◽  
Canonical Wnt Pathway ◽  
Noncanonical Pathway ◽  
Canonical Wnt

Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing β-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of β-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and β-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote β-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.

Transplantation of Neural Progenitor Cells into the Developing Retina of the Brazilian Opossum: An in vivo System for Studying Stem/Progenitor Cell Plasticity

2004 ◽  
Vol 26 (5-6) ◽  
pp. 336-345 ◽  
Author(s):  
D.S. Sakaguchi ◽  
S.J. van Hoffelen ◽  
E. Theusch ◽  
E. Parker ◽  
J. Orasky ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Cell Plasticity

Neonatal growth and regeneration of β-cells are regulated by the Wnt/β-catenin signaling in normal and diabetic rats

2010 ◽  
Vol 298 (2) ◽  
pp. E245-E256 ◽  
Author(s):  
Florence Figeac ◽  
Benjamin Uzan ◽  
Monique Faro ◽  
Noura Chelali ◽  
Bernard Portha ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Wnt Pathway ◽  
Diabetic Rats ◽  
Β Cells ◽  
Β Cell ◽  
Ductal Cells ◽  
Gsk 3Β ◽  
Canonical Wnt

Wnt/β-catenin signaling is critical for a variety of fundamental cellular processes. Here, we investigated the implication of the Wnt/β-catenin signaling in the in vivo regulation of β-cell growth and regeneration in normal and diabetic rats. To this aim, TCF7L2, the distal effector of the canonical Wnt pathway, was knocked down in groups of normal and diabetic rats by the use of specific antisense morpholino-oligonucleotides. In other groups of diabetic rats, the Wnt/β-catenin pathway was activated by the inhibition of its negative regulator GSK-3β. GSK-3β was inactivated by either LiCl or anti-GSK-3β oligonucleotides. The β-cell mass was evaluated by morphometry. β-cell proliferation was assessed in vivo and in vitro by BrdU incorporation method. In vivo β-cell neogenesis was estimated by the evaluation of PDX1-positive ductal cells and GLUT2-positive ductal cells and the number of β cells budding from the ducts. We showed that the in vivo disruption of the canonical Wnt pathway resulted in the alteration of normal and compensatory growth of β-cells mainly through the inhibition of β-cell proliferation. Conversely, activation of the Wnt pathway through the inhibition of GSK-3β had a significant stimulatory effect on β-cell regeneration in diabetic rats. In vitro, GSK-3β inactivation resulted in the stimulation of β-cell proliferation. This was mediated by the stabilization of β-catenin and the induction of cyclin D. Taken together, our results demonstrate the involvement of the canonical Wnt signaling in the neonatal regulation of normal and regenerative growth of pancreatic β-cells. Moreover, we provide evidence that activation of this pathway by pharmacological maneuvers can efficiently improve β-cell regeneration in diabetic rats. These findings might have potential clinical applications in the regenerative therapy of diabetes.

scholarly journals Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells

2020 ◽  
Author(s):  
John Parkin Russell ◽  
Xinhong Lim ◽  
Alice Santambrogio ◽  
Val Yianni ◽  
Yasmine Kemkem ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pituitary Gland ◽  
Progenitor Cells ◽  
Wnt Pathway ◽  
Tissue Expansion ◽  
Paracrine Signalling ◽  
Physiological Demand ◽  
Wnt Ligands

ABSTRACTIn response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.

Influence of PI-3K/Akt Pathway on Wnt Signalling in Myeloid Progenitor Cells. Evidence for a Role of Autocrine/Paracrine Wnt Regulation in CFU-GM Proliferation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2892-2892
Author(s):  
Georgios Nteliopoulos ◽  
Stephen B Marley ◽  
Myrtle Y Gordon
Keyword(s):  
Conditioned Medium ◽  
Progenitor Cell ◽  
Wnt Pathway ◽  
Wnt Signalling ◽  
Myeloid Progenitor ◽  
Wnt Proteins ◽  
Cd34 Cells ◽  
Myeloid Progenitor Cell ◽  
Progenitor Cell Proliferation ◽  
Canonical Wnt

Abstract We have used a colony replating assay in conjunction with manipulation of the Wnt and PI-3K pathways to investigate regulation of myeloid progenitor cell proliferation/differentiation. We found that PI-3 kinase pathway via Akt acts as a proliferative brake and promotes differentiation in IL3-driven myelopoiesis, since inhibition of PI-3K/Akt pathway with LY294002 (PI-3 kinase inhibitor) and SH-5 (Akt inhibitor) increased proliferation (reduced differentiation). We investigated the involvement of Wnt signalling in CFU-GM proliferation by using exogenous recombinant canonical Wnt3a and non-canonical Wnt5a. We showed that both of the Wnt members cannot support colony growth alone, but when added to IL3 they increased proliferation potential compared with the IL3 control, indicating an involvement of canonical Wnt/β-catenin and non-canonical Wnt pathways in the myeloid progenitor cell proliferation. Immunoblotting analysis indicated that Wnt5a acts independently of β-catenin. Dkk-1 (Wnt-pathway inhibitor) alone did not affect IL-3 dependent proliferation but when combined with recombinant Wnts as expected it abrogated the effects of Wnt3a but not Wnt5a (acts as canonical-Wnt inhibitor). This was confirmed by β-catenin protein levels. Surprisingly, when Dkk-1 was added to LY294002 or SH-5, it blocked their proliferative effects. Dkk-1 acts as functional Wnt-receptor disabler and the finding that it blocks proliferation induced by PI-3K/Akt inhibitors’ indicates a link between the PI-3K and the Wnt signalling pathways. We hypothesised that increased proliferation induced by LY294002 or SH-5 was not mediated by downstream activation of the Wnt pathway but by induced endogenous expression of Wnt proteins and activation of the surface receptor. We conclude that there is a production of endogenous Wnt proteins that increases proliferation. Endogenous Wnt production has been reported in primitive haematopoietic cells so there is potential for a paracrine or autocrine role for these cell regulators. We tested this hypothesis in CD34+ cells and found the addition of SH-5 to IL3 creates an autocrine loop of endogenous Wnt production, which results in the phosphorylation and activation of the LRP6 receptor and the initiation of the canonical signalling pathway. Furthermore, the conditioned medium of cultured CD34+ cells was concentrated by using filtration devices (30kD cut-off) and added to IL3 to support the growth of progenitors of another sample in a CFU-GM assay. We indicated that Wnt production and secretion can act in a paracrine way as well, since IL3+SH-5 conditioned medium increased the proliferative index of CFU-GM cells whereas IL3 conditioned medium did not have significant effect. Dkk-1 abrogated the IL3+SH-5 conditioned medium’s induced proliferation, suggesting that the growth factors that had the proliferative effects were Wnt members. In conclusion, our data suggest that IL3 via PI-3K pathway promotes differentiation of progenitor myeloid cells through inhibition of endogenous Wnt production.

scholarly journals Efficiency of Cell Therapy to GC-Induced ONFH: BMSCs with Dkk-1 Interference Is Not Superior to Unmodified BMSCs

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Wei Zhun ◽  
Li Donghai ◽  
Yang Zhouyuan ◽  
Zhao Haiyan ◽  
Kang Pengde
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cell Therapy ◽  
Wnt Pathway ◽  
Allograft Bone ◽  
Canonical Wnt Pathway ◽  
Canonical Wnt ◽  
Dickkopf 1

Glucocorticoid-induced osteonecrosis of the femoral head (ONFH) is a hip disorder, and it threatens patients who require megadose of steroid therapies. Nowadays, no valid therapies can reverse the development of GC-induced ONFH once it occurs. Stem cell therapy to GC-induced ONFH would be a promising choice. Although the pathogenesis of GC-induced ONFH is not yet fully clear, Dickkopf-1 (Dkk-1) upregulated by excessive GC use, which hinders the canonical Wnt pathway, could be an explanation. Thus, the aim of the present work lies in investigating the efficiency of the allograft bone marrow stem cells (BMSCs) with Dkk-1 interference in preventing the progression of the GC-induced ONFH. Lentivirus-meditated Dkk-1 RNAi was introduced into BMSCs which was exposed to dexamethasone (10−6 mol/L) in vitro. This interference blocked Dkk-1 overexpression by GC and afterwards prompted the transduction of Wnt/β-catenin in which the Runx2 and PPARγ were upregulated and downregulated, respectively. Thus, the osteogenesis was promoted while adipogenesis was inhibited. In vivo, GC-induced ONFH rats were treated by allotransplantation of BMSCs with Dkk-1 interference, and the progression of the disease was prevented. However, the effects were not significantly superior to treatment with nongenetically modified or normal BMSCs.

scholarly journals Wnt7b Activates Canonical Signaling in Epithelial and Vascular Smooth Muscle Cells through Interactions with Fzd1, Fzd10, and LRP5

2005 ◽  
Vol 25 (12) ◽  
pp. 5022-5030 ◽  
Author(s):  
Zhishan Wang ◽  
Weiguo Shu ◽  
Min Min Lu ◽  
Edward E. Morrisey
Keyword(s):  
Cell Surface ◽  
Wnt Signaling ◽  
Airway Epithelium ◽  
Lung Development ◽  
Wnt Pathway ◽  
Vascular Development ◽  
Placental Development ◽  
Surface Receptors ◽  
Wnt Ligands ◽  
Canonical Wnt

ABSTRACT Wnt7b is a Wnt ligand that has been demonstrated to play critical roles in several developmental processes, including lung airway and vascular development and chorion-allantois fusion during placental development. Wnt signaling involves the binding of Wnt ligands to cell surface receptors of the frizzled family and coreceptors of the LRP5/6 family. However, little is known of the ligand-receptor specificity exhibited by different Wnts, Fzds, and LRPs in Wnt signaling. Expression analysis of Fzds and LRP5/6 in the developing lung and vasculature showed that Fzd1, -4, -7, and -10 and LRP5/6 are expressed in tissue-specific patterns during lung development. Fzd1, -4, and -7 are expressed primarily in the developing lung mesenchyme, and Fzd10 is expressed in airway epithelium. LRP5 and LRP6 are expressed in airway epithelium during lung development, whereas LRP5 but not LRP6 expression is observed in the muscular component of large blood vessels, including the aorta. Cell transfection studies demonstrate that Wnt7b can activate the canonical Wnt pathway but not the noncanonical Wnt pathway in a cell-specific manner. Biochemical analysis demonstrates that Wnt7b can bind to Fzd1 and -10 on the cell surface and cooperatively activate canonical Wnt signaling with these receptors in the presence of LRP5. Together, these data demonstrate that Wnt7b signals through Fzd1 and -10 and LRP5 and implicate these Wnt coreceptors in the regulation of lung airway and vascular development.

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