CHIR99021 enhances Klf4 Expression through β-Catenin Signaling and miR-7a Regulation in J1 Mouse Embryonic Stem Cells

Ai, Zhiying; Shao, Jingjing; Wu, Yongyan; Yu, Mengying; Du, Juan; Shi, Xiaoyan; Shi, Xinglong; Zhang, Yong; Guo, Zekun

doi:10.1371/journal.pone.0150936

Cited by 18 publications

(18 citation statements)

References 53 publications

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“…40 However, enhancing WNT signaling by blocking the endogenous β-catenin/WNT inhibitor GSK3 reduced atherosclerosis and inflammatory endothelial VCAM-1 expression 41 , further supporting an atheroprotective role of WNT at least partially at the endothelial level. Findings that endothelial KLF4 is itself a β-catenin target gene 42 , drives VE-cadherin expression 43 and is atheroprotective in ECs 44 , may provide additional evidence for a down-stream link of CXCL12-induced β-catenin and VE-cadherin expression. Given the involvement of SHP2 in Akt signaling 45 , our data unveil that the CXCL12-CXCR4 axis can sustain endothelial integrity through i) SHP2/Akt/WNT signaling inducing VE-cadherin expression, and ii) VE-cadherin-associated phosphatases, namely VE-PTP, supporting VE-cadherin stability and function.…”

Section: Discussionmentioning

confidence: 99%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

147

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Background The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, particularly as the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (EC, BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific-deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results The cell-specific deletion of CXCR4 in arterial ECs (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin-signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4-deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4-deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259,796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Döring¹,

Noels²,

Vorst³

et al. 2017

Circulation

147

View full text Add to dashboard Cite

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“…miRNAs may sharpen morphogen gradients in the developing embryo or serve as a positive regulator by amplifying signal strength in duration to allow cell responsiveness to subthreshold stimuli (Inui et al, 2010). Recent studies have shown that many miRNAs that are involved in the mitochondrial biogenesis of different cell types are thought to regulate the expression of PGC-1α (Ong et al, 2015;Wu et al, 2015;Ai et al, 2016;Cha et al, 2017;Jiang et al, 2017;Portius et al, 2017;Saini et al, 2018). A study found that CHIR-99021 decreased the mature miRNA levels of most miRNA species in mouse ESCs (Wu et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation

Sun

et al. 2019

Journal of Cell Science

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Mitochondrial remodelling is a central feature of stem cell differentiation. However, little is known about the regulatory mechanisms during these processes. Previously, we found that a pharmacological inhibitor of glycogen synthase kinase-3α and-3β, CHIR-99021, initiates human adipose stem cell differentiation into human definitive endodermal progenitor cells (hEPCs), which were directed to differentiate synchronously into hepatocyte-like cells after further treatment with combinations of soluble factors. In this study, we show that CHIR-99021 promotes mitochondrial biogenesis, the expression of PGC-1α (also known as PPARGC1A), TFAM and NRF1 (also known as NFE2L1), oxidative phosphorylation capacities, and the production of reactive oxygen species in hEPCs. Blocking mitochondrial dynamics using siRNA targeting DRP1 (also known as DNM1L) impaired definitive endodermal differentiation. Downregulation of β-catenin (CTNNB1) expression weakened the effect of CHIR-99021 on the induction of mitochondrial remodelling and the expression of transcription factors for mitochondrial biogenesis. Moreover, CHIR-99021 decreased the expression of miR-19b-2-5p, miR-23a-3p, miR-23c, miR-130a-3p and miR-130a-5p in hEPCs, which target transcription factors for mitochondrial biogenesis. These data demonstrate that CHIR-99021 plays a role in mitochondrial structure and function remodelling via activation of the β-catenin signalling pathway and inhibits the expression of miRNAs during definitive endodermal differentiation. This article has an associated First Person interview with the first author of the paper.

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“…Although we assessed that the transcriptional effects of Chiron in absence of β-catenin are negligible, the DGEs in the KOC/WTC comparison were dependent solely on the presence of β-catenin. A similar approach has been used previously [23] by comparing mESCs treated [17][18][19]24]. However, with the exception of a slight Tcfp2l1 upregulation and Dppa3 downregulation, we were not able to identify any change at transcriptional levels of pluripotency marker genes upon Chiron treatment in wild-type cells ( Figure S3C).…”

Section: Canonical Wnt Signalling Inhibits Differentiation Of Mescs Tmentioning

confidence: 58%

Canonical Wnt pathway controls mESCs self-renewal through inhibition of spontaneous differentiation via β-catenin/TCF/LEF functions

Aulicino

Sottile

Pedone

et al. 2019

Preprint

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The Wnt/β-catenin signalling pathway is a key regulator of embryonic stem cell self-renewal and differentiation. Constitutive activation of this pathway has been shown to significantly increase mouse embryonic stem cell (mESC) self-renewal and pluripotency marker expression. In this study, we generated a novel β-catenin knock-out model in mESCs by using CRISPR/Cas9 technology to delete putatively functional N-terminally truncated isoforms observed in previous knock-out models. While we showed that aberrant N-terminally truncated isoforms are not functional in mESCS, we observed that canonical Wnt signalling is not active in mESCs, as β-catenin ablation does not alter mESC transcriptional profile in LIFenriched culture conditions; on the other hand, Wnt signalling activation represses mESC spontaneous differentiation. We also showed that transcriptionally silent β-catenin (ΔC) isoforms can rescue β-catenin knock-out self-renewal defects in mESCs, cooperating with TCF1 and LEF1 in the inhibition of mESC spontaneous differentiation in a Gsk3 dependent manner.

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CHIR99021 enhances Klf4 Expression through β-Catenin Signaling and miR-7a Regulation in J1 Mouse Embryonic Stem Cells

Cited by 18 publications

References 53 publications

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity

CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation

Canonical Wnt pathway controls mESCs self-renewal through inhibition of spontaneous differentiation via β-catenin/TCF/LEF functions

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