Wnt/β-Catenin/TCF Pathway Is a Phase-Dependent Promoter of Colony Formation and Mesendodermal Differentiation During Human Somatic Cell Reprogramming

Cevallos, Ricardo R.; Rodríguez‐Martínez, Griselda; Gazarian, Karlen

doi:10.1002/stem.2788

Cited by 15 publications

(21 citation statements)

References 61 publications

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“…Inhibiting chromatin H3K79 methyltransferase DOT1L improves OSKM-induced reprogramming efficiency from human fibroblasts 13 . Also, inhibiting canonical WNT/β-CATENIN signaling at late reprogramming stage prevents differentiation of the reprogrammed cells 20 . We have shown that the DOT1L inhibitor (iDOT1L) 13 and canonical WNT signaling inhibitor (IWR1) 21 improve total TRA-1-60+ colony number and the homogeneity of individual TRA-1-60+ colonies, respectively 19 .…”

Section: Resultsmentioning

confidence: 99%

FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming

Wang

Huang

et al. 2019

Sci Rep

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FOXH1 is a primitive-streak specifier and ACTIVIN co-effector that plays an important role in development, and positively regulates the generation of human induced pluripotent stem cells (iPSCs) from somatic cells by OCT4, SOX2, KLF4, and MYC (OSKM) transduction. However, the mechanism and upstream regulation for FOXH1 expression in reprogramming are unclear. We found FOXH1 expression plays a significant role to enhance epithelial marker and suppress mesenchymal gene expression in OSKM-mediated human cell reprogramming. Furthermore, NANOG and LIN28 (NL) co-stimulate FOXH1 expression, which correlates with the enhanced reprogramming efficiency by NL-factors. FOXH1 expression is also stimulated by a specific inhibitor for H3K79 methyltransferase DOT1L (iDOT1L) but not by inhibition of the canonical WNT signaling. We further show that blocking endogenous FOXH1 expression eliminates the enhanced reprogramming effect by NL and iDOT1L. However, overexpressing FOXH1 in NL plus iDOT1L condition results in significantly reduced TRA-1-60 positively expressed cells and decreases pluripotent marker expression in reprogramming. Our study elucidated an essential role for properly stimulated FOXH1 expression by NANOG, LIN28, and H3K79 demethylation for dramatic enhancement of reprograming.

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Section: Resultsmentioning

confidence: 99%

FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming

Wang

Huang

et al. 2019

Sci Rep

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“…Overexpression of TCF7L1 causes downregulation of mesodermal gene expression, and leads to an improved somatic cell reprogramming and colony formation [81]. However, stabilization of βcatenin has been shown to also enhance self-renewal in naïve mouse ESCs in a TCF independent manner, whereby nuclear β-catenin acts by directly interacting with the master transcription factor, OCT4, to induce the expression of pluripotent genes [82].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds

McKee

Brown

Bakshi

et al. 2020

Preprint

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Derivation of primed and naïve human embryonic stem cells (ESCs) have prompted an increased interest in devising culture conditions for maintaining their pluripotency and differential potential. Naïve ESCs are characterized by improved viability, proliferation, and differentiation capacity in comparison to primed ESCs. However, traditional two-dimensional (2-D) cell culture techniques fail to mimic the three-dimensional (3-D) in vivo microenvironment, which results in altered morphological and molecular characteristics of ESCs. Here, we describe the use of 3-D self-assembling scaffolds that support growth and maintenance of the naïve state characteristics of human ESC line, Elf1. Scaffolds were formed via a Michael addition reaction upon combination of two 8-arm polyethylene glycol (PEG) polymers functionalized with thiol (PEG-8-SH) and acrylate (PEG-8-Acr) end groups. 3-D scaffolds not only maintained the naïve state, but also supported long-term growth for up to 3 weeks without requiring routine passaging and manipulation. 3-D grown cells exhibited upregulation of core (OCT4, NANOG, and SOX2) and naïve (KLF17, KLF4, TFCP2L1, DPPA3, and DNMT3L) genes. These genes returned to normal levels when 3-D grown cells were propagated under 2-D culture conditions. Examination of RNA-sequencing demonstrated significant changes in gene expression profiles between 2-D and 3-D grown Elf1 cells. Gene Ontology analysis revealed upregulation of biological processes involved in the regulation of transcription and translation, as well as β-catenin-TCF complex assembly, extracellular matrix organization, and chromatin remodeling in 3-D grown Elf1 cells. 3-D culture conditions also induced upregulation of genes associated with several signaling pathways including Wnt signaling and focal adhesion. However, p53 signaling pathway associated genes were downregulated under these culture conditions. Our findings provide insight into the possible mechanisms of prolonged self-renewal as well as upregulation of pluripotent genes stimulated by the transduction of mechanical signals from the 3-D microenvironment.

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“…Some researchers have studied the effect of miR-21 on the Wnt signaling pathway by stably transfecting miR-21-overexpressing HCT-116 cells. Their results indicated that miR-21 overexpression leads to the activation of Wnt/β-catenin signaling, such as decreased levels of axin (a negative regulator of the Wnt signaling pathway), increased levels of β-catenin, the induction of TCF/LEF (a group of transcription factors that bind to DNA through a high-mobility group domain and are involved in the Wnt signaling pathway) activity, and the increased expression of the downstream target proteins c-Myc and cyclin D1 (32–36). These conclusions are consistent with our present results.…”

Section: Discussionmentioning

confidence: 99%

Promotion of ovarian cancer cell invasion, migration and colony formation by the miR‑21/Wnt/CD44v6 pathway

et al. 2019

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Ovarian cancer (OC) has the highest mortality rate among female malignant tumors, and OC commonly relapses and metastasizes. The mechanisms underlying the occurrence and development of ovarian cancer are numerous and complicated. The aim of the present study was to explore an important molecular mechanism that may provide a theoretical basis for the clinical treatment of ovarian cancer. In the present study, the expression level of miR-21 was analyzed in clinical specimens, normal ovarian epithelial cells and three different ovarian cancer epithelial cell lines. Then, in vitro experiments were performed following the transient transfection of miR-21 mimics and inhibitors into SKOV3 cells. RT-PCR, western blot analysis, colony formation assay, and Transwell migration and invasion assays were used to explore the role of miR-21 in ovarian cancer. In addition, Wnt signaling pathway inhibitors and activators were used to validate the hypothesis that the miR-21/Wnt/CD44v6 pathway plays an important role in OC. In ovarian cancer tissues and cells, miR-21 was highly expressed, and the high expression of miR-21 could activate the Wnt signaling pathway to regulate the expression of CD44v6 and affect the proliferation, invasion and migration of OC cells. miR-21 regulated the expression of CD44v6 by activating the Wnt signaling pathway, which plays an important role in the development of ovarian cancer. These findings provide a potential new therapeutic target for the clinical diagnosis and treatment of ovarian cancer.

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Wnt/β-Catenin/TCF Pathway Is a Phase-Dependent Promoter of Colony Formation and Mesendodermal Differentiation During Human Somatic Cell Reprogramming

Cited by 15 publications

References 61 publications

FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming

FOXH1 Is Regulated by NANOG and LIN28 for Early-stage Reprogramming

Transcriptomic analysis of naïve human embryonic stem cells cultured in three-dimensional PEG scaffolds

Promotion of ovarian cancer cell invasion, migration and colony formation by the miR‑21/Wnt/CD44v6 pathway

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