E-cadherin and, in Its Absence, N-cadherin Promotes Nanog Expression in Mouse Embryonic Stem Cells via STAT3 Phosphorylation

Hawkins, Kate; Mohamet, Lisa; Ritson, Sarah; Merry, Catherine L.R.; Ward, Christopher M.

doi:10.1002/stem.1148

Cited by 71 publications

(63 citation statements)

References 31 publications

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“…stemness. This was addressed by using Cdh1 2/2 or b-catenin knockout (Ctnnb1 2/2 ) mESCs (del Valle et al, 2013;Hawkins et al, 2012;Soncin et al, 2011). The results indicate that complex mechanisms exist, with different genotypes of the mESCs becoming dependent on different growth factors that influence their stemness.…”

Section: Box 1 Stem Cells In Various Flavorsmentioning

confidence: 99%

“…Constitutive activation of STAT3 in mESCs is sufficient to keep cells undifferentiated when LIF is absent (Matsuda et al, 1999). Cdh1 2/2 mESCs fail to respond to LIF signaling (del Valle et al, 2013;Soncin et al, 2009;Soncin et al, 2011) and STAT3 is not activated (del Valle et al, 2013;Hawkins et al, 2012). Nonetheless, Cdh1 2/2 mESCs sustain selfrenewal in the absence of LIF (Soncin et al, 2009;Soncin et al, 2011).…”

Section: Box 1 Stem Cells In Various Flavorsmentioning

confidence: 99%

“…Nonetheless, Cdh1 2/2 mESCs sustain selfrenewal in the absence of LIF (Soncin et al, 2009;Soncin et al, 2011). However, culture of Cdh1 2/2 mESCs in the presence of LIF and BMP induces N-cadherin (CDH2), and this partially restored naive stemness is indicated by increased cell-cell contacts, activation of STAT3 and upregulation of Klf4 and Nanog transcription (Hawkins et al, 2012). This partial restoration is sensitive to both a JAK inhibitor and an E-and N-cadherin-inhibiting peptide (Hawkins et al, 2012).…”

Section: Box 1 Stem Cells In Various Flavorsmentioning

confidence: 99%

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Role of cell–cell adhesion complexes in embryonic stem cell biology

Pieters

Roy

2014

Journal of Cell Science

121

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Pluripotent embryonic stem cells (ESCs) can self-renew or differentiate into any cell type within an organism. Here, we focus on the roles of cadherins and catenins -their cytoplasmic scaffold proteins -in the fate, maintenance and differentiation of mammalian ESCs. E-cadherin is a master stem cell regulator that is required for both mouse ESC (mESC) maintenance and differentiation. Ecadherin interacts with key components of the naive stemness pathway and ablating it prevents stem cells from forming welldifferentiated teratomas or contributing to chimeric animals. In addition, depleting E-cadherin converts naive mouse ESCs into primed epiblast-like stem cells (EpiSCs). In line with this, a mesenchymal-to-epithelial transition (MET) occurs during reprogramming of somatic cells towards induced pluripotent stem cells (iPSCs), leading to downregulation of N-cadherin and acquisition of high E-cadherin levels. b-catenin exerts a dual function; it acts in cadherin-based adhesion and in WNT signaling and, although WNT signaling is important for stemness, the adhesive function of b-catenin might be crucial for maintaining the naive state of stem cells. In addition, evidence is rising that other junctional proteins are also important in ESC biology. Thus, precisely regulated levels and activities of several junctional proteins, in particular E-cadherin, safeguard naive pluripotency and are a prerequisite for complete somatic cell reprogramming.

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Section: Box 1 Stem Cells In Various Flavorsmentioning

confidence: 99%

Section: Box 1 Stem Cells In Various Flavorsmentioning

confidence: 99%

Section: Box 1 Stem Cells In Various Flavorsmentioning

confidence: 99%

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Role of cell–cell adhesion complexes in embryonic stem cell biology

Pieters

Roy

2014

Journal of Cell Science

121

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“…These authors further hypothesize that sustained cell adhesion prevents the breakdown of the transcriptional network underlying pluripotency gene expression and self-renewal in a Lif-dependent manner. Interestingly, loss of cell adhesion in mES cells due to the knockout of E-cadherin also results in impaired expression of the pluripotency-associated transcription factors Nanog and Klf4, despite the presence of β-catenin (Hawkins et al, 2012). Therefore, intact cell adhesion seems to be a crucial determinant in preserving mES cell 'stemness'.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, intact cell adhesion seems to be a crucial determinant in preserving mES cell 'stemness'. More importantly, E-cadherin -/-mES cells have lost their ability to respond to Lif signaling, which is reflected in a defect in activation of Stat3 (Hawkins et al, 2012;Soncin et al, 2011). The functional dualism of β-catenin imposes a scientific challenge to clearly distinguish the signaling contribution from the adhesive contribution of β-catenin to the maintenance of mES cells.…”

Section: Introductionmentioning

confidence: 99%

E-cadherin is required for the proper activation of the Lifr/Gp130 signaling pathway in mouse embryonic stem cells

et al. 2013

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SUMMARYThe leukemia inhibitory factor (Lif) signaling pathway is a crucial determinant for mouse embryonic stem (mES) cell self-renewal and pluripotency. One of the hallmarks of mES cells, their compact growth morphology, results from tight cell adhesion mediated through E-cadherin, β-catenin (Ctnnb1) and α-catenin with the actin cytoskeleton. β-catenin is also involved in canonical Wnt signaling, which has also been suggested to control mES cell stemness. Here, we analyze Ctnnb1 −/− mES cells in which cell adhesion is preserved by anEα mES cells), and show that mimicking only the adhesive function of β-catenin is necessary and sufficient to maintain the mES cell state, making β-catenin/Wnt signaling obsolete in this process. Furthermore, we propose a role for E-cadherin in promoting the Lif signaling cascade, showing an association of E-cadherin with the Lifr-Gp130 receptor complex, which is most likely facilitated by the extracellular domain of E-cadherin. Without Eα, and thus without maintained cell adhesion, Ctnnb1 −/− mES cells downregulate components of the Lif signaling pathway, such as Lifr, Gp130 and activated Stat3, as well as pluripotency-associated markers. From these observations, we hypothesize that the changes in gene expression accompanying the loss of pluripotency are a direct consequence of dysfunctional cell adhesion. Supporting this view, we find that the requirement for intact adhesion can be circumvented by the forced expression of constitutively active Stat3. In summary, we put forward a model in which mES cells can be propagated in culture in the absence of Ctnnb1, as long as E-cadherin-mediated cell adhesion is preserved.

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Growing Human Dermal Fibroblasts as Spheroids Renders Them Susceptible for Early Expression of Pluripotency Genes

Raghunath²,

Lee

2019

Adv. Biosys.

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approaches have been adopted to coax cells in single cell suspension to aggregate and form spheroids, such as i) hanging drop culture, ii) growing cells on low-attachment culture surfaces, and iii) culturing cells in rotating bioreactors. The principle of these methods is to prevent cells from adhering to the cell culture vessel surface and instead encourage the cells to adhere to each other. This would then force the cells to form aggregates/spheroids, establish close cell-cell contacts and communication. Spheroid cultures are considered to be better suited for studying a wide range of cellular activities, such as tissue development and disease. [3] In the past decade, the use of spheroid culture to investigate cancer biology in vitro has increased significantly because it morphologically resembles a tumor. It has been reported that cancer cell spheroids mimic a more "realistic" cellular response to radioactive [4] and chemical [5] treatments than cancer cells maintained as 2-dimensional (2D) monolayer culture. Thus, cancer spheroids are emerging as a preferable model for identifying and translating new types of cancer therapies.Several studies have highlighted that the expression of numerous genes change when the same cell type is grown as spheroid instead of monolayer culture. These genes relate to cell differentiation and cell reprogramming, particularly key pluripotency genes Oct4, Sox2, and Nanog. This was observed in mouse embryonic stem cells, [6] human mesenchymal stem cells [7] (MSCs), human cancer cell lines, [8] and mouse fibroblasts. [9] Research has also revealed that spheroid cultures favors mesenchymal-to-epithelial transition (MET), maintenance and even induction of epithelial phenotypes in various cell types. [9][10][11] MET is an essential initiation step in stem cell reprogramming and thus dedifferentiation of mesenchymal lineage cell types. [12] Indeed, MSC spheroids have been reported to acquire enhanced multipotency so that the MSCs could differentiate into more diverse cell types. Cesarz and Tamama claimed that MSC cultured as spheroids were capable to differentiating into more lineages than otherwise possible when cultured as monolayer. [13] Together, these findings suggest the use spheroid cultures might induce spontaneous induction of dedifferentiation, and initial expression of pluripotency markers, and this might be useful at a later stage to increase reprogramming efficiency in the iPSC field.Suspension spheroid cultures of anchorage-dependent cell types have been widely used in cancer and stem cell research, as well as for producing organoids. It is believed that the 3-dimensional spheroid presents cells with a more physiological microenvironment to grow so that they behave more like cells in vivo, which is lacking in conventional 2-dimensional monolayer cultures. Recently, it has been reported that cancer cells grown as spheroids could express stem cell-associated genes. Hence, it is investigated whether normal mouse and human fibroblasts cultured as spheroids could also be induced...

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E-cadherin and, in Its Absence, N-cadherin Promotes Nanog Expression in Mouse Embryonic Stem Cells via STAT3 Phosphorylation

Cited by 71 publications

References 31 publications

Role of cell–cell adhesion complexes in embryonic stem cell biology

Role of cell–cell adhesion complexes in embryonic stem cell biology

E-cadherin is required for the proper activation of the Lifr/Gp130 signaling pathway in mouse embryonic stem cells

Growing Human Dermal Fibroblasts as Spheroids Renders Them Susceptible for Early Expression of Pluripotency Genes

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