Differentiation of Embryonic Stem Cells into Anterior Definitive Endoderm

Livigni, Alessandra; Villegas, Santiago Nahuel; Oikonomopoulou, Ifigenia; Rahman, Afifah; Morrison, Gillian; Brickman, Joshua M.

doi:10.1002/9780470151808.sc01g03s10

Cited by 13 publications

(13 citation statements)

References 25 publications

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“…To address the basis of the requirement for FGF during endoderm differentiation and anterior specification, we applied several small molecule inhibitors to a defined adherent mESC endoderm differentiation model ( Figure 1A ; Livigni et al, 2009 ). Differentiation conditions are shown in Figure 1A and the medium used is defined in ‘Materials and methods’ section.…”

Section: Resultsmentioning

confidence: 99%

PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix

Villegas

Rothová

Barrios-Llerena

et al. 2013

eLife

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During embryonic development signalling pathways act repeatedly in different contexts to pattern the emerging germ layers. Understanding how these different responses are regulated is a central question for developmental biology. In this study, we used mouse embryonic stem cell (mESC) differentiation to uncover a new mechanism for PI3K signalling that is required for endoderm specification. We found that PI3K signalling promotes the transition from naïve endoderm precursors into committed anterior endoderm. PI3K promoted commitment via an atypical activity that delimited epithelial-to-mesenchymal transition (EMT). Akt1 transduced this activity via modifications to the extracellular matrix (ECM) and appropriate ECM could itself induce anterior endodermal identity in the absence of PI3K signalling. PI3K/Akt1-modified ECM contained low levels of Fibronectin (Fn1) and we found that Fn1 dose was key to specifying anterior endodermal identity in vivo and in vitro. Thus, localized PI3K activity affects ECM composition and ECM in turn patterns the endoderm.DOI: http://dx.doi.org/10.7554/eLife.00806.001

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Section: Resultsmentioning

confidence: 99%

PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix

Villegas

Rothová

Barrios-Llerena

et al. 2013

eLife

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“…Genetic studies in mouse suggest that FGF signalling is required for this EMT-like event in the primitive streak [Ciruna and Rossant, 2001] and any requirement for FGF signalling in endoderm specification has been viewed as indirect effect due to a defect in this EMT-like event. Differentiating ES cells appear to transit into a primitive streak like state undergoing a degree of EMT that recapitulates a component of gastrulation in vitro [D'Amour et al, 2005;Morrison et al, 2008;Livigni et al, 2009;Unpublished observations]. Moreover, ES cells differentiating towards endoderm rapidly down regulate markers of mesenchyme and upregulate E-cadherin, apparently regaining a degree of epithelial morphology [Villegas and Brickman, unpublished observations;Tada et al, 2005;Yasunaga et al, 2005].…”

Section: Differentiation Towards the Mesoderm And Endoderm Lineagesmentioning

confidence: 99%

“…Interestingly, there is no in vivo evidence for FGF playing a part in this later step in endodermal epithelialisation. However, in both human and mouse ES cell differentiation, FGF signalling appears absolutely required for the specification of endoderm [Morrison et al, 2008;Shiraki et al, 2008;Hansson et al, 2009;Livigni et al, 2009] and reduced levels of FGF signalling from the primitive streak stage appears to favour mesoderm differentiation [Morrison et al, 2008]. Thus FGF signalling maybe required for multiple morphogenetic changes in this lineage and ES cell differentiation may afford a unique tool to dissect the role of this pathway at these subsequent stages of differentiation.…”

Section: Differentiation Towards the Mesoderm And Endoderm Lineagesmentioning

confidence: 99%

FGF signalling as a mediator of lineage transitions—Evidence from embryonic stem cell differentiation

Villegas¹,

Canham²,

Brickman³

2010

J of Cellular Biochemistry

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The fibroblast growth factor (FGF) signalling pathway is one of the most ubiquitous in biology. It has diverse roles in development, differentiation and cancer. Embryonic stem (ES) cells are in vitro cell lines capable of differentiating into all the lineages of the conceptus. As such they have the capacity to differentiate into derivatives of all three germ layers and to some extent the extra-embryonic lineages as well. Given the prominent role of FGF signalling in early embryonic development, we explore the role of this pathway in early ES cell differentiation towards the major lineages of the embryo. As early embryonic differentiation is intricately choreographed at the level of morphogenetic movement, adherent ES cell culture affords a unique opportunity to study the basic steps in early lineage specification in the absence of ever shifting complex in vivo microenvironments. Thus recent experiments in ES cell differentiation are able to pinpoint specific FGF dependent lineage transitions that are difficult to resolve in vivo. Here we review the role of FGF signalling in early development alongside the ES cell data and suggest that FGF dependent signalling via phospho-Erk activation maybe a major mediator of transitions in lineage specification.

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“…The liver originates from the foregut definitive endoderm (DE), which forms from the mesendoderm of the anterior region of the primitive streak [ 1 ]. These endodermal precursors give rise to cells for both the liver and pancreas.…”

Section: Introductionmentioning

confidence: 99%

Hhex Is Necessary for the Hepatic Differentiation of Mouse ES Cells and Acts via Vegf Signaling

Arterbery

Bogue

2016

PLoS ONE

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Elucidating the molecular mechanisms involved in the differentiation of stem cells to hepatic cells is critical for both understanding normal developmental processes as well as for optimizing the generation of functional hepatic cells for therapy. We performed in vitro differentiation of mouse embryonic stem cells (mESCs) with a null mutation in the homeobox gene Hhex and show that Hhex-/- mESCs fail to differentiate from definitive endoderm (Sox17+/Foxa2+) to hepatic endoderm (Alb+/Dlk+). In addition, hepatic culture elicited a >7-fold increase in Vegfa mRNA expression in Hhex-/- cells compared to Hhex+/+ cells. Furthermore, we identified VEGFR2+/ALB+/CD34- in early Hhex+/+ hepatic cultures. These cells were absent in Hhex-/- cultures. Finally, through manipulation of Hhex and Vegfa expression, gain and loss of expression experiments revealed that Hhex shares an inverse relationship with the activity of the Vegf signaling pathway in supporting hepatic differentiation. In summary, our results suggest that Hhex represses Vegf signaling during hepatic differentiation of mouse ESCs allowing for cell-type autonomous regulation of Vegfr2 activity independent of endothelial cells.

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Differentiation of Embryonic Stem Cells into Anterior Definitive Endoderm

Cited by 13 publications

References 25 publications

PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix

PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix

FGF signalling as a mediator of lineage transitions—Evidence from embryonic stem cell differentiation

Hhex Is Necessary for the Hepatic Differentiation of Mouse ES Cells and Acts via Vegf Signaling

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