Functional evaluation of ES cell-derived endodermal populations reveals differences between Nodal and Activin A-guided differentiation

Chen, Alice E.; Borowiak, Malgorzata; Sherwood, Richard I.; Kweudjeu, Anastasie; Melton, Douglas A.

doi:10.1242/dev.085431

Cited by 49 publications

(58 citation statements)

References 71 publications

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“…However, the inductive pathways leading up to the PDX1 expression are disparate and may result in slightly different outcomes. This is similar to the induction of DE in vitro by activin A versus nodal [100]. Indeed, during early development, the ventral pancreas exhibits a predominance of PP cells and peptide YY-positive cells over other endocrine cell types [38].…”

Section: Generation Of Primitive Gut and Posterior Foregut Tissuesupporting

confidence: 66%

“…This suggests that the choice for either activin A or nodal is perhaps not without consequences for the successful induction of DE and the development of beta-cells downstream of that. Indeed, a recent report demonstrates that the use of nodal instead of activin A results in a greater frequency of mouse ES cell-derived beta-cells, despite only modest initial differences in global gene expression at the DE stage [100].…”

Section: Generation Of Definitive Endodermmentioning

confidence: 99%

“…For example, the use of nodal versus activin A results in highly similar DE with respect to general gene expression profile. However, it leads to a higher frequency of cells with high levels of PDX1, which in turn have a greater propensity to become insulin-positive cells [100]. PDX1-high cells derived via either method do not appear to differ in their ability to generate beta-cells in vivo, but the fraction of PDX1 cells that differentiate along the beta-cell lineage varies, based on the prior use of nodal vs. activin A for DE induction [100].…”

Section: Generation Of Pancreatic Endodermmentioning

confidence: 99%

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Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Meulen¹,

Huising²

2014

Rev Diabet Stud

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■ AbstractType 1 diabetes (T1D) is a devastating disease precipitated by an autoimmune response directed at the insulinproducing beta-cells of the pancreas for which no cure exists. Stem cell-derived beta-cells show great promise for a cure as they have the potential to supply unlimited numbers of cells that could be derived from a patient's own cells, thus eliminating the need for immunosuppression. Current in vitro protocols for the differentiation of stem cell-derived beta-cells can successfully generate pancreatic endoderm cells. In diabetic rodents, such cells can differentiate further along the beta-cell lineage until they are eventually capable of restoring normoglycemia. While these observations demonstrate that stem cell-derived pancreatic endoderm has the potential to differentiate into mature, glucose-responsive beta-cells, the signals that direct differentiation and maturation from pancreatic endoderm onwards remain poorly understood. In this review, we analyze the sequence of events that culminates in the formation of beta-cells during embryonic development, and we summarize how current protocols to generate beta-cells have sought to capitalize on this ontogenic template. We place particular emphasis on the current challenges and opportunities which occur in the later stages of beta-cell differentiation and maturation of transplantable stem cell-derived beta-cells. Another focus is on the question how the use of recently identified maturation markers such as urocortin 3 can be instrumental in guiding these efforts.

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Section: Generation Of Primitive Gut and Posterior Foregut Tissuesupporting

confidence: 66%

Section: Generation Of Definitive Endodermmentioning

confidence: 99%

Section: Generation Of Pancreatic Endodermmentioning

confidence: 99%

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Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Meulen¹,

Huising²

2014

Rev Diabet Stud

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“…These protocols vary in parameters such as the formulation of the basic culture medium, the combination of supplements used and the dosage and timing at which they are delivered to the differentiating cells. Of particular interest is that Activin A and Nodal, two TGF-b superfamily factors, have been reported to elicit similar signalling responses and can induce differentiation of embryonic stem cells to DE-like cells with very similar molecular phenotypes [30,34], but Nodal-treated cells display greater functional capacity than their Activin A counterpart to differentiate into functionally competent pancreatic endoderm cells [30]. In our study, we observed different responses of EpiSCs to Nodal and Activin A during differentiation in culture.…”

Section: Nodal Promotes Differentiation Of Epiblast Stem Cells With Ementioning

confidence: 51%

Differential response of epiblast stem cells to Nodal and Activin signalling: a paradigm of early endoderm development in the embryo

Kaufman‐Francis

Goh

Studdert

et al. 2014

Phil. Trans. R. Soc. B

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Mouse epiblast stem cells (EpiSCs) display temporal differences in the upregulation of Mixl1 expression during the initial steps of in vitro differentiation, which can be correlated with their propensity for endoderm differentiation. EpiSCs that upregulated Mixl1 rapidly during differentiation responded robustly to both Activin A and Nodal in generating foregut endoderm and precursors of pancreatic and hepatic tissues. By contrast, EpiSCs that delayed Mixl1 upregulation responded less effectively to Nodal and showed an overall suboptimal outcome of directed differentiation. The enhancement in endoderm potency in Mixl1-early cells may be accounted for by a rapid exit from the progenitor state and the efficient response to the induction of differentiation by Nodal. EpiSCs that readily differentiate into the endoderm cells are marked by a distinctive expression fingerprint of transforming growth factor (TGF)-β signalling pathway genes and genes related to the endoderm lineage. Nodal appears to elicit responses that are associated with transition to a mesenchymal phenotype, whereas Activin A promotes gene expression associated with maintenance of an epithelial phenotype. We postulate that the formation of definitive endoderm (DE) in embryoid bodies follows a similar process to germ layer formation from the epiblast, requiring an initial de-epithelialization event and subsequent re-epithelialization. Our results show that priming EpiSCs with the appropriate form of TGF-β signalling at the formative phase of endoderm differentiation impacts on the further progression into mature DE-derived lineages, and that this is influenced by the initial characteristics of the cell population. Our study also highlights that Activin A, which is commonly used as an in vitro surrogate for Nodal in differentiation protocols, does not elicit the same downstream effects as Nodal, and therefore may not effectively mimic events that take place in the mouse embryo.

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“…Despite the central role of Nodal in specifying endoderm during development, current protocols for directed in vitro differentiation of endoderm derivatives rely on the related ligand Activin A as a surrogate, presumably because Activin is more active than commercially available recombinant Nodal (2)(3)(4)(5)(6)(7)(8). However, a recent study showed that Nodal induces endoderm progenitors that are more competent to mature into functional insulin-producing cells if it is added to cultured mouse ES cells at a 20-fold higher concentration than Activin A (9). As this concentration likely exceeds physiological levels, it is important to determine how the specific activity of recombinant Nodal might be improved.…”

mentioning

confidence: 99%

Nodal·Gdf1 Heterodimers with Bound Prodomains Enable Serum-independent Nodal Signaling and Endoderm Differentiation

Fuerer

Nostro

Constam

2014

Journal of Biological Chemistry

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Background: To generate active Nodal suited for directed stem cell differentiation, we purified it as a heterodimer with Gdf1. Results: Heterodimeric Nodal⅐Gdf1 copurified with their cleaved prodomains, potentiated receptor activation and endoderm differentiation, and enabled paracrine signaling in serum-free conditions. Conclusion: Cell-non-autonomous high Nodal signaling thresholds depend on low molecular weight heterodimers. Significance: Nodal⅐Gdf1 is a new reagent to differentiate endoderm.

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Functional evaluation of ES cell-derived endodermal populations reveals differences between Nodal and Activin A-guided differentiation

Cited by 49 publications

References 71 publications

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Maturation of Stem Cell-Derived Beta-cells Guided by the Expression of Urocortin 3

Differential response of epiblast stem cells to Nodal and Activin signalling: a paradigm of early endoderm development in the embryo

Nodal·Gdf1 Heterodimers with Bound Prodomains Enable Serum-independent Nodal Signaling and Endoderm Differentiation

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