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Background  Retinoic acid (RA) and fibroblast growth factor 4 (FGF4) signaling control endoderm patterning and pancreas induction/expansion. Based on these findings, RA and FGFs, excluding FGF4, have frequently been used in differentiation protocols to direct differentiation of hESCs into endodermal and pancreatic cell types. In vivo, these signaling pathways act in a temporal and concentration-dependent manner. However, in vitro, the underlying basis for the time of addition of growth and differentiation factors (GDFs), including RA and FGFs, as well as the concentration is lacking. Thus, in order to develop robust and reliable differentiation protocols of ESCs into mature pancreatic cell types, including insulin-producing β cells, it will be important to mechanistically understand each specification step. This includes differentiation of mesendoderm/definitive endoderm into foregut endoderm- the origin of pancreatic endoderm.    Methodology/Principal Findings  Here, we provide data on the individual and combinatorial role of RA and FGF4 in directing differentiation of ActivinA (AA)-induced hESCs into  PDX1 -expressing cells. FGF4's ability to affect endoderm patterning and specification in vitro has so far not been tested. By testing out the optimal concentration and timing of addition of FGF4 and RA, we present a robust differentiation protocol that on average generates 32% PDX1 +  cells. Furthermore, we show that RA is required for converting AA-induced hESCs into PDX1 +  cells, and that part of the underlying mechanism involves FGF receptor signaling. Finally, further characterization of the PDX1 +  cells suggests that they represent foregut endoderm not yet committed to pancreatic, posterior stomach, or duodenal endoderm.    Conclusion/Significance  In conclusion, we show that RA and FGF4 jointly direct differentiation of PDX1 +  foregut endoderm in a robust and efficient manner. RA signaling mediated by the early induction of RARβ through AA/Wnt3a is required for PDX1 expression. Part of RA's activity is mediated by FGF signaling.

FGF4 and Retinoic Acid Direct Differentiation of hESCs into PDX1-Expressing Foregut Endoderm in a Time- and Concentration-Dependent Manner