Endoderm Marker Proteins

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 Endoderm Marker Proteins Background

Endoderm Induction

Developmental signals in the early embryo lead to the induction and specification of the definitive endoderm. Subsequent patterning of definitive endoderm leads to the formation of many major organs including the liver, pancreas, intestines, thymus, thyroid, and lung. Studies have shown that the Nodal signaling pathway regulates proper mesoderm and endoderm formation. Established morphogen zones in the early and late PS of the developing mouse embryo show low Wingless-Ing (Wnt) and Nodal signaling in the posterior region, with regions of increasingly stronger Nodal signaling distally. NODAL ligands are members of the Transforming Growth Factor Beta (TGFβ) family. Whereas low levels of NODAL signaling induces the formation of mesoderm, by mimicking endogenous NODAL signaling during gastrulation through high concentrations of the TGFβ ligand ACTIVIN A to pluripotent stem cells in vitro, formation of a definitive endoderm fate is induced, defined by the co-expression of CXCR4 and EpCAM.

Anterior-Posterior (AP) Patterning of Definitive Endoderm

Subsequent to gastrulation, the endoderm germ layer forms a primitive gut tube from which organ buds emerge. During this time, signals from the anterior visceral endoderm (AVE) and mesoderm are believed to pattern the definitive endoderm along the AP axis. The AVE, a region of the visceral endoderm found on the anterior side of the embryo, expresses the Wnt inhibitor, Dkk1, and the Nodal inhibitors, Cerberus-like and Lefty1. expression of these inhibitors is important for anterior patterning of the epiblast and for restricting PS formation to the posterior side of the embryo.

In the endoderm, the AP axis is marked by the segregation of transcription factors, with Sox2 expression in the anterior region of the endoderm, and Cdx2 expression in the posterior region. This Sox2-Cdx2 boundary is located slightly posterior to the foregut-midgut junction. Sox2+ foregut endoderm gives rise to the thymus, thyroid, esophagus, trachea, lungs, stomach, and liver, while Sox2+ Cdx2+ midgut endoderm gives rise to the pancreas. Cdx2+ hindgut endoderm gives rise to the intestine. While the generation of midgut and hindgut cell types from pluripotent stem cells has been successful, efforts in generating foregut endoderm cell types have focused primarily on the posterior aspect, with the generation of hepatic cells from pluripotent stem cells.

The efficient generation of hepatocytes, marked by the expression of α- fetoprotein and albumin proteins in differentiating ESC, relies on the addition of BMP4 and basic Fibroblast Growth Factor (FGF) to Activin A-induced definitive endoderm cultures. This finding is consistent with the regulatory role of BMP and FGF in liver induction. While this discovery is instrumental for future cellular replacement therapies of the liver, focus on the cell types of the anterior region of the foregut endoderm is needed. Mimicking the signaling pathways seen in the developing embryo in ESC, our lab has shown that exposure of both BMP inhibition and TGFβ inhibition to ACTIVIN-A-induced definitive endoderm cultures results in anterior patterning of the foregut endoderm, marked by SOX2+ FOXA2+ expression.

Dorsal-Ventral (DV) Patterning of Anterior Foregut Endoderm (AFE)

Following AP patterning of the definitive endoderm, the aspect of the endoderm anterior to the stomach undergoes DV patterning, giving rise to a dorsally positioned esophagus and ventrally located trachea, pharyngeal pouches, and lung buds. Starting at E9.5 in the mouse and the third week of development in humans, four outcroppings, or pharyngeal pouches, are formed from the pharyngeal endoderm. Pouch segmentation leads to the development of specific organs: Eustachian tube and tympanic cavity (1st pouch), palatine tonsil (2nd pouch), inferior parathyroid and thymus (3rd pouch), and superior parathyroid (4th pouch). The lung field develops posterior to the pharyngeal endoderm. Studies have shown that FGFs, BMP, and canonical WNT signals from the ventral mesoderm contribute to the DV patterning of the AFE, leading to the specification of trachea, pharyngeal pouch endoderm, and lung buds.