title: FGF2 specifies hESC-derived definitive endoderm into foregut/midgut cell lineages in a concentration-dependent manner.
abstract: Fibroblast growth factor (FGF) signaling controls axis formation during endoderm development. Studies in lower vertebrates have demonstrated that FGF2 primarily patterns the ventral foregut endoderm into liver and lung, whereas FGF4 exhibits broad anterior-posterior and left-right patterning activities. Furthermore, an inductive role of FGF2 during dorsal pancreas formation has been shown. However, whether FGF2 plays a similar role during human endoderm development remains unknown. Here, we show that FGF2 specifies hESC-derived definitive endoderm (DE) into different foregut lineages in a dosage-dependent manner. Specifically, increasing concentrations of FGF2 inhibits hepatocyte differentiation, whereas intermediate concentration of FGF2 promotes differentiation toward a pancreatic cell fate. At high FGF2 levels specification of midgut endoderm into small intestinal progenitors is increased at the expense of PDX1(+) pancreatic progenitors. High FGF2 concentrations also promote differentiation toward an anterior foregut pulmonary cell fate. Finally, by dissecting the FGF receptor intracellular pathway that regulates pancreas specification, we demonstrate for the first time to the best of our knowledge that induction of PDX1(+) pancreatic progenitors relies on FGF2-mediated activation of the MAPK signaling pathway. Altogether, these observations suggest a broader gut endodermal patterning activity of FGF2 that corresponds to what has previously been advocated for FGF4, implying a functional switch from FGF4 to FGF2 during evolution. Thus, our results provide new knowledge of how cell fate specification of human DE is controlled-facts that will be of great value for future regenerative cell therapies.
authors.affiliation: Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ameri
authors.forename: Anders
authors.initials: A
authors.lastname: Ståhlberg
authors.forename: Jesper
authors.initials: J
authors.lastname: Pedersen
authors.forename: Jenny K
authors.initials: JK
authors.lastname: Johansson
authors.forename: Martina M
authors.initials: MM
authors.lastname: Johannesson
authors.forename: Isabella
authors.initials: I
authors.lastname: Artner
authors.forename: Henrik
authors.initials: H
authors.lastname: Semb
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D005075:Biological Evolution; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D004064:Digestive System / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005775:Gastrula / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D022781:Hepatocytes / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000196:embryology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010179:Pancreas / Q000196:embryology / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
chemical_list: D018398:Homeodomain Proteins; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor; D015534:Trans-Activators; D051153:Wnt Proteins; D060508:Wnt3 Protein; C422405:activin A; C084010:pancreatic and duodenal homeobox 1 protein; D016222:Fibroblast Growth Factor 2; D028341:Activins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3