Document Detail


FGF2 specifies hESC-derived definitive endoderm into foregut/midgut cell lineages in a concentration-dependent manner.
MedLine Citation:
PMID:  19890880     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Jacqueline Ameri; Anders Ståhlberg; Jesper Pedersen; Jenny K Johansson; Martina M Johannesson; Isabella Artner; Henrik Semb
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Stem cells (Dayton, Ohio)     Volume:  28     ISSN:  1549-4918     ISO Abbreviation:  Stem Cells     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-19     Completed Date:  2010-03-01     Revised Date:  2011-06-01    
Medline Journal Info:
Nlm Unique ID:  9304532     Medline TA:  Stem Cells     Country:  United States    
Other Details:
Languages:  eng     Pagination:  45-56     Citation Subset:  IM    
Affiliation:
Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Activins / metabolism
Animals
Biological Evolution
Cell Differentiation* / drug effects,  genetics
Cell Line
Cell Lineage* / drug effects,  genetics
Digestive System / drug effects,  embryology,  metabolism*
Dose-Response Relationship, Drug
Embryonic Stem Cells / drug effects,  metabolism*
Endoderm / cytology,  drug effects,  metabolism*
Fibroblast Growth Factor 2 / metabolism*
Gastrula / cytology,  drug effects,  metabolism*
Gene Expression Regulation, Developmental
Hepatocytes / metabolism
Homeodomain Proteins / metabolism
Humans
Intestine, Small / embryology,  metabolism
MAP Kinase Signaling System / drug effects
Mice
Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors,  metabolism
Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors,  metabolism
Pancreas / embryology,  metabolism
Protein Kinase Inhibitors / pharmacology
Receptors, Fibroblast Growth Factor / antagonists & inhibitors,  metabolism
Time Factors
Trans-Activators / metabolism
Wnt Proteins / metabolism
Chemical
Reg. No./Substance:
0/Homeodomain Proteins; 0/Protein Kinase Inhibitors; 0/Receptors, Fibroblast Growth Factor; 0/Trans-Activators; 0/Wnt Proteins; 0/Wnt-3 protein; 0/activin A; 0/pancreatic and duodenal homeobox 1 protein; 103107-01-3/Fibroblast Growth Factor 2; 104625-48-1/Activins; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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