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FGF2 Specifies hESC-Derived Definitive Endoderm into Foregut/Midgut Cell Lineages in a Concentration-Dependent Manner.

Ameri, Jacqueline LU ; Ståhlberg, Anders; Pedersen, Jesper; Johansson, Jenny LU ; Johannesson, Martina LU ; Artner, Isabella LU and Semb, Henrik LU (2010) In Stem Cells 28. p.45-56
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... (More)
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 towards 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 towards 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 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Stem Cells
volume
28
pages
45 - 56
publisher
AlphaMed Press
external identifiers
  • WOS:000274496600008
  • PMID:19890880
  • Scopus:75349111313
ISSN
1549-4918
DOI
10.1002/stem.249
language
English
LU publication?
yes
id
564b0dea-d2ba-47a3-b170-5a05a3d5c160 (old id 1512232)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19890880?dopt=Abstract
date added to LUP
2009-12-01 11:26:41
date last changed
2016-11-20 04:24:06
@misc{564b0dea-d2ba-47a3-b170-5a05a3d5c160,
  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 towards 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 towards 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 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.},
  author       = {Ameri, Jacqueline and Ståhlberg, Anders and Pedersen, Jesper and Johansson, Jenny and Johannesson, Martina and Artner, Isabella and Semb, Henrik},
  issn         = {1549-4918},
  language     = {eng},
  pages        = {45--56},
  publisher    = {ARRAY(0x7434458)},
  series       = {Stem Cells},
  title        = {FGF2 Specifies hESC-Derived Definitive Endoderm into Foregut/Midgut Cell Lineages in a Concentration-Dependent Manner.},
  url          = {http://dx.doi.org/10.1002/stem.249},
  volume       = {28},
  year         = {2010},
}