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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Jacqueline Ameri
  • Anders Ståhlberg
  • Jesper Pedersen
  • Jenny Johansson
  • Martina Johannesson
  • Isabella Artner
  • Henrik Semb
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
Original languageEnglish
Pages (from-to)45-56
JournalStem Cells
Volume28
Publication statusPublished - 2010
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019), Stem Cell and Pancreas Developmental Biology (013212044)

Related research output

Ameri, J., 2010, Stem Cells and Pancreas Development Biology. 91 p.

Research output: ThesisDoctoral Thesis (compilation)

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