FGFR-mediated ERK1/2 signaling contributes to mesendoderm and definitive endoderm formation in vitro

The differentiation of human pluripotent stem cells into the SOX17+ definitive endoderm (DE) germ layer is important for generating tissues for regenerative medicine. Multiple developmental and stem cell studies have demonstrated that Activin/Nodal signaling is the primary driver of definitive endod...

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Published iniScience Vol. 26; no. 8; p. 107265
Main Authors Lau, Hwee Hui, Amirruddin, Nur Shabrina, Loo, Larry Sai Weng, Chan, Jun Wei, Iich, Elhadi, Krishnan, Vidhya Gomathi, Hoon, Shawn, Teo, Adrian Kee Keong
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 18.08.2023
Elsevier
Subjects
Biological sciences
Developmental biology
Embryology
Molecular biology
Embryology
Biological sciences
Molecular biology
Developmental biology
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ISSN2589-0042
2589-0042
DOI10.1016/j.isci.2023.107265

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Summary:The differentiation of human pluripotent stem cells into the SOX17+ definitive endoderm (DE) germ layer is important for generating tissues for regenerative medicine. Multiple developmental and stem cell studies have demonstrated that Activin/Nodal signaling is the primary driver of definitive endoderm formation. Here, we uncover that the FGF2-FGFR-ERK1/2 signaling contributes to mesendoderm and SOX17+ DE formation. Without ERK1/2 signaling, the Activin/Nodal signaling is insufficient to drive mesendoderm and DE formation. Besides FGF2-FGFR-mediated signaling, IGF1R signaling possibly contributes to the ERK1/2 signaling for DE formation. We identified a temporal relationship between Activin/Nodal-SMAD2 and FGF2-FGFR-ERK1/2 signaling in which Activin/Nodal-SMAD2 participates in the initiation of mesendoderm and DE specification that is followed by increasing activity of FGF2-FGFR-ERK1/2 to facilitate and permit the successful generation of SOX17+ DE. Overall, besides the role of Activin/Nodal signaling for DE formation, our findings shed light on the contribution of ERK1/2 signaling for mesendoderm and DE formation. [Display omitted] •FGF2 potentiates mesendoderm and DE formation through FGFR2 and ERK1/2 signaling•ERK1/2 signaling is involved in cell cycle process•IGF1R- but not IR-mediated ERK1/2 signaling also contributes to DE formation•Increased pSMAD2 on inhibition of FGFR2-ERK1/2 signaling fails to direct DE formation Biological sciences; Molecular biology; Developmental biology; Embryology
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.107265