Lau Hwee Hui, Amirruddin Nur Shabrina, Loo Larry Sai Weng, Chan Jun Wei, Iich Elhadi, Krishnan Vidhya Gomathi, Hoon Shawn, Teo Adrian Kee Keong
Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Proteos, Singapore, Singapore.
School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
iScience. 2023 Jul 3;26(8):107265. doi: 10.1016/j.isci.2023.107265. eCollection 2023 Aug 18.
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.
将人类多能干细胞分化为SOX17定形内胚层（DE）胚层对于生成再生医学所需的组织非常重要。多项发育和干细胞研究表明，激活素/节点信号是定形内胚层形成的主要驱动因素。在此，我们发现FGF2-FGFR-ERK1/2信号有助于中胚层和SOX17 DE的形成。没有ERK1/2信号，激活素/节点信号不足以驱动中胚层和DE的形成。除了FGF2-FGFR介导的信号外，IGF1R信号可能有助于ERK1/2信号促进DE的形成。我们确定了激活素/节点-SMAD2和FGF2-FGFR-ERK1/2信号之间的时间关系，其中激活素/节点-SMAD2参与中胚层和DE特化的起始，随后FGF2-FGFR-ERK1/2的活性增加，以促进并允许成功生成SOX17 DE。总体而言，除了激活素/节点信号对DE形成的作用外，我们的研究结果还揭示了ERK1/2信号对中胚层和DE形成的贡献。
