FGF Signaling Pathway: A Key Regulator of Stem Cell Pluripotency

Abstract

Pluripotent stem cells (PSCs) isolated in vitro from embryonic stem cells (ESCs), induced PSC (iPSC) and also post-implantation epiblast-derived stem cells (EpiSCs) are known for their two unique characteristics: the ability to give rise to all somatic lineages and the self-renewal capacity. Numerous intrinsic signaling pathways contribute to the maintenance of the pluripotency state of stem cells by tightly controlling key transcriptional regulators of stemness including sex determining region Y box 2 (Sox-2), octamer-binding transcription factor (Oct)3/4, krueppel-like factor 4 (Klf-4), Nanog, and c-Myc. Signaling by fibroblast growth factor (FGF) is of critical importance in regulating stem cells pluripotency. The FGF family is comprised of 22 ligands that interact with four FGF receptors (FGFRs). FGF/FGFR signaling governs fundamental cellular processes such as cell survival, proliferation, migration, differentiation, embryonic development, organogenesis, tissue repair/regeneration, and metabolism. FGF signaling is mediated by the activation of RAS - mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT, Phospholipase C Gamma (PLCγ), and signal transducers and activators of transcription (STAT), which intersects and synergizes with other signaling pathways such as Wnt, retinoic acid (RA) and transforming growth factor (TGF)-β signaling. In the current review, we summarize the role of FGF signaling in the maintenance of pluripotency state of stem cells through regulation of key transcriptional factors.

Keywords: FGF; pluripotency; self-renewal; stem cells; transcription factor.

FIGURE 1

Extrinsic signaling pathways governing stemness of pluripotent stem cells. Pluripotency and self-renewal characteristics of stem cells modulated by positive or negative regulation of SOX2, NANOG, and OCT3/4 by various signaling pathways in the nucleus of both mouse and human. (A) Mouse naïve pluripotency mainly controlled by LIF/STAT3, BMP4, Wnt/β-Catenin, and FGF4/ERK signaling pathways. LIF maintains pluripotency through binding to its receptor, gp130/LIFR, followed by activation of JAK/STAT3. Phosphorylated STAT3 interacts with KLF4 and maintains the pluripotency through OCT3/4. BMP4/SMAD signaling controls core transcriptional TFs through interaction with KLF4. FGF4/ERK signaling promotes differentiation of mESCs through JNK/c-JUN and MEK/ERK pathways as downstream regulators. (B) Primed state of pluripotency in mEpiSCs, hESC, and hiPSCs is mainly controlled by FGF2/ERK and TGFβ/Activin/Nodal pathways. FGF2 acts through PI3K/AKT, PLCγ and MEK/ERK. TGF/SMAD pathway directly controls pluripotency through interaction with NANOG. IGF2 binding to IGF1R activates PI3K/AKT pathway and regulates stemness by interaction with SOX2. Inhibitors and activators of signaling pathways showed by red blunt-headed and dark blue arrows, respectively.

FIGURE 2

Controlling pluripotency using small molecule inhibitors and growth factors. Primed and Naïve pluripotent stem cells cultured in various conditions in the presence of small molecule inhibitors and multiple growth factors to govern the self-renewal, pluripotency, and conversion of primed to naïve pluripotent stem cells. (A) All the inhibitors indicated by “i.” Red blunt-headed arrow demonstrates the inhibition of differentiation and expression of lineage-committed markers such as Nestin, FGF5, Sox17, Lefty, T-Brachyury, and Lefty2. (B) Pluripotent characteristics of PSCs controlled by multiple growth factors. Key growth factors contributing to maintainance of pluripotency of PSCs are summarized.