A Complex Role for FGF-2 in Self-Renewal, Survival, and Adhesion of Human Embryonic Stem Cells

Abstract

The transcription program that is responsible for the pluripotency of human ESCs (hESCs) is believed to be comaintained by exogenous fibroblast growth factor-2 (FGF-2), which activates FGF receptors (FGFRs) and stimulates the mitogen-activated protein kinase (MAPK) pathway. However, the same pathway is stimulated by insulin receptors, insulin-like growth factor 1 receptors, and epidermal growth factor receptors. This mechanism is further complicated by intracrine FGF signals. Thus, the molecular mechanisms by which FGF-2 promotes the undifferentiated growth of hESCs are unclear. Here we show that, in undifferentiated hESCs, exogenous FGF-2 stimulated the expression of stem cell genes while suppressing cell death and apoptosis genes. Inhibition of autocrine FGF signaling caused upregulation of differentiation-related genes and downregulation of stem cell genes. Thus, exogenous FGF-2 reinforced the pluripotency maintenance program of intracrine FGF-2 signaling. Consistent with this hypothesis, expression of endogenous FGF-2 decreased during hESC differentiation and FGF-2 knockdown-induced hESC differentiation. In addition, FGF-2 signaling via FGFR2 activated MAPK kinase/extracellular signal-regulated kinase and AKT kinases, protected hESC from stress-induced cell death, and increased hESC adhesion and cloning efficiency. This stimulation of self-renewal, cell survival, and adhesion by exogenous and endogenous FGF-2 may synergize to maintain the undifferentiated growth of hESCs. Stem Cells 2009;27:1847–1857

The Lamina Propria of Adult Human Oral Mucosa Harbors a Novel Stem Cell Population

“…This increased self-renewal capacity of OMLP-fibroblasts was telomerase-independent, but was related to increased telomeres length compared with skin fibroblasts suggesting that the OMPL population is endowed with inherent mechanisms that preserves telomere length. Endogenous FGF-2 has recently been proposed to contribute to maintaining pluripotency genes expression and reduce stress-induced apoptosis in hESC [55]. It might be possible that similar endogenous FGF-2 activity in hOMSC increases their lifespan and maintain them in a relatively undifferentiated state.…”

Overexpression of BCL2 enhances survival of human embryonic stem cells during stress and obviates the requirement for serum factors

“…Although several defined media have optimized the growth and maintenance condition for hESCs without the requirement of a feeder layer, these media still rely on bFGF supplementation. FGF signaling plays a critical role in the survival, self-renewal, proliferation, and maintenance of the undifferentiated hESC state in vitro (8)(9)(10)(11)(12)(13)(14).…”

Inhibition of Caspase-mediated Anoikis Is Critical for Basic Fibroblast Growth Factor-sustained Culture of Human Pluripotent Stem Cells

“…Many FGF receptors and ligands are expressed in human ES cells (17,18) with FGFR1 (19) and FGF4 (20) being the most abundant species. Expression of endogenous bFGF decreases during human ES cell differentiation (21). Inhibition of FGF receptors with SU5402 decreases phosphorylation/activation of ERK in human ES cells and induces differentiation (22), whereas exogenous bFGF increases phosphorylation/ activation of ERK in the cells (18,19).…”