Thermal Stability of Fibroblast Growth Factor Protein Is a Determinant Factor in Regulating Self-Renewal, Differentiation, and Reprogramming in Human Pluripotent Stem Cells

Chen, Guokai; Gulbranson, Daniel R.; Yu, Pengzhi; Hou, Zhonggang; Thomson, James A.

doi:10.1002/stem.1021

Cited by 112 publications

(99 citation statements)

References 36 publications

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“…FGF-MEK signaling is required for the maintenance of pluripotency through NANOG expression in hESCs [46], but not mESCs. Additionally, the FGF-MEK signaling pathway has been proposed to be required for mammalian neural induction [47,48].…”

Section: Resultsmentioning

confidence: 99%

SMAD7 Directly Converts Human Embryonic Stem Cells to Telencephalic Fate by a Default Mechanism

et al. 2012

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Human embryonic stem cells (hESCs) provide a valuable window into the dissection of the molecular circuitry underlying the early formation of the human forebrain. However, dissection of signaling events in forebrain development using current protocols is complicated by non-neural contamination and fluctuation of extrinsic influences. Here we show that SMAD7, a cell-intrinsic inhibitor of TGFβ signaling, is sufficient to directly convert pluripotent hESCs to an anterior neural fate. Time-course gene expression revealed down-regulation of MAPK components, and combining MEK1/2 inhibition with SMAD7-mediated TGFβ inhibition promoted telencephalic conversion. FGF-MEK and TGFβ-SMAD signaling maintain hESCs by promoting pluripotency genes and repressing neural genes. Our findings suggest that in the absence of these cues, pluripotent cells simply revert to a program of neural conversion. Hence the “primed” state of hESCs requires inhibition of the “default” state of neural fate acquisition. This has parallels in amphibians, suggesting an evolutionarily conserved mechanism.

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Section: Resultsmentioning

confidence: 99%

SMAD7 Directly Converts Human Embryonic Stem Cells to Telencephalic Fate by a Default Mechanism

et al. 2012

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“…signaling plays a role in SC self-renewal and differentiation (35)(36)(37)(38). We first employed RT-PCR analyses to characterize the expression of Fgfr genes in the CLs and in DESC spheres (Fig.…”

Section: Fgf Signaling In Descs Is Required For Sphere Formation and mentioning

confidence: 99%

Fibroblast Growth Factor Signaling Is Essential for Self-renewal of Dental Epithelial Stem Cells

Chang

Liu

Huang

et al. 2013

Journal of Biological Chemistry

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Background:Understanding of the self-renewal and differentiation of dental epithelial stem cells (DESCs) is important for tooth regeneration therapies. Results: Depletion of FGF signaling suppressed self-renewal and led to differentiation of DESCs. Conclusion: FGF signaling is essential for maintenance of DESCs. Significance: The finding sheds new light on the mechanism by which the homeostasis, expansion, and differentiation of DESCs are regulated.

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“…A recent study demonstrated that among 17 FGFs tested, only FGF2, FGF4, FGF6, and FGF9 activate FGF receptor (FGFR) signaling in human embryonic stem cells (hESC). Moreover, normal FGFR activation was observed in hESC stimulated by stable FGF1 mutant but not its wild-type (wt) counterpart, suggesting that failure to signal in hESC may stem from instability in as many as 13 different members of FGF family [10].…”

Section: Introductionmentioning

confidence: 99%

Instability restricts signaling of multiple fibroblast growth factors

Buchtová

Chaloupková

Zakrzewska

et al. 2015

Cell. Mol. Life Sci.

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Fibroblast growth factors (FGFs) deliver extracellular signals that govern many developmental and regenerative processes, but the mechanisms regulating FGF signaling remain incompletely understood. Here, we explored the relationship between intrinsic stability of FGF proteins and their biological activity for all 18 members of the FGF family. We report that FGF1, FGF3, FGF4, FGF6, FGF8, FGF9, FGF10, FGF16, FGF17, FGF18, FGF20, and FGF22 exist as unstable proteins, which are rapidly degraded in cell cultivation media. Biological activity of FGF1, FGF3, FGF4, FGF6, FGF8, FGF10, FGF16, FGF17, and FGF20 is limited by their instability, manifesting as failure to activate FGF receptor signal transduction over long periods of time, and influence specific cell behavior in vitro and in vivo. Stabilization via exogenous heparin binding, introduction of stabilizing mutations or lowering the cell cultivation temperature rescues signaling of unstable FGFs. Thus, the intrinsic ligand instability is an important elementary level of regulation in the FGF signaling system.

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Thermal Stability of Fibroblast Growth Factor Protein Is a Determinant Factor in Regulating Self-Renewal, Differentiation, and Reprogramming in Human Pluripotent Stem Cells

Cited by 112 publications

References 36 publications

SMAD7 Directly Converts Human Embryonic Stem Cells to Telencephalic Fate by a Default Mechanism

SMAD7 Directly Converts Human Embryonic Stem Cells to Telencephalic Fate by a Default Mechanism

Fibroblast Growth Factor Signaling Is Essential for Self-renewal of Dental Epithelial Stem Cells

Instability restricts signaling of multiple fibroblast growth factors

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