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Glycocalyx remodeling with proteoglycan mimetics promotes neural specification in embryonic stem cells.

Huang ML, Smith RA, Trieger GW, Godula K - J. Am. Chem. Soc. (2014)

Bottom Line: Interactions of GFs with their receptors are often mediated by heparan sulfate proteoglycans (HSPGs).There, the neoPGs assumed the function of native HSPGs, rescued FGF2-mediated kinase activity, and promoted neural specification.This glycocalyx remodeling strategy is versatile and may be applicable to other types of differentiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , San Diego, California 92093-0358, United States.

ABSTRACT
Growth factor (GF) signaling is a key determinant of stem cell fate. Interactions of GFs with their receptors are often mediated by heparan sulfate proteoglycans (HSPGs). Here, we report a cell surface engineering strategy that exploits the function of HSPGs to promote differentiation in embryonic stem cells (ESCs). We have generated synthetic neoproteoglycans (neoPGs) with affinity for the fibroblast growth factor 2 (FGF2) and introduced them into plasma membranes of ESCs deficient in HS biosynthesis. There, the neoPGs assumed the function of native HSPGs, rescued FGF2-mediated kinase activity, and promoted neural specification. This glycocalyx remodeling strategy is versatile and may be applicable to other types of differentiation.

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Neural differentiationof neoPG-remodeled Ext1–/– mESCs. NeoPG 11D with affinity toward FGF2 promoteddifferentiation into neural rosettes (A), while cells remodeled withneoPGs 11A and N (B and C) or left untreated(D) retained their embryonic characteristics. Soluble heparin alsopromoted differentiation (E). The ability to produce rosettes improvedin cells treated at increasing concentrations of neoPG 11D (F).
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fig4: Neural differentiationof neoPG-remodeled Ext1–/– mESCs. NeoPG 11D with affinity toward FGF2 promoteddifferentiation into neural rosettes (A), while cells remodeled withneoPGs 11A and N (B and C) or left untreated(D) retained their embryonic characteristics. Soluble heparin alsopromoted differentiation (E). The ability to produce rosettes improvedin cells treated at increasing concentrations of neoPG 11D (F).

Mentions: To assess whether neoPGs can induce neuralspecification in Ext1–/– mESCs, we performeddifferentiation in monolayerculture.20 Concordant with previous work,Ext1–/– mESCs failed to undergo neural specificationafter 6 days, as evidenced by expression of the pluripotency marker,Oct4.4c Gratifyingly, mESCs remodeled withneoPG 11D, which promotes FGF2 recruitment to the cells’surface and stimulates the associated Erk1/2 signaling, successfullyexited from their pluripotent state and formed characteristic nestin-positiveneural rosettes with decreased Oct4 expression (Figure 4A).21 In comparison, neoPGs 11A and N, which do not engage FGF2, had no effecton differentiation and colonies expressing high levels of Oct4 similarto those in untreated Ext1–/– mESCs remainedabundant (Figure 4B–D).


Glycocalyx remodeling with proteoglycan mimetics promotes neural specification in embryonic stem cells.

Huang ML, Smith RA, Trieger GW, Godula K - J. Am. Chem. Soc. (2014)

Neural differentiationof neoPG-remodeled Ext1–/– mESCs. NeoPG 11D with affinity toward FGF2 promoteddifferentiation into neural rosettes (A), while cells remodeled withneoPGs 11A and N (B and C) or left untreated(D) retained their embryonic characteristics. Soluble heparin alsopromoted differentiation (E). The ability to produce rosettes improvedin cells treated at increasing concentrations of neoPG 11D (F).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4121001&req=5

fig4: Neural differentiationof neoPG-remodeled Ext1–/– mESCs. NeoPG 11D with affinity toward FGF2 promoteddifferentiation into neural rosettes (A), while cells remodeled withneoPGs 11A and N (B and C) or left untreated(D) retained their embryonic characteristics. Soluble heparin alsopromoted differentiation (E). The ability to produce rosettes improvedin cells treated at increasing concentrations of neoPG 11D (F).
Mentions: To assess whether neoPGs can induce neuralspecification in Ext1–/– mESCs, we performeddifferentiation in monolayerculture.20 Concordant with previous work,Ext1–/– mESCs failed to undergo neural specificationafter 6 days, as evidenced by expression of the pluripotency marker,Oct4.4c Gratifyingly, mESCs remodeled withneoPG 11D, which promotes FGF2 recruitment to the cells’surface and stimulates the associated Erk1/2 signaling, successfullyexited from their pluripotent state and formed characteristic nestin-positiveneural rosettes with decreased Oct4 expression (Figure 4A).21 In comparison, neoPGs 11A and N, which do not engage FGF2, had no effecton differentiation and colonies expressing high levels of Oct4 similarto those in untreated Ext1–/– mESCs remainedabundant (Figure 4B–D).

Bottom Line: Interactions of GFs with their receptors are often mediated by heparan sulfate proteoglycans (HSPGs).There, the neoPGs assumed the function of native HSPGs, rescued FGF2-mediated kinase activity, and promoted neural specification.This glycocalyx remodeling strategy is versatile and may be applicable to other types of differentiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of California , San Diego, California 92093-0358, United States.

ABSTRACT
Growth factor (GF) signaling is a key determinant of stem cell fate. Interactions of GFs with their receptors are often mediated by heparan sulfate proteoglycans (HSPGs). Here, we report a cell surface engineering strategy that exploits the function of HSPGs to promote differentiation in embryonic stem cells (ESCs). We have generated synthetic neoproteoglycans (neoPGs) with affinity for the fibroblast growth factor 2 (FGF2) and introduced them into plasma membranes of ESCs deficient in HS biosynthesis. There, the neoPGs assumed the function of native HSPGs, rescued FGF2-mediated kinase activity, and promoted neural specification. This glycocalyx remodeling strategy is versatile and may be applicable to other types of differentiation.

Show MeSH
Related in: MedlinePlus