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Surfen Towards Glycan-mediated Control of Embryonic Stem Cells

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Review of “Small Molecule Antagonist of Cell Surface Glycosaminoglycans Restricts Mouse Embryonic Stem Cells in a Pluripotent State” from STEM CELLS by Stuart P. Atkinson

Studies into the pluripotent state and differentiation of pluripotent stem cells (PSCs) have led to the development of many small molecules that target receptors, kinases, and epigenetic enzymes to influence cell fate. However, molecules with the potential to modulate critical interactions between cell surface glycans and extracellular elements represent a less studied area [1, 2].

Now, researchers from the laboratory of Kamil Godula (University of California San Diego, USA) describe how surfen, an aminoquinoline with heparin-neutralizing properties [3], can promote the maintenance of pluripotency in mouse embryonic stem cells (mESCs) by controlling glycan-mediated growth factor association and signaling [4]. Could we be “surfen” towards the glycan-mediated control of embryonic stem cells?

Initial analyses by Huang et al. noted that surfen successfully inhibited neural differentiation in a dose-dependent manner and promoted the maintenance of the pluripotent state after six days of differentiation without an effect on cell proliferation rates. Importantly, mESCs underwent successful neural differentiation following removal of surfen, suggesting the reversibility of the differentiation block. 

The authors next established that surfen had the ability to inhibit MAPK signaling by blocking FGF2 binding sites, while also inhibiting the phosphorylation of platelet-derived growth factor (PDGFRα), ErbB2, epidermal growth factor receptor (EGFR), macrophage-stimulating protein receptor (MSPR), and the vascular endothelial growth factor (VEGF) receptors 1 and 2.

The authors warn against extrapolating data from mESC studies directly to human ESC studies, given the differences in cell surface receptor expression [5], and so they hope that this study will serve as a stimulus to explore the potential for molecules such as surfen in relation to human ESC pluripotency and differentiation. Furthermore, the team expects that the molecular design and synthesis of chemical antagonists with enhanced selectivity will provide an improved means to specifically target classes of cell surface glycans [6] and explore their potential use in differentiation strategies.

To see more on this exciting new avenue for ESC biology, keep “surfen” and stay tuned to the Stem Cells Portal!

References

  1. Izumikawa T, Sato B, and Kitagawa H, Chondroitin Sulfate Is Indispensable for Pluripotency and Differentiation of Mouse Embryonic Stem Cells. Scientific Reports 2014;4:3701.
  2. Kraushaar Daniel C, Dalton S, and Wang L, Heparan sulfate: a key regulator of embryonic stem cell fate, in Biological Chemistry. 2013. p. 741.
  3. Hunter DT, Jr. and Hill JM, Surfen: a quinoline with oncogenic and heparin-neutralizing properties. Nature 1961;191:1378-9.
  4. Huang ML, Michalak AL, Fisher CJ, et al., Small Molecule Antagonist of Cell Surface Glycosaminoglycans Restricts Mouse Embryonic Stem Cells in a Pluripotent State. STEM CELLS 2018;36:45-54.
  5. Schnerch A, Cerdan C, and Bhatia M, Distinguishing Between Mouse and Human Pluripotent Stem Cell Regulation: The Best Laid Plans of Mice and Men. STEM CELLS 2010;28:419-430.
  6. Wang Y-C, Stein JW, Lynch CL, et al., Glycosyltransferase ST6GAL1 contributes to the regulation of pluripotency in human pluripotent stem cells. Scientific Reports 2015;5:13317.