Small Molecule Antagonist of Cell Surface Glycosaminoglycans Restricts Mouse Embryonic Stem Cells in a Pluripotent State

• Published in: Stem cells (Dayton, Ohio) Ohio), 2018-01, Vol.36 (1), p.45-54
• Main Authors: Huang, Mia L., Michalak, Austen L., Fisher, Christopher J., Christy, Mitchell, Smith, Raymond A. A., Godula, Kamil
• Format: Article
• Language: English
• Subjects: Animals; Carbohydrate; Cell Differentiation; Cell fate; Cell surface; Cues; Differentiation; Embryo cells; Embryonic stem cell; Embryos; Fibroblast growth factors; Glycosaminoglycans; Glycosaminoglycans - metabolism; Growth factor receptors; Growth factors; Heparan sulfate; Intracellular signalling; Kinases; Mice; Modulators; Mouse Embryonic Stem Cells - metabolism; Pluripotency; Pluripotent Stem Cells - metabolism; Receptors; Regeneration; Silence; Stem cell transplantation; Stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.2714

Recently, the field of stem cell‐based regeneration has turned its attention toward chemical approaches for controlling the pluripotency and differentiation of embryonic stem cells (ESCs) using drug‐like small molecule modulators. Growth factor receptors or their associated downstream kinases that regulate intracellular signaling pathways during differentiation are typically the targets for these molecules. The glycocalyx, which plays an essential role in actuating responses to growth factors at the cellular boundary, offers an underexplored opportunity for intervention using small molecules to influence differentiation. Here, we show that surfen, an antagonist of cell‐surface glycosaminoglycans required for growth factor association with cognate receptors, acts as a potent and general inhibitor of differentiation and promoter of pluripotency in mouse ESCs. This finding shows that drugging the stem cell Glycome with small molecules to silence differentiation cues can provide a powerful new alternative to existing techniques for controlling stem cell fate. Stem Cells 2018;36:45–54 The stem cell glycocalyx presents an attractive opportunity for pharmacological targeting with small molecules to control pluripotency and cellular differentiation. Here, we demonstrate that the small molecule, surfen, maintains mouse embryonic stem cell pluripotency by antagonizing heparan sulfate glycosaminoglycans in the stem cell glycocalyx. By blocking binding sites for FGF2, it silences MAPK signaling and gene expression. Image magnification: ×20.