Long-Lived Engineering of Glycans to Direct Stem Cell Fate

Glycans mediate many critical, long‐term biological processes, such as stem cell differentiation. However, few methods are available for the sustained remodeling of cells with specific glycan structures. A new strategy that enables the long‐lived presentation of defined glycosaminoglycans on cell surfaces using HaloTag proteins (HTPs) as anchors is reported. By controlling the sulfation patterns of heparan sulfate (HS) on pluripotent embryonic stem cell (ESC) membranes, it is demonstrated that specific glycans cause ESCs to undergo accelerated exit from self‐renewal and differentiation into neuronal cell types. Thus, the stable display of glycans on HTP scaffolds provides a powerful, versatile means to direct key signaling events and biological outcomes such as stem cell fate. Sweet display: A method for the long‐lived presentation of specific glycans on cell surfaces is reported. HaloTag proteins (HTP) were utilized to covalently attach defined heparan sulfate (HS) structures to embryonic stem cell membranes. Highly sulfated HS induced differentiation into neuronal cell types, thus demonstrating the potential of glycan engineering to drive important physiological processes.