Multivalent Ligands to Control Stem Cell Fate

There is currently significant interest in designing nanostructured materials that can interact with cells and regulate key cellular functions. We demonstrate for the first time the design of potent multivalent conjugates that can organize stem cell receptors into nanoscale clusters on the cell membrane and control stem cell fate, both in vitro and in vivo. The ectodomain of ephrin-B2, normally an integral membrane protein ligand, was conjugated to a soluble biopolymer to yield multivalent nanoscale conjugates that potently induced signaling in neural stem cells and promoted their neuronal differentiation both in culture and within the adult brain. Furthermore, synthetic multivalent conjugates of ephrin-B1 strongly enhanced human embryonic and induced pluripotent stem cell differentiation into functional dopaminergic neurons. Multivalent bioconjugates thus represent a powerful tool for controlling stem cell fate in vitro and in vivo. These results also highlight the potential of nanoscale therapeutics that interact with target cells and elicit desired cellular responses.