Differentiation of Human Pluripotent Cell-derived Neural Rosettes to Dopaminergic Neurons by Small Molecules

A major challenge for regenerative medicine is differentiation of pluripotent cells to one of the hundreds of specialized cell types in the human body, without the introduction of animal traits or pathogens that would make them useless for transplantation. One approach to this problem is differentiation promoted by small molecules. In this work, a chemical library was prepared based on compounds that are neurotrophic for rat dopaminergic neurons and mimic some effects of glial-cell derived neurotrophic factor (GDNF). Members of a library of a N-(heteroarylsulfamoyl)-phenyl cinnamides were studied in a low-throughput phenotypic screen for their ability to promote differentiation of human pluripotent stem cell-derived neural rosettes to dopaminergic neurons, with morphological scoring. A hit series was identified and the cells resulting from compound treatments were shown by phenotypic assays to exhibit traits of the A9 dopaminergic neuron subtype. The method is effective with both hES cell- and hiPS cell-derived rosettes.