title: The effect of multivalent Sonic hedgehog on differentiation of human embryonic stem cells into dopaminergic and GABAergic neurons.
abstract: Stem cell differentiation is regulated by complex repertoires of signaling ligands which often use multivalent interactions, where multiple ligands tethered to one entity interact with multiple cellular receptors to yield oligomeric complexes. One such ligand is Sonic hedgehog (Shh), whose posttranslational lipid modifications and assembly into multimers enhance its biological potency, potentially through receptor clustering. Investigations of Shh typically utilize recombinant, monomeric protein, and thus the impact of multivalency on ligand potency is unexplored. Among its many activities, Shh is required for ventralization of the midbrain and forebrain and is therefore critical for the development of midbrain dopaminergic (mDA) and forebrain gamma-aminobutyric acid (GABA) inhibitory neurons. We have designed multivalent biomaterials presenting Shh in defined spatial arrangements and investigated the role of Shh valency in ventral specification of human embryonic stem cells (hESCs) into these therapeutically relevant cell types. Multivalent Shh conjugates with optimal valencies, compared to the monomeric Shh, increased the percentages of neurons belonging to mDA or forebrain GABAergic fates from 33% to 60% or 52% to 86%, respectively. Thus, multivalent Shh bioconjugates can enhance neuronal lineage commitment of pluripotent stem cells and thereby facilitate efficient derivation of neurons that could be used to treat Parkinson's and epilepsy patients.
authors.affiliation: Chemical and Biomolecular Engineering, and The Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
authors.forename: Tandis
authors.initials: T
authors.lastname: Vazin
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Ashton
authors.forename: Anthony
authors.initials: A
authors.lastname: Conway
authors.forename: Nikhil A
authors.initials: NA
authors.lastname: Rode
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lee
authors.forename: Verenice
authors.initials: V
authors.lastname: Bravo
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Healy
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Kane
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D059330:GABAergic Neurons / Q000166:cytology* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D053823:Hedgehog Proteins; D006820:Hyaluronic Acid
keywords: Bioconjugates; Dopaminergic; GABAergic; Human pluripotent stem cells; Multivalency; Sonic hedgehog