Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons

Human induced pluripotent stem cell (hiPSC) technologies offer a unique resource for modeling neurological diseases. However, iPSC models are fraught with technical limitations including abnormal aggregation and inefficient maturation of differentiated neurons. These problems are in part due to the absence of synergistic cues of the native extracellular matrix (ECM). We report on the use of three artificial ECMs based on peptide amphiphile (PA) supramolecular nanofibers. All nanofibers display the laminin-derived IKVAV signal on their surface but differ in the nature of their non-bioactive domains. We find that nanofibers with greater intensity of internal supramolecular motion have enhanced bioactivity toward hiPSC-derived motor and cortical neurons. Proteomic, biochemical, and functional assays reveal that highly mobile PA scaffolds caused enhanced β1-integrin pathway activation, reduced aggregation, increased arborization, and matured electrophysiological activity of neurons. Our work highlights the importance of designing biomimetic ECMs to study the development, function, and dysfunction of human neurons. [Display omitted] •ECM-mimetic PAs with distinct non-bioactive domains show different molecular motion•Culturing hiPSC-neurons on highly mobile IKVAV-PA2 nanofibers enhances ITGB1 activation•IKVAV-PA2 coatings reduce neuronal aggregation, increase functional maturity•IKVAV-PA2 coatings facilitate modeling of neurodegenerative pathology in vitro The utilization of iPSC technologies to model neurological diseases in vitro is challenging due to the inherent tendency of neurons to aggregate and their immature profile. Kiskinis and colleagues developed artificial extracellular matrix biomimetic molecules exhibiting unprecedented molecular motion that promote advanced functional neuronal maturation and facilitate modeling of neurodegeneration.