biostudies-literatureKjar ANICHD NIH HHSNCATS NIH HHSNCRR NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNIA NIH HHSNational Institute on AgingNEI NIH HHSNIDDK NIH HHSThe Chan Zuckerberg InitiativeNINDS NIH HHSNCI NIH HHSNIGMS NIH HHSNational Science Foundation114874https://www.ebi.ac.uk/biostudies/studies/S-EPMC11682736biostudies-literatureUnknown43(11)Human neural organoid models have become an important tool for studying neurobiology. However, improving the representativeness of neural cell populations in such organoids remains a major effort. In this work, we compared Matrigel, a commercially available matrix, to a neural cadherin (N-cadherin) peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids. We determined that peptide presentation can tune cell fate and diversity in gelatin-based matrices during differentiation. Of particular note, cortical organoids cultured in GelMA-Cad hydrogels mapped more closely to human fetal populations and produced neurons with more spontaneous excitatory postsynaptic currents relative to Matrigel. These results provide compelling evidence that matrix-tethered signaling peptides can influence neural organoid differentiation, opening an avenue to control stem cell fate. Moreover, outcomes from this work showcase the technical utility of GelMA-Cad as a simple and defined hydrogel alternative to Matrigel for neural organoid culture.Cell reportsBiofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids.PMC11682736UL1 TR002243S10 RR025677T32 AG058524P30 DK058404P30 EY008126P50 HD103537R01 DK103831F99 NS125829UL1 RR024975P30 CA068485G20 RR030956R01 NS110665R35 GM128915Fernandez MDrake LECurry CWChavarria DKim HMoen RKHaschert MRAbdulrahman AMGrueter BKjar ARobertson GLau KSGama VYates AZepeda JCO'Grady BJMarguerite NTLippmann ESSimmons AJBrunger JMfalseBiofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids.Human neural organoid models have become an important tool for studying neurobiology. However, improving the representativeness of neural cell populations in such organoids remains a major effort. In this work, we compared Matrigel, a commercially available matrix, to a neural cadherin (N-cadherin) peptide-functionalized gelatin methacryloyl hydrogel (termed GelMA-Cad) for culturing cortical neural organoids. We determined that peptide presentation can tune cell fate and diversity in gelatin-based matrices during differentiation. Of particular note, cortical organoids cultured in GelMA-Cad hydrogels mapped more closely to human fetal populations and produced neurons with more spontaneous excitatory postsynaptic currents relative to Matrigel. These results provide compelling evidence that matrix-tethered signaling peptides can influence neural organoid differentiation, opening an avenue to control stem cell fate. Moreover, outcomes from this work showcase the technical utility of GelMA-Cad as a simple and defined hydrogel alternative to Matrigel for neural organoid culture.2024-01-01T00:00:00Z2024 Nov2026-06-01T23:03:29.633Z2025-04-04T21:48:51.536ZS-EPMC116827363942312910.1016/j.celrep.2024.114874