biostudies-literatureMoore STNIDCD NIH HHS950-961.e7https://www.ebi.ac.uk/biostudies/studies/S-EPMC10695300biostudies-literatureUnknown30(7)Mechanosensitive hair cells in the cochlea are responsible for hearing but are vulnerable to damage by genetic mutations and environmental insults. The paucity of human cochlear tissues makes it difficult to study cochlear hair cells. Organoids offer a compelling platform to study scarce tissues in vitro; however, derivation of cochlear cell types has proven non-trivial. Here, using 3D cultures of human pluripotent stem cells, we sought to replicate key differentiation cues of cochlear specification. We found that timed modulations of Sonic Hedgehog and WNT signaling promote ventral gene expression in otic progenitors. Ventralized otic progenitors subsequently give rise to elaborately patterned epithelia containing hair cells with morphology, marker expression, and functional properties consistent with both outer and inner hair cells in the cochlea. These results suggest that early morphogenic cues are sufficient to drive cochlear induction and establish an unprecedented system to model the human auditory organ.Cell stem cellGenerating high-fidelity cochlear organoids from human pluripotent stem cells.PMC10695300R01 DC015495R01 DC015788R01 DC020574K08 DC016034R01 DC020628R01 DC013294Romano DRSolivais AJManikandan MReddy VSHoffman JRNie JNelson RFMoore STUeda YPerrin BJFrolenkov GIHashino EAristizabal-Ramirez IChuva de Sousa Lopes SMNakamura TfalseGenerating high-fidelity cochlear organoids from human pluripotent stem cells.Mechanosensitive hair cells in the cochlea are responsible for hearing but are vulnerable to damage by genetic mutations and environmental insults. The paucity of human cochlear tissues makes it difficult to study cochlear hair cells. Organoids offer a compelling platform to study scarce tissues in vitro; however, derivation of cochlear cell types has proven non-trivial. Here, using 3D cultures of human pluripotent stem cells, we sought to replicate key differentiation cues of cochlear specification. We found that timed modulations of Sonic Hedgehog and WNT signaling promote ventral gene expression in otic progenitors. Ventralized otic progenitors subsequently give rise to elaborately patterned epithelia containing hair cells with morphology, marker expression, and functional properties consistent with both outer and inner hair cells in the cochlea. These results suggest that early morphogenic cues are sufficient to drive cochlear induction and establish an unprecedented system to model the human auditory organ.2023-01-01T00:00:00Z2023 Jul2026-06-01T23:38:43.847Z2025-04-04T12:21:29.883ZS-EPMC106953003741910510.1016/j.stem.2023.06.006