title: Generation of sensory hair cells by genetic programming with a combination of transcription factors.
abstract: Mechanosensory hair cells (HCs) are the primary receptors of our senses of hearing and balance. Elucidation of the transcriptional networks regulating HC fate determination and differentiation is crucial not only to understand inner ear development but also to improve cell replacement therapies for hearing disorders. Here, we show that combined expression of the transcription factors Gfi1, Pou4f3 and Atoh1 can induce direct programming towards HC fate, both during in vitro mouse embryonic stem cell differentiation and following ectopic expression in chick embryonic otic epithelium. Induced HCs (iHCs) express numerous HC-specific markers and exhibit polarized membrane protrusions reminiscent of stereociliary bundles. Transcriptome profiling confirms the progressive establishment of a HC-specific gene signature during in vitro iHC programming. Overall, this work provides a novel approach to achieve robust and highly efficient HC production in vitro, which could be used as a model to study HC development and to drive inner ear HC regeneration.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa 1649-028, Portugal.
authors.forename: Aida
authors.initials: A
authors.lastname: Costa
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa 1649-028, Portugal Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Avenida Brasilia, Lisboa 1400-038, Portugal.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Guardado
authors.affiliation: UCL Ear Institute, University College London, 332 Gray's Inn Road, London WC1X 8EE, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Juniat
authors.affiliation: UCL Ear Institute, University College London, 332 Gray's Inn Road, London WC1X 8EE, UK.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Gale
authors.affiliation: UCL Ear Institute, University College London, 332 Gray's Inn Road, London WC1X 8EE, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Daudet
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa 1649-028, Portugal Champalimaud Neuroscience Programme, Champalimaud Centre for the Unknown, Avenida Brasilia, Lisboa 1400-038, Portugal henrique@medicina.ulisboa.pt.
authors.forename: Domingos
authors.initials: D
authors.lastname: Henrique
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects; D002642:Chick Embryo; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005453:Fluorescence; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter; D006198:Hair Cells, Auditory / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D051880:Receptors, Notch; D014157:Transcription Factors; D014212:Tretinoin
keywords: Atoh1; Cell type programming; Gene regulation; Gfi1; Hair cells