title: Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells.
abstract: Death of cochlear hair cells, which do not regenerate, is a cause of hearing loss in a high percentage of the population. Currently, no approach exists to obtain large numbers of cochlear hair cells. Here, using a small-molecule approach, we show significant expansion (>2,000-fold) of cochlear supporting cells expressing and maintaining Lgr5, an epithelial stem cell marker, in response to stimulation of Wnt signaling by a GSK3β inhibitor and transcriptional activation by a histone deacetylase inhibitor. The Lgr5-expressing cells differentiate into hair cells in high yield. From a single mouse cochlea, we obtained over 11,500 hair cells, compared to less than 200 in the absence of induction. The newly generated hair cells have bundles and molecular machinery for transduction, synapse formation, and specialized hair cell activity. Targeting supporting cells capable of proliferation and cochlear hair cell replacement could lead to the discovery of hearing loss treatments.
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA; Program in Speech and Hearing Bioscience and Technology, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Will J
authors.initials: WJ
authors.lastname: McLean
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Yin
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Lenz
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
authors.forename: Dalton
authors.initials: D
authors.lastname: McLean
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, MIT, Cambridge, MA 02142, USA. Electronic address: rlanger@mit.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA. Electronic address: jmkarp@partners.org.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Karp
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA; Program in Speech and Hearing Bioscience and Technology, Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: albert_edge@meei.harvard.edu.
authors.forename: Albert S B
authors.initials: ASB
authors.lastname: Edge
mesh_terms: D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D003051:Cochlea / Q000378:metabolism*; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006801:Humans; D008297:Male; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled