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Cell Rep. 2017 Feb 21;18(8):1917-1929. doi: 10.1016/j.celrep.2017.01.066.

Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells.

Author information

1
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.
2
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.
3
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.
4
Department of Otology and Laryngology, Harvard Medical School, Boston, MA 02115, USA; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
5
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.
6
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.
7
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.

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.

PMID:
28228258
PMCID:
PMC5395286
DOI:
10.1016/j.celrep.2017.01.066
[Indexed for MEDLINE]
Free PMC Article

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