2026-09-19T18:45:16Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/781492026-06-16T18:17:18Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
Albert Edge.
Bramhall, Naomi F
Harvard--MIT Program in Health Sciences and Technology.
Harvard University--MIT Division of Health Sciences and Technology
2013-03-28T18:08:30Z
2013-03-28T18:08:30Z
2012
2012
http://hdl.handle.net/1721.1/78149
829388230
Thesis (Ph. D. in Speech and hearing Bioscience and technology)--Harvard-MIT Program in Health Sciences and Technology, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 86-91).
Unlike lower vertebrates, capable of spontaneous hair cell regeneration, mammals experience permanent sensorineural hearing loss following hair cell damage. Although low levels of hair cell regeneration have been demonstrated in the immature mammalian vestibular system, the cochlea has been thought to lack any spontaneous regenerative potential. Inhibition of the Notch pathway can stimulate hair cell generation in neonatal mammals, but the specific source of these new hair cells has been unclear. Here, using in vitro lineage tracing with the supporting cell markers Sox2 and Lgr5, we show that Lgr5-positive inner pillar and 3rd Deiter's cells in gentamicin-damaged organs of Corti from neonatal mice give rise to new hair cells following treatment with a Notch inhibitor. These new hair cells are generated primarily through direct transdifferentiation of supporting cells, although a small number show evidence of proliferation. Inner pillar cells show the greatest transdifferentation capability, giving rise to immature outer hair cells, and transdifferentiating in response to damage even in the absence of Notch inhibition. In vivo pharmacologic inhibition of Notch and in vivo lineage tracing with Sox2 during genetic Notch inhibition provide generally consistent results, although additional new hair cells develop in the inner hair cell region. These data suggest a spontaneous capacity for hair cell regeneration in the neonatal mammalian cochlea. In addition, the data identify Lgr5-positive supporting cells as potential hair cell progenitors, making them an attractive target for future hair cell regeneration treatments.
by Naomi F. Bramhall.
Ph.D. in Speech and hearing Bioscience and technology
91 p.
eng
Massachusetts Institute of Technology
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http://dspace.mit.edu/handle/1721.1/7582
Harvard--MIT Program in Health Sciences and Technology.
Cochlear hair cell regeneration from neonatal mouse supporting cells
Thesis
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<Abstract>Unlike lower vertebrates, capable of spontaneous hair cell regeneration, mammals experience permanent sensorineural hearing loss following hair cell damage. Although low levels of hair cell regeneration have been demonstrated in the immature mammalian vestibular system, the cochlea has been thought to lack any spontaneous regenerative potential. Inhibition of the Notch pathway can stimulate hair cell generation in neonatal mammals, but the specific source of these new hair cells has been unclear. Here, using in vitro lineage tracing with the supporting cell markers Sox2 and Lgr5, we show that Lgr5-positive inner pillar and 3rd Deiter's cells in gentamicin-damaged organs of Corti from neonatal mice give rise to new hair cells following treatment with a Notch inhibitor. These new hair cells are generated primarily through direct transdifferentiation of supporting cells, although a small number show evidence of proliferation. Inner pillar cells show the greatest transdifferentation capability, giving rise to immature outer hair cells, and transdifferentiating in response to damage even in the absence of Notch inhibition. In vivo pharmacologic inhibition of Notch and in vivo lineage tracing with Sox2 during genetic Notch inhibition provide generally consistent results, although additional new hair cells develop in the inner hair cell region. These data suggest a spontaneous capacity for hair cell regeneration in the neonatal mammalian cochlea. In addition, the data identify Lgr5-positive supporting cells as potential hair cell progenitors, making them an attractive target for future hair cell regeneration treatments.</Abstract>
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