Generation of inner ear hair cells by direct lineage conversion of primary somatic cells

The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limi...

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Published ineLife Vol. 9
Main Authors Menendez, Louise, Trecek, Talon, Gopalakrishnan, Suhasni, Tao, Litao, Markowitz, Alexander L, Yu, Haoze V, Wang, Xizi, Llamas, Juan, Huang, Chichou, Lee, James, Kalluri, Radha, Ichida, Justin, Segil, Neil
Format Journal Article
LanguageEnglish
Published England eLife Sciences Publications Ltd 30.06.2020
eLife Sciences Publications, Ltd
Subjects
Online AccessGet full text
ISSN2050-084X
2050-084X
DOI10.7554/eLife.55249

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Abstract The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing. Worldwide, hearing loss is the most common loss of sensation. Most cases of hearing loss are due to the death of specialized hair cells found deep inside the ear. These hair cells convert sounds into nerve impulses which can be understood by the brain. Hair cells naturally degrade as part of aging and can be damaged by other factors including loud noises, and otherwise therapeutic drugs, such as those used in chemotherapy for cancer. In humans and other mammals, once hair cells are lost they cannot be replaced. Hair cells have often been studied using mice, but the small number of hair cells in their ears, and their location deep inside the skull, makes it particularly difficult to study them in this way. Scientists are seeking ways to grow hair cells in the laboratory to make it easier to understand how they work and the factors that contribute to their damage and loss. Different cell types in the body are formed in response to specific combinations of biological signals. Currently, scientists do not have an efficient way to grow hair cells in the laboratory, because the correct signals needed to create them are not known. Menendez et al. have now identified four proteins which, when activated, convert fibroblasts, a common type of cell, into hair cells similar to those in the ear. These proteins are called Six1, Atoh1, Pou4f3 and Gfi1. Menendez et al. termed the resulting cells induced hair cells, or iHCs for short, and analyzed these cells to identify those characteristics that are similar to normal hair cells, as well as their differences. Importantly, the iHCs were found to be damaged by the same chemicals that specifically harm normal hair cells, suggesting they are useful test subjects. The ability to create hair cells in the laboratory using more easily available cells has many uses. These cells can help to understand the normal function of hair cells and how they become damaged. They can also be used to test new drugs to assess their success in preventing or reversing hearing loss. These findings may also lead to genetic solutions to curing hearing loss.
AbstractList The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.
The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing. Worldwide, hearing loss is the most common loss of sensation. Most cases of hearing loss are due to the death of specialized hair cells found deep inside the ear. These hair cells convert sounds into nerve impulses which can be understood by the brain. Hair cells naturally degrade as part of aging and can be damaged by other factors including loud noises, and otherwise therapeutic drugs, such as those used in chemotherapy for cancer. In humans and other mammals, once hair cells are lost they cannot be replaced. Hair cells have often been studied using mice, but the small number of hair cells in their ears, and their location deep inside the skull, makes it particularly difficult to study them in this way. Scientists are seeking ways to grow hair cells in the laboratory to make it easier to understand how they work and the factors that contribute to their damage and loss. Different cell types in the body are formed in response to specific combinations of biological signals. Currently, scientists do not have an efficient way to grow hair cells in the laboratory, because the correct signals needed to create them are not known. Menendez et al. have now identified four proteins which, when activated, convert fibroblasts, a common type of cell, into hair cells similar to those in the ear. These proteins are called Six1, Atoh1, Pou4f3 and Gfi1. Menendez et al. termed the resulting cells induced hair cells, or iHCs for short, and analyzed these cells to identify those characteristics that are similar to normal hair cells, as well as their differences. Importantly, the iHCs were found to be damaged by the same chemicals that specifically harm normal hair cells, suggesting they are useful test subjects. The ability to create hair cells in the laboratory using more easily available cells has many uses. These cells can help to understand the normal function of hair cells and how they become damaged. They can also be used to test new drugs to assess their success in preventing or reversing hearing loss. These findings may also lead to genetic solutions to curing hearing loss.
The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.
The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing. Worldwide, hearing loss is the most common loss of sensation. Most cases of hearing loss are due to the death of specialized hair cells found deep inside the ear. These hair cells convert sounds into nerve impulses which can be understood by the brain. Hair cells naturally degrade as part of aging and can be damaged by other factors including loud noises, and otherwise therapeutic drugs, such as those used in chemotherapy for cancer. In humans and other mammals, once hair cells are lost they cannot be replaced. Hair cells have often been studied using mice, but the small number of hair cells in their ears, and their location deep inside the skull, makes it particularly difficult to study them in this way. Scientists are seeking ways to grow hair cells in the laboratory to make it easier to understand how they work and the factors that contribute to their damage and loss. Different cell types in the body are formed in response to specific combinations of biological signals. Currently, scientists do not have an efficient way to grow hair cells in the laboratory, because the correct signals needed to create them are not known. Menendez et al. have now identified four proteins which, when activated, convert fibroblasts, a common type of cell, into hair cells similar to those in the ear. These proteins are called Six1, Atoh1, Pou4f3 and Gfi1. Menendez et al. termed the resulting cells induced hair cells, or iHCs for short, and analyzed these cells to identify those characteristics that are similar to normal hair cells, as well as their differences. Importantly, the iHCs were found to be damaged by the same chemicals that specifically harm normal hair cells, suggesting they are useful test subjects. The ability to create hair cells in the laboratory using more easily available cells has many uses. These cells can help to understand the normal function of hair cells and how they become damaged. They can also be used to test new drugs to assess their success in preventing or reversing hearing loss. These findings may also lead to genetic solutions to curing hearing loss.
The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors ( , and ) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.
Author Llamas, Juan
Segil, Neil
Yu, Haoze V
Markowitz, Alexander L
Huang, Chichou
Kalluri, Radha
Ichida, Justin
Lee, James
Gopalakrishnan, Suhasni
Tao, Litao
Menendez, Louise
Trecek, Talon
Wang, Xizi
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  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States
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  givenname: Suhasni
  surname: Gopalakrishnan
  fullname: Gopalakrishnan, Suhasni
  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States
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  givenname: Alexander L
  surname: Markowitz
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  givenname: Haoze V
  surname: Yu
  fullname: Yu, Haoze V
  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States
– sequence: 7
  givenname: Xizi
  surname: Wang
  fullname: Wang, Xizi
  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States
– sequence: 8
  givenname: Juan
  surname: Llamas
  fullname: Llamas, Juan
  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States
– sequence: 9
  givenname: Chichou
  surname: Huang
  fullname: Huang, Chichou
  organization: DRVision Technologies, Bellevue, United States
– sequence: 10
  givenname: James
  surname: Lee
  fullname: Lee, James
  organization: DRVision Technologies, Bellevue, United States
– sequence: 11
  givenname: Radha
  orcidid: 0000-0002-0360-8965
  surname: Kalluri
  fullname: Kalluri, Radha
  organization: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States, USC Caruso Department of Otolaryngology – Head and Neck Surgery, University of Southern California, Los Angeles, United States
– sequence: 12
  givenname: Justin
  surname: Ichida
  fullname: Ichida, Justin
  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States
– sequence: 13
  givenname: Neil
  orcidid: 0000-0002-0441-2067
  surname: Segil
  fullname: Segil, Neil
  organization: Department of Stem Cell and Regenerative Medicine, University of Southern California, Los Angeles, United States, Eli and Edythe Broad Center, University of Southern California, Los Angeles, United States, USC Caruso Department of Otolaryngology – Head and Neck Surgery, University of Southern California, Los Angeles, United States
BackLink https://www.ncbi.nlm.nih.gov/pubmed/32602462$$D View this record in MEDLINE/PubMed
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Keywords reprogramming
mouse
stem cells
screening
sensory hair cell
regeneration
developmental biology
regenerative medicine
inner ear
ototoxin
Language English
License 2020, Menendez et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Snippet The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack...
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SourceType Open Website
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SubjectTerms Animals
Cell Lineage
Cytology
Developmental Biology
Ears & hearing
Efficiency
Embryo fibroblasts
Epigenetics
Fibroblasts
Fibroblasts - physiology
Gene expression
Gene therapy
Hair cells
Hair Cells, Auditory, Inner - physiology
Hearing loss
Hearing protection
Inner ear
Labyrinth Supporting Cells - physiology
Mammals
Math1 protein
Mice - physiology
Mice, Transgenic
Morphology
ototoxin
regeneration
reprogramming
screening
sensory hair cell
SIX gene family
Somatic cells
Stem cells
Stem Cells and Regenerative Medicine
Tail
Transcription factors
Transcription Factors - metabolism
Vestibular system
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Title Generation of inner ear hair cells by direct lineage conversion of primary somatic cells
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https://doi.org/10.7554/elife.55249
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