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

• Published in: eLife 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
• Language: English
• Published: England eLife Sciences Publications Ltd 30.06.2020; eLife Sciences Publications, Ltd
• Subjects: 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; reprogramming; mouse; stem cells; screening; sensory hair cell; regeneration; developmental biology; regenerative medicine; inner ear; ototoxin
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.55249

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.