Inner Ear Organoids: Recapitulating Inner Ear Development in 3D Culture
The inner ear contains sensory epithelia composed of mechanosensitive hair cells, supporting cells, and sensory neurons that work in concert to detect sound and positional information and transmit those signals to the brain. Within the backdrop of embryogenesis, inner ear development follows an intricate pathway of signaling cues and morphological changes, leading to its complex final three-dimensional (3D) structure. Application of various small molecules and recombinant proteins to mouse embryonic stem cells at specific time points in vitro has enabled recapitulation of developmental cues with subsequent formation of inner ear organoids. This has resulted in a model system of inner ear development that is easily derived, manipulated, and analyzed. These organoids contain functional mechanosensitive hair cells, supporting cells, and sensory neurons, which phenocopy functional components of the inner ear responsible for detection of positional information. The potential applications of this system include investigation of inner ear development, disease modeling, drug screening, and therapy development. This chapter highlights the process of in vivo inner ear development, the rationale and process behind inner ear organoid formation, and potential applications and limitations of this in vitro model system.
KeywordsInner ear Hearing Balance Embryonic development Stem cells 3D culture Organogenesis
The authors would like to thank Atsushi Shimomura for the schematic drawing and Rachel DeJonge and Andrew Mikosz for some of the image data. This work was supported by a National Institutes of Health grant R01 DC013294 (to E.H.), an Indiana Clinical and Translational Research Institute predoctoral fellowship (to A.N.E.), and a Centralized Otolaryngology Research Effort (CORE) grant (to R.F.N.).
- Bailey AP, Streit A (2005) Sensory organs: making and breaking the pre-placodal region. In: Current topics in developmental biology, vol 72. Academic, San Diego/London, pp 167–204Google Scholar
- Chambers S, Fasano C, Papapetrou E (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Nanotechnol 27:275–280Google Scholar
- Groves A, Bronner-Fraser M (2000) Competence, specification and commitment in otic placode induction. Development 139:3489–3499Google Scholar
- Kalinec F (2005) High-throughput screening of ototoxic and otoprotective pharmacologic drugs. Volta Rev 105(3):383–406Google Scholar
- Misui K, Tokuzawa Y, Itoh H, Segawa K et al (2003) The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell 30(113):631–642Google Scholar
- Sai X, Ladher R (2015) Early steps in inner ear development: induction and morphogenesis of the otic placode. Front Pharmacol 6(19):1–8Google Scholar
- Schlosser G (2014) Early embryonic specification of vertebrate cranial placodes. Dev Biol 3:349–363Google Scholar