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Inner ear regeneration

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Inner ear regeneration refers to the biological process by which the hair cells and supporting cells (i.e. Hensen's cells and Deiters cells) of the ear proliferate (cell proliferation) and regrow after hair cell injury. This page covers anatomy of the inner ear epithelia, loss of hair cells, current therapeutics for hair cell loss in humans, hair cell regeneration in anamniotes, avians and mammals, induction of hair cell regeneration in mammals, and obstacles and future directions for therapeutics.

Anatomy

Hair Cells

Hair cells and supporting cells are both located in the cochlea inside the inner ear[1][2]. In mammals, hair cells are located in the Organ of Corti and convert energy from sound waves and physical movement into electrical signals[2]. This is accomplished through neurons that are integrated with the hair cells that transmit signals to the auditory nerve to the brain[2]. There are three rows of outer hair cells and one row of inner hair cells on the Organ of Corti[2]. 95% of neurons that transmit signals to the auditory nerve are connected to inner hair cells, making inner hair cells mainly responsible for auditory sensory input[3]. While inner hair cells are the sensory receptors, outer hair cells are the efferent receptors and are important in fine-tuning sensory input by contracting and relaxing to alter the tectorial membrane on the surface of the hair cells[3].

File:Hair cells.jpg
Electron micrograph of hair cells in cochlea
Uncoiled cochlea with basilar membrane

Supporting Cells

Supporting cells are critical for maintaining inner ear sensory cells, and reside both on the surface and throughout the epithelium of the inner ear, communicating through gap junctions[4][2]. Supporting cells have been found to be critical for maintaining the physical structure of the inner ear, as well as maintaining the environment of the sensory epithelium of the inner ear[2]. Maintaining appropriate ion concentrations and pH in the inner ear epithelium is important for hair cells to initiate action potentials to transmit signals to the brain[1][2]. Supporting cells are also responsible for removing damaged hair cells from the inner ear[2].

Outer hair cell and Deiter's cell

Hair cells and most supporting cells are ectoderm-derived[2]. The main types of supporting cells are Hensen’s cells, Deiters’ cells, Claudius cells, inner phalangeal cells, and inner and outer pillar cells[1]. Hensen’s cells, Deiter’s cells, and outer hair cells make up the outer tunnel and are mainly responsible for allowing the hair cells to function[1]. Hensen’s cells are columnar in shape, have many phagosomes in their cytoplasm, and also contain lipid droplets that correlate with the amount of innervation[1][5]. Deiters’ cells are attached to outer hair cells and have phalanges that extend to and create tight junctions with nearby outer hair cells[6][1]. Because Deiters’ cells interact with a few outer hair cells, they play a key role in coordinating shifts and mechanical force between outer hair cells[1].

Loss of Hair Cells

Hair cells are very sensitive and become damaged easily, resulting in cell death[2]. The supporting cells may also become damaged, but are typically more hearty and survive better than hair cells[2]. Hair cells die as a function of age, acoustic overstimulation, and other traumas[2]. Oxotoxin exposure, such as aminoglycoside antibiotics and cisplatin, is also a major contributor to hair cell death[7]. Because mammals have very limited hair cell regeneration, hearing loss is essentially irreversible and therefore a therapeutic target for regeneration[8][2]. There are also genetic diseases that can cause hair cell death, such as Osteogenesis Imperfecta [9].

Cartoon representation of healthy vs damaged hair cells

Current Therapeutics for Hair Cell Loss in Humans

Because mammals have very limited hair cell regenerative capacity compared to other groups of animals, other methods of making up for hearing loss have been created. Hearing aids are devices that sit in the ear and amplify sound, which is good for partial hair cell loss that occurs with age[10]. Cochlear implants are a more invasive treatment that bypasses the hair cells completely by sending electrical signals from the environment straight to the auditory nerve fibers[11]. This is a great option for patients with minimal to nonexistent hair cell activity[11]. The cochlear implant involves a surgically implanted electrode array and an external device that processes sound[11].

Hair Cell Regeneration

Anamniotes

Hair cell regeneration has been studied in fish (zebrafish). All nonmammalian vertebrates studied can regenerate inner ear hair cells (mechanoreceptor) [12] [13] [14]. Or, lower vertebrates can recover from deafness due to hair cell loss. Hair cell loss triggers supporting cells to re-enter the cell cycle; mitotic (mitosis) divisions of quiescent supporting cells in the sensory epithelium of the cochlea give rise to both new hair cells and supporting cells[12]. In some cases, proliferating supporting cells directly transdifferentiate into new hair cells, resulting in the recovery of hearing [15]. Direct transdifferentiation refers to a cell fate change when neighboring supporting cells convert into hair cells without cell division. Inner ear sensory epithelium is highly conserved (conservation genetics) in all vertebrates[16]. Thus, study of these nonmammalian vertebrates can lead to a better understanding of the mechanism of hair cell regeneration in mammals.

Zebrafish

The study of the hair cell regeneration mechanism in adult zebrafish may be transferable to inducing hair cell regeneration in mammals. The basic structure and function of the fish inner ear is similar to that of other vertebrates. Mammals share homologous genes with zebrafish that are known to affect inner ear structure and function[17]. In zebrafish, spontaneous and damage-induced hair cell regeneration has been demonstrated in the inner ear [18] [19]. The Stat3/SOCS3 pathway has been identified as key in promoting hair cell regeneration through stem cell activation, cell division, and differentiation [20].

Avian

Avian species, unlike mammals, have significantly greater ability to regenerate hair cells from surrounding supporting cells[8]. There are two identified mechanisms behind hair cell regeneration; the first is that supporting cells re-enter the mitotic cycle to create and differentiate new hair cells[8]. The second process is direct transdifferentiation of supporting cells into hair cells, which occurs via a change in the gene expression profile of supporting cells[8]. These two mechanisms are distinct and likely regulated in different ways to allow for spatial and temporal patterning (spatiotemporal pattern) [8]. Avian hair cells remain in a quiescent state even before birth, which means that they are in a mitotic rest stage and do not replicate[21]. Hair cells are not regenerated on a regular basis, but only after damage is already done[21]. Hair cells in chicks are regenerated just three days after damage is inflicted, and the hair cells fully recover by 30 days[22]. Supporting cells begin to replicate to form hair cells within 18-24 hours after damage, and this process peaks around 2-3 days[23]. Despite that it is unclear which supporting cells form new hair cells in avians and if a progenitor cell type exists, it is a promising model to study because avian studies may be applicable to humans[23].

Mammalian

Mouse

In the adult mouse, hair cell regeneration is not observed. However, the neonatal mouse cochlea can, to a limited extent, replace damaged or lost hair cells [24]. Hair cell restoration can occur by direct transdifferentiation and mitotic regeneration. Mitotic division occurs when a supporting cell first divides and, subsequently, one or both daughter cells (cytokinesis) becomes a hair cell [25] [14]. In the neonatal mouse both mitotic division and direct transdifferentiation occur. Proliferating supporting cells can acquire hair cell fate in mitotic division. The mouse neonatal supporting cells proliferate after hair cell death, and regenerate hair cells after damage [26].

The neonatal cochlea is resistant to hair cell damage caused by exposure to noise or drugs toxic to the cochlea or auditory nerve in vivo [26]. In addition, this regenerative capability extends up to the first postnatal week. In cell culture, neonatal mouse inner ear supporting cells retain the capacity to proliferate and transdifferentiate [15].

Green fluorescent protein image of the mouse cochlea

Human

In human newborns, the inner ear is fully mature. Thus, hair cell loss results in loss of hearing at any postnatal stage. The adult mammalian inner ear lacks the capacity to divide or regenerate spontaneously hair cells [27]. This is to say that neither direct transdifferentiation nor mitotic division have the innate ability to restore hair cells. Once hair cells are damaged, hearing loss is likely permanent.

Inducing Hair Cell Regeneration in Mammals

To recover from deafness due to hair cell loss in mammals, reprogramming of adult supporting cells is likely necessary for induction of regeneration of hair cells and renewed proliferation. This has been done in adult mouse supporting cells [15]. Cell reprogramming is the process of reverting mature, specialized cells into induced pluripotent or progenitor cells[28].

Supporting cells primed by exposure to the cell cycle activator Myc and the inner ear progenitor gene Notch 1 induces proliferation of adult mouse cochlear sensory epithelial cell types. Their activity enables adult supporting cells to respond to the transcription factor ATOH1 and efficiently transdifferentiate into hair cell-like cells [15]. The mTOR pathway participates in MYC/NOTCH-mediated proliferation and regeneration. These regenerated hair cell-like cells likely form connections with adult spiral ganglion neurons[15]. Myc and Notch 1 co-activation is sufficient to reprogram fully mature supporting cells to proliferate and regenerate hair cell-like cells in adult mammalian auditory organs[15].

In cell culture, neonatal mouse inner ear supporting cells retain the capacity to proliferate and transdifferentiate. Supporting cells serve essential roles in hearing and balance and deficits in supporting cells can result in deafness [29]. If supporting cells directly transdifferentiate to restore hair cell loss, there must also be some replenishment of supporting cells as a deficit in these cells is also harmful. An ideal system for regeneration of hair cells by direct supporting cell transdifferentiation would require replacement of lost supporting cells, by renewed proliferation. Adult supporting cells and hair cells do not change their cell identities when dividing, which suggests limited reprogramming. In order for renewed proliferation and transdifferentiation into hair calls to occur, adult supporting cells must be reprogrammed [15].

In the adolescent mouse, inner ear supporting cell-to-hair cell transdifferentiation can be induced by the overexpression of hair cell fate-determining transcription factor Atoh1 [30]. In the adult inner ear, overexpression of Atoh1 in supporting cells alone is inefficient in promoting hair cell regeneration [31]. Supporting cells are the fully differentiated progeny of pluripotent progenitor cells. Those supporting cell progenitor populations have been found to be inducible to mature into hair cell-like cells. Mature supporting cells likely must regain the properties of younger biological cells in order to respond to hair cell induction signals [15].

Shu et al. used adeno-associated virus-mediated delivery and inducible transgenic mouse models to demonstrate the proliferation of both hair cells and supporting cells by combined Notch 1 and Myc activation in in vitro and in vivo inner ear adult mouse models [15]. Both hair cells and supporting cells maintain their respective identities. Reprogrammed adult supporting cells show transdifferentiation into hair cell-like cells upon exposure to hair cell induction signals (Atoh1) [15]. The mTOR pathway is downstream of Myc/Notch 1 activation and so is required in proliferation and supporting cell-to-hair cell transdifferentiation in the adult cochlea. These regenerated hair cells have functional signal transduction channels, which are necessary for sensory processing. Moreover, the regenerated cells seem to be able to form connections with the adult auditory system [15]. In the mouse, Shu et al. found extensive neurite outgrowth to the sensory epithelial region, with the neurites wrapping around new hair cell-like cells. In contrast, in control cochleae without hair cell regeneration, virtually all the neurites retracted with few in contact with the existing hair cells [15].

Obstacles and Future Directions

These studies were published on 04 December 2019 and are being studied in non-human cells. The field is likely a long way from potential therapeutics in humans. While preclinical (preclinical development) and clinical (clinical trial) successes in adeno-associated virus-mediated gene therapies in humans have attributed to the popularity of this therapeutic viral vector, continued study and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success [32]. It is important to recognize that this therapy is cutting edge and very new, likely decades away from clinical application. The inner ear sensory epithelium is highly conserved among vertebrates, which gives us hope that animal models, especially mammal models such as mouse, are going to be very applicable to clinical use in humans[33]. Before this becomes a therapeutic in humans, experiments must be done in human mammalian cells, perhaps inner ear epithelial organoids, and brought into an in-vivo context in clinical trials[34]. Clinical trials typically take many years and are for the most part unsuccessful and result in unpublished data[35][36][37]. Any time you are reprogramming cells into another cell type by way of a pluripotent progenitor cell, including adenovirus delivery methods, there is a risk of disrupting the genome and triggering the formation of a tumor/cancer[38][39]. There is a long road ahead for hair cell regeneration in humans.

References

  1. ^ a b c d e f g Li–dong Z, Jun L, Yin–yan H, Jian–he S, Shi–ming Y. Supporting Cells–a New Area in Cochlear Physiology Study. J Otol. 2008 Jun 1;3(1):9–17.
  2. ^ a b c d e f g h i j k l m Wan, G., Corfas, G., & Stone, J. S. (2013). Inner ear supporting cells: Rethinking the silent majority. Seminars in Cell & Developmental Biology, 24(5), 448–459. https://doi.org/10.1016/j.semcdb.2013.03.009
  3. ^ a b Purves, D., Augustine, G. J., Fitzpatrick, D., Katz, L. C., LaMantia, A.-S., McNamara, J. O., & Williams, S. M. (2001). Two Kinds of Hair Cells in the Cochlea. Neuroscience. 2nd Edition. https://www.ncbi.nlm.nih.gov/books/NBK11122/
  4. ^ Boettger, T., Hübner, C. A., Maier, H., Rust, M. B., Beck, F. X., & Jentsch, T. J. (2002). Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4. Nature, 416(6883), 874–878. https://doi.org/10.1038/416874a
  5. ^ Merchan, M. A., Merchan, J. A., & Ludeña, M. D. (1980). Morphology of Hensen’s cells. Journal of Anatomy, 131(Pt 3), 519–523.
  6. ^ Dulon, D., Blanchet, C., & Laffon, E. (1994). Photo-released intracellular Ca2+ evokes reversible mechanical responses in supporting cells of the guinea-pig organ of Corti. Biochemical and Biophysical Research Communications, 201(3), 1263–1269. https://doi.org/10.1006/bbrc.1994.1841
  7. ^ Cheng, A. G., Cunningham, L. L., & Rubel, E. W. (2005). Mechanisms of hair cell death and protection. Current Opinion in Otolaryngology & Head and Neck Surgery, 13(6), 343–348. https://doi.org/10.1097/01.moo.0000186799.45377.63
  8. ^ a b c d e Stone, J. S., & Cotanche, D. A. (2007). Hair cell regeneration in the avian auditory epithelium. The International Journal of Developmental Biology, 51(6–7), 633–647. https://doi.org/10.1387/ijdb.072408js
  9. ^ Pillion, J. P., Vernick, D., & Shapiro, J. (2011). Hearing Loss in Osteogenesis Imperfecta: Characteristics and Treatment Considerations. Genetics Research International, 2011. https://doi.org/10.4061/2011/983942
  10. ^ Edwards, B. (2007). The Future of Hearing Aid Technology. Trends in Amplification, 11(1), 31–45. https://doi.org/10.1177/1084713806298004
  11. ^ a b c Lenarz, T. (2018). Cochlear implant – state of the art. GMS Current Topics in Otorhinolaryngology, Head and Neck Surgery, 16. https://doi.org/10.3205/cto000143
  12. ^ a b Corwin, J. T., & Cotanche, D. A. (1988). Regeneration of sensory hair cells after acoustic trauma. Science, 240(4860), 1772–1774. https://doi.org/10.1126/science.3381100
  13. ^ Lombarte, A., Yan, H. Y., Popper, A. N., Chang, J. S., & Platt, C. (1993). Damage and regeneration of hair cell ciliary bundles in a fish ear following treatment with gentamicin. Hearing Research, 64(2), 166–174. https://doi.org/10.1016/0378-5955(93)90002-i
  14. ^ a b Baird, R. A., Steyger, P. S., & Schuff, N. R. (1996). Mitotic and nonmitotic hair cell regeneration in the bullfrog vestibular otolith organs. Annals of the New York Academy of Sciences, 781, 59–70. https://doi.org/10.1111/j.1749-6632.1996.tb15693.x
  15. ^ a b c d e f g h i j k l Shu, Y., Li, W., Huang, M., Quan, Y.-Z., Scheffer, D., Tian, C., Tao, Y., Liu, X., Hochedlinger, K., Indzhykulian, A. A., Wang, Z., Li, H., & Chen, Z.-Y. (2019). Renewed proliferation in adult mouse cochlea and regeneration of hair cells. Nature Communications, 10(1), 5530. https://doi.org/10.1038/s41467-019-13157-7
  16. ^ Fritzsch, B., Beisel, K. W., Pauley, S., & Soukup, G. (2007). Molecular evolution of the vertebrate mechanosensory cell and ear. The International Journal of Developmental Biology, 51(6–7), 663–678. https://doi.org/10.1387/ijdb.072367bf
  17. ^ Fay, Richard R, & Popper, Arthur N. (1999). Comparative Hearing. New York: Springer New York.
  18. ^ Bang, P. I., Sewell, W. F., & Malicki, J. J. (2001). Morphology and cell type heterogeneities of the inner ear epithelia in adult and juvenile zebrafish (Danio rerio). Journal of Comparative Neurology, 438(2), 173–190. https://doi.org/10.1002/cne.1308
  19. ^ Schuck, J. B., & Smith, M. E. (2009). Cell proliferation follows acoustically-induced hair cell bundle loss in the zebrafish saccule. Hearing Research, 253(1–2), 67–76. https://doi.org/10.1016/j.heares.2009.03.008
  20. ^ Liang, J., Wang, D., Renaud, G., Wolfsberg, T. G., Wilson, A. F., & Burgess, S. M. (2012). The stat3/socs3a Pathway Is a Key Regulator of Hair Cell Regeneration in Zebrafish stat3/socs3a Pathway: Regulator of Hair Cell Regeneration. The Journal of Neuroscience, 32(31), 10662–10673. https://doi.org/10.1523/JNEUROSCI.5785-10.2012
  21. ^ a b Oesterle, E. C., & Rubel, E. W. (1993). Postnatal production of supporting cells in the chick cochlea. Hearing Research, 66(2), 213–224. https://doi.org/10.1016/0378-5955(93)90141-m
  22. ^ Girod, D. A., Duckert, L. G., & Rubel, E. W. (1989). Possible precursors of regenerated hair cells in the avian cochlea following acoustic trauma. Hearing Research, 42(2–3), 175–194. https://doi.org/10.1016/0378-5955(89)90143-3
  23. ^ a b Stone, J. S., & Rubel, E. W. (2000). Cellular studies of auditory hair cell regeneration in birds. Proceedings of the National Academy of Sciences, 97(22), 11714–11721. https://doi.org/10.1073/pnas.97.22.11714
  24. ^ White, P. M., Doetzlhofer, A., Lee, Y. S., Groves, A. K., & Segil, N. (2006). Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature, 441(7096), 984–987. https://doi.org/10.1038/nature04849
  25. ^ Adler, H. J., & Raphael, Y. (1996). New hair cells arise from supporting cell conversion in the acoustically damaged chick inner ear. Neuroscience Letters, 205(1), 17–20. https://doi.org/10.1016/0304-3940(96)12367-3
  26. ^ a b Cox, B. C., Chai, R., Lenoir, A., Liu, Z., Zhang, L., Nguyen, D.-H., Chalasani, K., Steigelman, K. A., Fang, J., Cheng, A. G., & Zuo, J. (2014). Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Development (Cambridge, England), 141(4), 816–829. https://doi.org/10.1242/dev.103036
  27. ^ Warchol, M. E., Lambert, P. R., Goldstein, B. J., Forge, A., & Corwin, J. T. (1993). Regenerative Proliferation in Inner Ear Sensory Epithelia from Adult Guinea Pigs and Humans. Science, 259(5101), 1619–1622.
  28. ^ Kanherkar, R. R., Bhatia-Dey, N., Makarev, E., & Csoka, A. B. (2014). Cellular reprogramming for understanding and treating human disease. Frontiers in Cell and Developmental Biology, 2. https://doi.org/10.3389/fcell.2014.00067
  29. ^ Monzack, E. L., & Cunningham, L. L. (2013). Lead roles for supporting actors: Critical functions of inner ear supporting cells. Hearing Research, 303, 20–29. https://doi.org/10.1016/j.heares.2013.01.008
  30. ^ Zheng, J. L., & Gao, W.-Q. (2000). Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears. Nature Neuroscience, 3(6), 580–586. https://doi.org/10.1038/75753
  31. ^ Izumikawa, M., Minoda, R., Kawamoto, K., Abrashkin, K. A., Swiderski, D. L., Dolan, D. F., Brough, D. E., & Raphael, Y. (2005). Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Medicine, 11(3), 271–276. https://doi.org/10.1038/nm1193
  32. ^ Wang, D., Tai, P. W. L., & Gao, G. (2019). Adeno-associated virus vector as a platform for gene therapy delivery. Nature Reviews. Drug Discovery, 18(5), 358–378. https://doi.org/10.1038/s41573-019-0012-9
  33. ^ Fritzsch, B., & Beisel, K. W. (2003). Molecular Conservation and Novelties in Vertebrate Ear Development. Current Topics in Developmental Biology, 57, 1–44.
  34. ^ Jeong, M., O’Reilly, M., Kirkwood, N. K., Al-Aama, J., Lako, M., Kros, C. J., & Armstrong, L. (2018). Generating inner ear organoids containing putative cochlear hair cells from human pluripotent stem cells. Cell Death & Disease, 9(9), 1–13. https://doi.org/10.1038/s41419-018-0967-1
  35. ^ Ross, J. S., Mocanu, M., Lampropulos, J. F., Tse, T., Zarin, D. A., & Krumholz, H. M. (2013). TIME TO PUBLICATION AMONG COMPLETED CLINICAL TRIALS. JAMA Internal Medicine, 173(9), 825–828. https://doi.org/10.1001/jamainternmed.2013.136
  36. ^ Umscheid, C. A., Margolis, D. J., & Grossman, C. E. (2011). Key Concepts of Clinical Trials: A Narrative Review. Postgraduate Medicine, 123(5), 194–204. https://doi.org/10.3810/pgm.2011.09.2475
  37. ^ Wong, C. H., Siah, K. W., & Lo, A. W. (2019). Estimation of clinical trial success rates and related parameters. Biostatistics (Oxford, England), 20(2), 273–286. https://doi.org/10.1093/biostatistics/kxx069
  38. ^ Shao, L., & Wu, W.-S. (2010). Gene-delivery systems for iPS cell generation. Expert Opinion on Biological Therapy, 10(2), 231–242. https://doi.org/10.1517/14712590903455989
  39. ^ Zhou, W., & Freed, C. R. (2009). Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells. STEM CELLS, 27(11), 2667–2674. https://doi.org/10.1002/stem.201
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