Skip to main content

Advertisement

Log in

Pluripotent stem cell-derived cochlear cells: a challenge in constant progress

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Hearing loss is a common affection mainly resulting from irreversible loss of the sensory hair cells of the cochlea; therefore, developing therapies to replace missing hair cells is essential. Understanding the mechanisms that drive their formation will not only help to unravel the molecular basis of deafness, but also give a roadmap for recapitulating hair cells development from cultured pluripotent stem cells. In this review, we provide an overview of the molecular mechanisms involved in hair cell production from both human and mouse embryonic stem cells. We then provide insights how this knowledge has been applied to differentiate induced pluripotent stem cells into otic progenitors and hair cells. Finally, we discuss the current limitations for properly obtaining functional hair cell in a Petri dish, as well as the difficulties that have to be overcome prior to consider stem cell therapy as a potential treatment for hearing loss.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Koehler KR, Mikosz AM, Molosh AI et al (2013) Generation of inner ear sensory epithelia from pluripotent stem cells in 3D culture. Nature 500:217–221. https://doi.org/10.1038/nature12298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Koehler KR, Nie J, Longworth-Mills E et al (2017) Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol 35:583–589. https://doi.org/10.1038/nbt.3840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Pieper M, Ahrens K, Rink E et al (2012) Differential distribution of competence for panplacodal and neural crest induction to non-neural and neural ectoderm. Development 139:1175–1187. https://doi.org/10.1242/dev.074468

    Article  CAS  PubMed  Google Scholar 

  4. Saint-Jeannet JP, Moody SA (2014) Establishing the pre-placodal region and breaking it into placodes with distinct identities. Dev Biol 389:13–27. https://doi.org/10.1016/j.ydbio.2014.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Basch ML, Brown RM, Jen HI, Groves AK (2016) Where hearing starts: the development of the mammalian cochlea. J Anat 228:233–254. https://doi.org/10.1111/joa.12314

    Article  PubMed  Google Scholar 

  6. Freter S, Muta Y, Mak S-S et al (2008) Progressive restriction of otic fate: the role of FGF and Wnt in resolving inner ear potential. Development 135:3415–3424. https://doi.org/10.1242/dev.026674

    Article  CAS  PubMed  Google Scholar 

  7. Hidalgo-Sánchez M, Alvarado-Mallart R, Alvarez IS (2000) Pax2, Otx2, Gbx2 and Fgf8 expression in early otic vesicle development. Mech Dev 95(1–2):225–9

    Article  PubMed  Google Scholar 

  8. Kelley MW (2006) Regulation of cell fate in the sensory epithelia of the inner ear. Nat Rev Neurosci 7:837–849. https://doi.org/10.1038/nrn1987

    Article  CAS  PubMed  Google Scholar 

  9. Fekete DM, Muthukumar S, Karagogeos D (1998) Hair cells and supporting cells share a common progenitor in the avian inner ear. J Neurosci 18:7811–7821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Laine H, Sulg M, Kirjavainen A, Pirvola U (2010) Cell cycle regulation in the inner ear sensory epithelia: role of cyclin D1 and cyclin-dependent kinase inhibitors. Dev Biol 337:134–146. https://doi.org/10.1016/j.ydbio.2009.10.027

    Article  CAS  PubMed  Google Scholar 

  11. Oesterle EC, Campbell S, Taylor RR et al (2008) Sox2 and Jagged1 expression in normal and drug-damaged adult mouse inner ear. JARO 9:65–89. https://doi.org/10.1007/s10162-007-0106-7

    Article  PubMed  Google Scholar 

  12. Wu DK, Kelley MW (2012) Molecular mechanisms of inner ear development. Cold Spring Harb Perspect Biol 4:a008409. https://doi.org/10.1101/cshperspect.a008409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lanford PJ, Lan Y, Jiang R et al (1999) Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 21:289–292. https://doi.org/10.1038/6804

    Article  CAS  PubMed  Google Scholar 

  14. Lee S, Jeong H-S, Cho H-H (2017) Atoh1 as a coordinator of sensory hair cell development and regeneration in the cochlea. Chonnam Med J Chonnam Med J 53:37–46. https://doi.org/10.4068/cmj.2017.53.1.37

    Article  CAS  PubMed  Google Scholar 

  15. White PM, Doetzlhofer A, Lee YS et al (2006) Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells. Nature 441:984–987. https://doi.org/10.1038/nature04849

    Article  CAS  PubMed  Google Scholar 

  16. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156. https://doi.org/10.1038/292154a0

    Article  CAS  PubMed  Google Scholar 

  17. Smith AG, Heath JK, Donaldson DD et al (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690. https://doi.org/10.1038/336688a0

    Article  CAS  PubMed  Google Scholar 

  18. Williams RL, Hilton DJ, Pease S et al (1988) Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 336:684–687. https://doi.org/10.1038/336684a0

    Article  CAS  PubMed  Google Scholar 

  19. Sato N, Meijer L, Skaltsounis L et al (2004) Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 10:55–63. https://doi.org/10.1038/nm979

    Article  CAS  PubMed  Google Scholar 

  20. Bain J, Plater L, Elliott M et al (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297–315. https://doi.org/10.1042/BJ20070797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Habibi E, Brinkman AB, Arand J et al (2013) Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell 13:360–369

    Article  CAS  PubMed  Google Scholar 

  22. Leitch HG, McEwen KR, Turp A et al (2013) Naive pluripotency is associated with global DNA hypomethylation. Nat Struct Mol Biol 20:311–316. https://doi.org/10.1038/nsmb.2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marks H, Kalkan T, Menafra R et al (2012) The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149:590–604. https://doi.org/10.1016/j.cell.2012.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Boroviak T, Loos R, Lombard P et al (2015) Lineage-specific profiling delineates the emergence and progression of naive pluripotency in mammalian embryogenesis. Dev Cell 35:366–382. https://doi.org/10.1016/j.devcel.2015.10.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Joshi O, Wang SY, Kuznetsova T et al (2015) Dynamic reorganization of extremely long-range promoter-promoter interactions between two states of pluripotency. Cell Stem Cell 17:748–757. https://doi.org/10.1016/j.stem.2015.11.010

    Article  CAS  PubMed  Google Scholar 

  26. Martin Gonzalez J, Morgani SM, Bone RA et al (2016) Embryonic stem cell culture conditions support distinct states associated with different developmental stages and potency. Stem Cell Reports 7:177–191. https://doi.org/10.1016/j.stemcr.2016.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Choi J, Huebner J, Clement K et al (2017) Prolonged Mek1/2 suppression impairs the developmental potential of embryonic stem cells. Nature 548(7666):219–223. https://doi.org/10.1038/nature23274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li H, Roblin G, Liu H, Heller S (2003) Generation of hair cells by stepwise differentiation of embryonic stem cells. Proc Natl Acad Sci USA 100:13495–13500. https://doi.org/10.1073/pnas.2334503100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ouji Y, Sakagami M, Omori H et al (2017) Efficient induction of inner ear hair cell-like cells from mouse ES cells using combination of Math1 transfection and conditioned medium from ST2 stromal cells. Stem Cell Res 23:50–56. https://doi.org/10.1016/j.scr.2017.06.013

    Article  CAS  PubMed  Google Scholar 

  30. Ouji Y, Ishizaka S, Nakamura-Uchiyama F, Yoshikawa M (2012) In vitro differentiation of mouse embryonic stem cells into inner ear hair cell-like cells using stromal cell conditioned medium. Cell Death Dis 3:e314. https://doi.org/10.1038/cddis.2012.56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Taura A, Ohnishi H, Ochi S et al (2014) Effects of mouse utricle stromal tissues on hair cell induction from induced pluripotent stem cells. BMC Neurosci 15:121. https://doi.org/10.1186/s12868-014-0121-7

    Article  CAS  Google Scholar 

  32. Oshima K, Shin K, Diensthuber M et al (2010) Mechanosensitive hair cell-like cells from embryonic and induced pluripotent stem cells. Cell 141:704–716. https://doi.org/10.1016/j.cell.2010.03.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yoshikawa M, Ouji Y (2016) Induction of inner ear hair cells from mouse embryonic stem cells in vitro. Methods Mol Biol. 1516:257–267. https://doi.org/10.1007/7651_2016_328

    Article  CAS  PubMed  Google Scholar 

  34. Longworth-Mills E, Koehler KR, Hashino E (2016) Generating inner ear organoids from mouse embryonic stem cells. Methods Mol Biol. 1341:391–406. https://doi.org/10.1007/7651_2015_215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koehler KR, Hashino E (2014) 3D mouse embryonic stem cell culture for generating inner ear organoids. Nat Protoc 9:1229–1244. https://doi.org/10.1038/nprot.2014.100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Abboud N, Fontbonne A, Watabe I et al (2016) Culture conditions have an impact on the maturation of traceable, transplantable mouse embryonic stem cell-derived otic progenitor cells. J Tissue Eng Regen, Med

    Google Scholar 

  37. Martignoni M, Groothuis GMM, de Kanter R (2006) Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2:875–894. https://doi.org/10.1517/17425255.2.6.875

    Article  CAS  PubMed  Google Scholar 

  38. Uhl EW, Warner NJ (2015) Mouse models as predictors of human responses: evolutionary medicine. Curr Pathobiol Rep 3:219–223. https://doi.org/10.1007/s40139-015-0086-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mestas J, Hughes CCW (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172:2731–2738. https://doi.org/10.4049/JIMMUNOL.172.5.2731

    Article  CAS  PubMed  Google Scholar 

  40. Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    Article  CAS  PubMed  Google Scholar 

  41. Thomson JA, Itskovitz-eldor J, Shapiro SS et al (2007) Embryonic stem cell lines derived from human blastocysts. Science (80-) 1145:. https://doi.org/10.1126/science.282.5391.1145

  42. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. https://doi.org/10.1016/j.cell.2006.07.024

    Article  CAS  PubMed  Google Scholar 

  43. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. https://doi.org/10.1016/j.cell.2007.11.019

    Article  CAS  PubMed  Google Scholar 

  44. Boyer LA, Lee TI, Cole MF et al (2005) Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122:947–956. https://doi.org/10.1016/j.cell.2005.08.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Loh Y-H, Wu Q, Chew J-L et al (2006) The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 38:431–440. https://doi.org/10.1038/ng1760

    Article  CAS  PubMed  Google Scholar 

  46. Fernandez PC, Frank SR, Wang L et al (2003) Genomic targets of the human c-Myc protein. Genes Dev 17:1115–1129. https://doi.org/10.1101/gad.1067003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Peng T, Dong Y, Zhu G, Xie D (2014) Induced pluripotent stem cells: landscape for studying and treating hereditary hearing loss. J Otol 9:151–155. https://doi.org/10.1016/j.joto.2015.02.001

    Article  Google Scholar 

  48. Fusaki N, Ban H, Nishiyama A et al (2009) Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc Jpn Acad Ser B Phys Biol Sci 85:348–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim D, Kim C-H, Moon J-I et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476. https://doi.org/10.1016/j.stem.2009.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Warren L, Manos PD, Ahfeldt T et al (2010) Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618–630. https://doi.org/10.1016/j.stem.2010.08.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen W, Jongkamonwiwat N, Abbas L et al (2012) Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature 490:278–282. https://doi.org/10.1038/nature11415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ding J, Tang Z, Chen J et al (2016) Induction of differentiation of human embryonic stem cells into functional hair-cell-like cells in the absence of stromal cells. Int J Biochem Cell Biol 81:208–222. https://doi.org/10.1016/j.biocel.2015.11.012

    Article  CAS  PubMed  Google Scholar 

  53. Tang Z-H, Chen J-R, Zheng J et al (2016) Genetic correction of induced pluripotent stem sells from a deaf patient with MYO7A mutation results in morphologic and functional recovery of the derived hair cell-like cells. Stem Cells Transl Med 5:561–571. https://doi.org/10.5966/sctm.2015-0252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen J-R, Tang Z-H, Zheng J et al (2016) Effects of genetic correction on the differentiation of hair cell-like cells from iPSCs with MYO15A mutation. Cell Death Differ 23:1347–1357. https://doi.org/10.1038/cdd.2016.16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ohnishi H, Skerleva D, Kitajiri S et al (2015) Limited hair cell induction from human induced pluripotent stem cells using a simple stepwise method. Neurosci Lett 599:49–54. https://doi.org/10.1016/j.neulet.2015.05.032

    Article  CAS  PubMed  Google Scholar 

  56. Ealy M, Ellwanger DC, Kosaric N et al (2016) Single-cell analysis delineates a trajectory toward the human early otic lineage. Proc Natl Acad Sci 113:8508–8513. https://doi.org/10.1073/pnas.1605537113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ronaghi M, Nasr M, Ealy M et al (2014) Inner ear hair cell-like cells from human embryonic stem cells. Stem Cells Dev 23:1275–1284. https://doi.org/10.1089/scd.2014.0033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ealy M, Ellwanger DC, Kosaric N et al (2016) Single-cell analysis delineates a trajectory toward the human early otic lineage. Proc Natl Acad Sci 113:201605537. https://doi.org/10.1073/pnas.1605537113

    Article  CAS  Google Scholar 

  59. Ohyama T, Mohamed OA, Taketo MM et al (2006) Wnt signals mediate a fate decision between otic placode and epidermis. Development 133:865–875. https://doi.org/10.1242/dev.02271

    Article  CAS  PubMed  Google Scholar 

  60. Lazarus HM, Haynesworth SE, Gerson SL et al (1995) Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transpl 16:557–564

    CAS  Google Scholar 

  61. Lee HS, Kim WJ, Gong JS, Park KH (2018) Clinical safety and efficacy of autologous bone marrow-derived mesenchymal stem cell transplantation in sensorineural hearing loss patients. J Audiol Otol 22:105–109. https://doi.org/10.7874/jao.2017.00150

    Article  PubMed  PubMed Central  Google Scholar 

  62. Nie J, Koehler KR, Hashino E (2017) Directed differentiation of mouse embryonic stem cells into inner ear sensory epithelia in 3D culture. Methods Mol Biol 1597:67–83. https://doi.org/10.1007/978-1-4939-6949-4_6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Liu X-P, Koehler KR, Mikosz AM et al (2016) Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nat Commun 7:11508. https://doi.org/10.1038/ncomms11508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lee AS, Tang C, Rao MS et al (2013) Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat Med. https://doi.org/10.1038/nm.3267

  65. Okano T, Kelley MW (2012) Stem cell therapy for the inner ear. Trends Amplif 16:4–18. https://doi.org/10.1177/1084713812440336

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hu Z, Ulfendahl M (2013) The potential of stem cells for the restoration of auditory function in humans. Regen Med 8:309–318. https://doi.org/10.2217/rme.13.32

    Article  CAS  PubMed  Google Scholar 

  67. Kürşat Gökcan M, Mülazimoğlu S, Ocak E et al (2016) Turkish journal of medical sciences study of mouse induced pluripotent stem cell transplantation into Wistar albino rat cochleae after hair cell damage. Turk J Med Sci 46:1603–1610. https://doi.org/10.3906/sag-1510-136

    Article  CAS  Google Scholar 

  68. Pauley S, Kopecky B, Beisel K et al (2008) Stem cells and molecular strategies to restore hearing. Panminerva Med 50:41–53

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Ortmann D, Vallier L, Wang J, Esteban M (2017) Variability of human pluripotent stem cell lines This review comes from a themed issue on Cell reprogramming. Curr Opin Genet Dev 46:179–185. https://doi.org/10.1016/j.gde.2017.07.004

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Brigitte Malgrange.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Czajkowski, A., Mounier, A., Delacroix, L. et al. Pluripotent stem cell-derived cochlear cells: a challenge in constant progress. Cell. Mol. Life Sci. 76, 627–635 (2019). https://doi.org/10.1007/s00018-018-2950-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-018-2950-5

Keywords

Navigation