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.
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References
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156. https://doi.org/10.1038/292154a0
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Okano T, Kelley MW (2012) Stem cell therapy for the inner ear. Trends Amplif 16:4–18. https://doi.org/10.1177/1084713812440336
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
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
Pauley S, Kopecky B, Beisel K et al (2008) Stem cells and molecular strategies to restore hearing. Panminerva Med 50:41–53
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
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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
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DOI: https://doi.org/10.1007/s00018-018-2950-5