Prerpints.org logo
Preprint
Review

Application of Human Stem Cells to Model Genetic Sensorineural Hearing Loss and Meniere Disease

Altmetrics

Downloads

200

Views

130

Comments

0

A peer-reviewed article of this preprint also exists.

Submitted:

15 February 2023

Posted:

20 February 2023

You are already at the latest version

Alerts
Abstract
Genetic sensorineural hearing loss and Meniere disease have been associated with rare variations in the coding and non-coding region of the human genome. Most of these variants are classified as likely pathogenic or variants of unknown significance and require functional validation in cellular or animal models. Given the difficulties to obtain human samples and the raising concerns about animal experimentation, human induced pluripotent stem cells emerge as cellular models to investigate the interaction of genetic and environmental factors in the pathogenesis of inner ear disorders. The generation of human sensory epithelia and neuron-like cells carrying the variants of interest may facilitate a better understanding of their role during differentiation. These cellular models will allow us to explore new strategies for restoring hearing and vestibular sensory epithelia as well as neurons. This review summarizes the use of human induced pluripotent stem cells in sensorineural hearing loss and Meniere disease and proposes some strategies for its application in clinical practice.
Keywords: 
Subject: Biology and Life Sciences  -   Cell and Developmental Biology

1. Introduction

Stem cell culture is essential in biomedical research to study cellular and developmental biology [1,2]. Several biological phenomena specific to humans, such as brain development and inner ear formation amongst others, are not reproduced in animal models. This limitation has promoted the generation of cellular models to reproduce more exactly human biology and development [1], leading to a better understanding of genetic disorders.
Stem cell science presents a highly promising direction in translational medicine, allowing the proliferation and differentiation of any cell type. Stem cell models are more clinically appropriate to study the molecular pathophysiology of certain diseases, and further develop better therapeutic strategies [2]. Therefore, human pluripotent stem cells (hPSCs) are progressively used to model rare diseases, as an alternative to animal models which may raise research costs and ethical issues [1]. Disease modeling of human disorders may allow the development of new therapies for rare diseases [1]. Henceforth, human organoids provide a unique opportunity to study them in a multicellular environment and complement animal models [3].
The most common sensory disorder is hearing loss, affecting around 15% of the population [4]. Sensorineural hearing loss (SNHL) and vestibular disorders are caused by damage to the sensory epithelia and neurons, which do not regenerate in humans. These could originate from a variety of causes, such as genetic and environmental factors, aging, and ototoxic drugs [5].
Extensive studies using animal models have expanded our learning about the human inner ear, although access into the inner ear is restricted in mouse models, slowing research advance in the area [6]. Access to human inner ear is also strictly restricted since tissue sampling may lead to irreversible damage and profound hearing loss or vestibular impairment. In addition, the non-invasive diagnostic imaging procedures such as magnetic resonance imaging or computerized tomography scan, do not supply enough resolution for the investigation of human inner ear disorders at the cellular and molecular levels [7].
Researchers have differentiated hPSCs into inner ear progenitors and sensory cells [8,9,10,11] using different induction protocols to form Hair cells-like cells. Many of these differentiation protocols are developed completely in 2D culture generating a homogeneous population of inner ear cells-like cells [12,13,14]. Instead, 3D cell culture presenting numerous cell types can better mimic the structure of the human organ in vivo [15,16,17,18]. Since Hair cells (HCs), supporting cells (SCs), and their associated neurons are damaged in SNHL, gene and cell-based therapies may restore hearing and vestibular impairment.
This scoping review describes the major achievements, gaps in research, and challenges to translating the application of hPSCs into clinical practice. Furthermore, we present their application in monogenic deafness and the potential use to model Meniere disease (MD).

2. Generation of Human Pluripotent Stem Cells

Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and hiPSCs, have emerged as a new model system that offers unique advantages for disease modeling [2].
hESCs are derived from the inner cell mass of the blastocyst of an embryo, while hiPSCs are derived from adult somatic tissues. Since their discovery in 2007 [19], hiPSCs have emerged as an alternative to hESCs, because they can be obtained from individual patients or healthy donors and immune rejection can be avoided when they are transplanted autologously [20,21]. Since then, researchers have shown the potential of reprogramming to convert a given somatic cell type to an iPSC state.
Reprogramming methods may be divided into two categories, integrative and non-integrative (Table 1). Integrative reprogramming approaches generate heterogeneous hiPSCs lines and present genomic mutation risks, which could obscure comparative analysis between lines. So, to avoid the risk of tumorigenesis, non-integrative reprogramming methods have been designed, including non-integrating viral vectors such as Sendai virus (SeV), adenovirus, and non-viral vectors like episomal DNA, Piggy-Bac transposons, modified synthetic mRNA (modRNA), microRNA and recombinant proteins.
The most commonly used reprogramming methods to generate hiPSCs are SeV, synthetic mRNAs, and episomal vectors due to their high reprogramming efficiency and their wide application to different cell types [20,22,23,24,25]. In addition, SeV reprogramming is highly effective, with a lower workload and no non-appearance of viral sequences in most cell lines at higher passages in culture. Moreover, the combination of bFGF, ascorbic acid (AA), and Y-27632 dihydrochloride – ROCK Inhibitor in the culture medium increase the reprogramming efficiency [54,55,56] (Figure 1). However, in the last years, modRNA-based somatic reprogramming has become a more effective alternative to the SeV system, since the modRNA molecules encode multiple pluripotent factors and can be applied successfully in reprogramming somatic cells [24,25,29].
Selecting the most suitable reprogramming method and implementing good manufacturing procedures for hiPSCs generation is key to obtaining high-quality hiPSCs cell lines.

3. Disease modeling by human induced Pluripotent Stem Cells

The advantages of hiPSCs are well-known at many distinct levels such as their capacity to self-renew indefinitely in culture and differentiate to any cell type in the human body. So, hiPSCs are the ideal source for generating a patient-derived personalized disease model [1,2].
Experimental human modeling of inherited rare disorders provides insight into the cellular and molecular mechanisms involved in the disease. It is worth mentioning the early success history of disease modeling using hiPSCs, which was based on neurodegenerative diseases [58]. Neuronal differentiation was one of the initially differentiated target tissues from several sources of stem cells due to their potential future therapeutic usage [59,60,61]. Neurodegenerative disorders such as amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease are among the most studied ones [62,63,64].
Recent advances in organoid technology have revolutionized the in vitro culture tools for biomedical research by creating powerful 3D models to recapitulate the cellular heterogeneity, structure, and functions of the primary tissues, compared with 2D cell models. Hence, is a methodology with many translational applications such as regenerative medicine, drug discovery, and precision medicine. In 2011, the first organoids from hPSCs were generated to recreate intestinal tissue in vitro [65]. In 2012, the first retinal organoids were generated from hPSCs [66]. These human retinal organoids are larger than mouse organoids and can grow into multilayered tissue containing both rods and cones [66,67]. In 2013, Lancaster et al. further established the 3D cerebral organoids containing different brain regions within single organoids [68].

4. Clinical applications in genetic deafness and vestibular disorders

According to the World Health Organization (WHO), hearing impairment, the partial or total inability to hear sounds, is among the top 10 disabilities of today’s society. (https://www.who.int/newsroom/factsheets/detail/deafness-and-hearing-loss).
Congenital SNHL is estimated to have a genetic origin in 70% of cases and, mutations can affect the organ of Corti, the spiral ganglion, and almost any part of the auditory pathway [41,42]. Monogenic SNHL are considered rare disorders [43,44]. There are around 126 genes associated with non-syndromic SNHL (https://hereditaryhearingloss.org/dominant) and many of them are related to inner ear homeostasis and mechano-electrical transduction [72].
Several otologic conditions may show fluctuating SNHL, including Meniere Disease (MD), a debilitating condition, characterized by episodes of spontaneous vertigo, tinnitus, and aural fullness [73,74]. It is associated with the progressive accumulation of endolymph in the cochlear duct [75]. The diagnosis is based on the characteristic presentation of the different clinical symptoms mentioned during the vertigo attacks [76]. MD prevalence is higher in European than Asian and African populations with a range of 10-225 cases/100,000 individuals. Most patients suffer from SNHL in one ear, but 25-40% of these patients with unilateral SNHL may develop hearing loss in the contralateral ear, after several years [77]. MD is known to have a genetic predisposition [74] and familial MD is found in around 8-10% of cases with several genes involved [78,79,80,81,82]. Some forms of monogenic SNHL and familial MD are rare diseases which may benefit from gene and cellular therapy.
Despite the extensive occurrence of genetic SNHL in the world, there are no Food and Drug Administration (FDA)-approved cellular or molecular therapies [4,50]. Current treatments for human SNHL and MD are medical therapy using steroids, hearing aids, surgery to correct the cause of the hearing loss, or cochlear implants [84,85,86,87,88,89]. Though these devices offer significant relief of the moderate and severe SNHL by amplifying sound or directly electrically stimulating the auditory nerve, they have significant limitations in terms of speech discrimination in complex acoustic environments [90]. These medical devices require the presence of functional auditory neurons in the inner ear. Therefore, in the last years, new studies focus on possibilities for neuronal replacement, including exogenous stem cell transplantation and endogenous cell source replacement. Several studies have proved that neural stem cell transplantation in the inner ear has an important therapeutic effect on the activation and regeneration of cells, restoring damaged neurons [91,92,93]. However, more research is still needed to improve and standardize the protocol for differentiating stem cells into inner ear HCs and neurons.
Transcriptional networks are key in governing the regeneration or replacement of auditory neurons from stem cells. Development of the inner ear is an organized molecular transformation of a set of epidermal cells (the otic placode) into the fully developed ear with its neurosensory component, necessary for signal extraction and transmission, and the non-sensory component, forming the labyrinth necessary for directing sensory stimuli to specific sensory epithelia [6,94]. The main genes involved in neurosensory development in the inner ear are MYO7A, HES5, SOX2, NEUROG1, NEUROD1, and POU4F1 [80,95,96,97,98].
Since animal models are only able to represent the chronic end stages of the disease when permanent damage of sensory epithelia has occurred, understanding, and identifying the transcription factors involved in the development and survival of auditory neurons is vital for the generation of disease models and the identification of more effective treatments for hearing loss in the future.

4.1. Modeling inner ear disorders: 2D and 3D cell culture

The inner ear is highly complex; both the anterior and posterior labyrinth are connected, and the extent of involvement in each organ may vary, resulting in hearing or vestibular disorders. Consequently, inner ear disorders may be caused by damage to sensory epithelia and neurons, which do not regenerate to any clinically relevant extent in humans. Since the pathophysiology of certain types of SNHL and MD have not yet been explained at cellular and molecular levels, it is difficult to generate an animal model that accurately reflects these diseases.
Several animal models, including zebrafish, bullfrog, chick, and several species of mammals have improved our knowledge of the biology of the inner ear. In addition, these animal models are only able to represent the chronic end stages of disease with permanent loss of hearing and vestibular function [5].
For this reason, the best option to study the inner ear development and disease is to generate human cell models. Several protocols have been devised to direct hPSCs into inner ear HCs and neuron-like cells. The efficiency, reproducibility, and scalability of these protocols are enhanced by incorporating knowledge of inner ear development [13,17,18,67,68,69,70]. Early studies on the transplantation of hPSCs-derived otic progenitors have been successful in certain animal models [103], but the hearing was transiently restored, and long-term cell survival continues to be a major challenge. To differentiate successfully hPSCs to HCs, SCs, and inner ear neurons in vitro is critical to know the transcription factors and signaling pathways involved in the inner development in vivo.
The last years have seen a surge in the number of studies that are conducted in vitro 2D and 3D hiPSCs models to study auditory and vestibular disorders.

4.1.1. Sensory Epithelia

Most of the induction protocols towards HCs-like cells derived from hPSCs are developed completely in 2D culture and others combined the embryoid bodies (EBs) formation with cytokines during 5 days until a 2D cell culture is finally obtained [12,13,14,67,72].
The first stages of the human inner ear development are the generation of the ectodermal germ layer followed by the pre-placodal ectoderm (PPE) formation. Differentiation protocols inhibit TGFβ and WNT signaling while activate BMP signaling to carry out non-neural ectoderm (NNE) generation [13,17,72]. The PPE generates the most of cranial placodes, including the otic placode. Physical environmental signals supplied by Matrigel, an extracellular matrix, enhance the hPSCs-differentiation protocols efficiency and the cellular assemblage [15,17,18]. The addition of Matrigel to the inner ear organoid cultures promotes the generation of fluid-filled vesicles which hold HCs and SCs-like cells [17]. Nevertheless, the protocols to generate organoids containing vestibular tissue from hPSCs use the rotary cell culture system (RCCS), a new 3D cell culture technology for culturing suspension cells and anchorage-dependent cells. This procedure allows to obtain HCs-like cells on the surface of the organoids generated [18]. To date, HCs-like cells from hPSCs show electrophysiological characteristics and molecular markers of vestibular HCs, but not cochlear HCs. So, it is necessary to identify new small molecules or culture methods to improve the generation of cochlear HCs from hPSCs.
SCs perform a key role in the ionic homeostasis, critical for the function of HCs. The gap junction proteins with higher expression in SCs are connexins. The autosomal recessive non-syndromic SNHL is commonly caused by mutations in GJB2 gene which encodes for connexin 26 (CX26) [105]. An in vitro model for the homozygous 235delC mutation in GJB2 has been developed from hPSC to develop a therapy for deafness [106] (Figure 2).
Frejo et al. have generated a hiPSC line derived from an MD patient. This model has been differentiated into HCs by a 2D protocol based on Boddy et al.[101]. This method consists of the generation of otic epithelial progenitors (OEPs) and consequently differentiation to HCs-like cells (Figure 3).
Moreover, we have started to generate inner ear organoids from the hiPSC-MD model derived from a patient with mutations in DTNA and FAM136A genes for studying the development of the inner ear in this patient as well as how mutations found in DTNA and FAM136A affect the development and functionality of the system itself when sensory organs mature [75,76]. Koehler et al. described the protocol [17] to generate inner ear sensory epithelium harboring HCs using an in vitro 3D differentiation system from hiPSCs. Cells are treated with recombinant proteins that modulate BMP, FGF, and WNT signaling pathways to induce the sequential formation of NNE, otic-epibranchial progenitor domain (OEPD), and otic placodes. The otic placodes subsequently undergo self-guided morphogenesis to form inner ear HCs and SCs (Figure 4).

4.1.2. Sensory Neuron

The first neural differentiation protocols from hPSCs were performed in stromal cells of skull bone marrow and generated dopaminergic neurons in an efficient manner [77,78]. These induction protocols have been remodeled to generate inner ear sensory neurons and glial cells derived from hPSCs. However, many of the culture protocols have been adapted to form hPSCs-dopaminergic neurons by their function in neurodegenerative diseases, including Parkinson disease [112]. The generation of glutamatergic neurons was a critical stage to recapitulate the afferent neural transmission in the human inner ear, since glutamate is the principal neurotransmitter of the synaptic transmission between HCs and the afferent sensory neurons in the inner ear [113].
The inner ear sensory neurons are obtained from the otic placode. Consequently, some of the first differentiation protocols steps to form sensory neurons have focused on the application of the otic placode developmental pathways. Some cytokines and growth factors like FGFs, BMP, SHH, and noggin protein are employed to aid neuronal growth from the otic placode [114,115,116]. BRN3A and β-III tubulin are regularly employed to confirm neuron formation. Matsuoka et al. differentiated hESCs to otic neuronal progenitors (ONPs) and spiral ganglion neurons (SGN)-like cells obtaining a 90% of neuron-like cells positives for peripherin and β-III tubulin, but only a 46% of cells were BRN3A+ [115]. So, to recreate in vitro the peripheral neural circuit by differentiating hPSCs into neuron-like cells is essential obtain sensory and innervating neurons.
Two methodologies can develop both tissues at the same time, providing complementary research tools for disease modeling: 2D and 3D cell cultures (Figure 5).
To generate both otic epithelial progenitors (OEPs) and otic neural progenitors (ONPs) in 2D culture from hPSCs, cells are treated with FGF during 10-12 days [103]. HCs-like cells can be obtained from OEP following the inhibition of Notch signaling and supplementation with retinoic acid (RA) and epidermal growth factor (EGF) [67,71]. On the other hand, sensory neuron-like cells can be generated from ONPs by the addition to the cell culture FGF and SHH factors and a subsequent supplementation of BDNF and NT3 proteins [103]. The co-culture of HCs and sensory neurons generated from hPSCs form neural connections in vitro. Nevertheless, this system demands separate differentiation protocols before co-culture these cells [117].
The 3D culture of inner ear organoids show sensory epithelia and sensory neuron-like cells [15,16,17]. Several studies have reproduced these induction protocols to generate neuron-like cells for different applications, including electrophysiological studies and disease modeling [118]. The inner ear organoid methodology is an in vitro powerful tool to study the peripheral sensory neural system in the human inner ear. The generation of human inner ear tissue from hPSCs offers the potential to study the inner ear biology and understand differences between mice and human inner ear development. Moreover, it would enable both, in vitro screening of drug candidates for the treatment of hearing loss and balance dysfunction and a source of cells for cell-based therapies of the inner ear. Nie and Hashino describe a 3D protocol to form inner ear neurons from hPSC [109]. Other studies have generated otic organoids with neuron-like cells from hiPSC models combining the 2D and 3D systems in the same differentiation protocol [100].
Stem cell science has also been applied to generate a hiPSCs model obtained from patients with severe tinnitus and rare variants in the ANK2 gene, and differentiating them to inner ear neurons using a 2D system [101]. This protocol consists of two phases, a first phase in which hiPSC-derived otic neural progenitors (ONPs) are generated by inhibiting Wnt signaling, which is accompanied by subsequent activation of this pathway, and a second phase consisting of ONPs expansion and enrichment, which will later differentiate into inner ear neurons (Figure 6).

5. Clinical Trials in Inner Ear Disorders

Several clinical trials have been performed using human stem cells to treat SNHL. Autologous human umbilical cord blood stem cells have been used for over twenty years, with excellent safety records. A study in 2015 used umbilical cord blood stem cells to improve inner ear function, audition, and language in children [119]. The potential of human mesenchymal stem cells has been evaluated for years for regenerating inner ear HCs [120].
The major achievements in disease modeling using a hiPSC-derived inner ear for genetic SNHL include the genes MYO7A, MYO15, and MERRF in HCs [70,89,90], and GJB2 and SLC26A4 (Pendred syndrome) in SCs [106,123,124,125] (Table 2). These studies have defined the molecular mechanisms involving each gene and showed the cellular effects of each mutation. Recently, a clinical trial using iPSC derived from patients with Pendred syndrome to generate cochlear cells has allowed to study the effects of low-dose oral administration of sirolimus for fluctuating and progressive hearing loss [126].
However, many research gaps have not been addressed and more than 150 genes in SNHL and familial MD remain to be modeled (https://deafnessvariationdatabase.org/). Some of the limitation of hPSCs to investigate human inner ear diseases involve time-consuming culture protocols that sometimes are not reproducible, with variable efficiency of tissue derivation, and restricted differentiation and integration in host tissues. Deciphering the disease molecular mechanisms is the first step to finding a drug target that may offer new opportunities for therapy.

6. Conclusions

Human iPSCs are a reliable model to study the functional consequences of rare variants in early stages of inner ear disease development and design novel gene therapies to restore the phenotype. The use of 3D models to generate patient-specific organoids allows us to elucidate the effect of rare variants in genetic deafness and vestibular disorders, investigate the molecular mechanisms underlying the disease, and analyze the effects of genetic mutations on the phenotype at the cellular and organoid levels. Modeling inner ear diseases by differentiating hiPSCs is a promising tool for designing novel therapies for the treatment of SNHL and MD.

Author Contributions

Mar Lamolda: paper search, literature review, writing and review. Lidia Frejo: design and search methods, literature review, writing and review. Alvaro Gallego-Martinez: Literature review, writing, and review. Jose Antonio Lopez-Escamez: Design and search methods, literature review, writing and review.

Funding

ML is funded by a Research Grant RH-0073-2021 from Andalusian Health Department. LF has received funds from Sara Borrell’s postdoctoral Fellowship (ISCIII; grant code: CD20/00153). AGM is funded by a postdoctoral Grant from Economic Change, Industry, Knowledge and Universities Department (DOC_01677). JALE and LF have also received funds for stem cell research from ibs.GRANADA (INTRAIBS-2021-07).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Avior, Y.; Sagi, I.; Benvenisty, N. Pluripotent Stem Cells in Disease Modelling and Drug Discovery. Nat. Rev. Mol. Cell Biol. 2016, 17, 170–182. [Google Scholar] [CrossRef] [PubMed]
  2. Bai, X. Stem Cell-Based Disease Modeling and Cell Therapy. Cells 2020, 9, E2193. [Google Scholar] [CrossRef]
  3. Kim, J.; Koo, B.-K.; Knoblich, J.A. Human Organoids: Model Systems for Human Biology and Medicine. Nat. Rev. Mol. Cell Biol. 2020, 21, 571–584. [Google Scholar] [CrossRef]
  4. Liu, H.; Zhou, K.; Zhang, X.; Peng, K.A. Fluctuating Sensorineural Hearing Loss. Audiol. Neurootol. 2019, 24, 109–116. [Google Scholar] [CrossRef] [PubMed]
  5. Tang, P.-C.; Hashino, E.; Nelson, R.F. Progress in Modeling and Targeting Inner Ear Disorders with Pluripotent Stem Cells. Stem Cell Rep. 2020, 14, 996–1008. [Google Scholar] [CrossRef] [PubMed]
  6. Toyoda, S.; Shiraki, N.; Yamada, S.; Uwabe, C.; Imai, H.; Matsuda, T.; Yoneyama, A.; Takeda, T.; Takakuwa, T. Morphogenesis of the Inner Ear at Different Stages of Normal Human Development. Anat. Rec. 2015, 298, 2081–2090. [Google Scholar] [CrossRef]
  7. Kayyali, M.N.; Wright, A.C.; Ramsey, A.J.; Brant, J.A.; Stein, J.M.; O’Malley, B.W.; Li, D. Challenges and Opportunities in Developing Targeted Molecular Imaging to Determine Inner Ear Defects of Sensorineural Hearing Loss. Nanomedicine Nanotechnol. Biol. Med. 2018, 14, 397–404. [Google Scholar] [CrossRef] [PubMed]
  8. Boddy, S.L.; Chen, W.; Romero-Guevara, R.; Kottam, L.; Bellantuono, I.; Rivolta, M.N. Inner Ear Progenitor Cells Can Be Generated in Vitro from Human Bone Marrow Mesenchymal Stem Cells. Regen. Med. 2012, 7, 757–767. [Google Scholar] [CrossRef] [PubMed]
  9. Durán Alonso, M.B.; Feijoo-Redondo, A.; Conde de Felipe, M.; Carnicero, E.; García, A.S.; García-Sancho, J.; Rivolta, M.N.; Giráldez, F.; Schimmang, T. Generation of Inner Ear Sensory Cells from Bone Marrow-Derived Human Mesenchymal Stem Cells. Regen. Med. 2012, 7, 769–783. [Google Scholar] [CrossRef]
  10. Mittal, R.; Ocak, E.; Zhu, A.; Perdomo, M.M.; Pena, S.A.; Mittal, J.; Bohorquez, J.; Eshraghi, A.A. Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Cochlear Function in an Experimental Rat Model. Anat. Rec. Hoboken NJ 2007 2020, 303, 487–493. [Google Scholar] [CrossRef]
  11. Xu, Y.-P.; Shan, X.-D.; Liu, Y.-Y.; Pu, Y.; Wang, C.-Y.; Tao, Q.-L.; Deng, Y.; Cheng, Y.; Fan, J.-P. Olfactory Epithelium Neural Stem Cell Implantation Restores Noise-Induced Hearing Loss in Rats. Neurosci. Lett. 2016, 616, 19–25. [Google Scholar] [CrossRef] [PubMed]
  12. Ding, J.; Tang, Z.; Chen, J.; Shi, H.; Chen, J.; Wang, C.; Zhang, C.; Li, L.; Chen, P.; Wang, J. 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. 2016, 81, 208–222. [Google Scholar] [CrossRef] [PubMed]
  13. Lahlou, H.; Lopez-Juarez, A.; Fontbonne, A.; Nivet, E.; Zine, A. Modeling Human Early Otic Sensory Cell Development with Induced Pluripotent Stem Cells. PloS One 2018, 13, e0198954. [Google Scholar] [CrossRef]
  14. Ohnishi, H.; Skerleva, D.; Kitajiri, S.; Sakamoto, T.; Yamamoto, N.; Ito, J.; Nakagawa, T. Limited Hair Cell Induction from Human Induced Pluripotent Stem Cells Using a Simple Stepwise Method. Neurosci. Lett. 2015, 599, 49–54. [Google Scholar] [CrossRef] [PubMed]
  15. Jeong, M.; O’Reilly, M.; Kirkwood, N.K.; Al-Aama, J.; Lako, M.; Kros, C.J.; Armstrong, L. Generating Inner Ear Organoids Containing Putative Cochlear Hair Cells from Human Pluripotent Stem Cells. Cell Death Dis. 2018, 9, 922. [Google Scholar] [CrossRef] [PubMed]
  16. Koehler, K.R.; Mikosz, A.M.; Molosh, A.I.; Patel, D.; Hashino, E. Generation of Inner Ear Sensory Epithelia from Pluripotent Stem Cells in 3D Culture. Nature 2013, 500, 217–221. [Google Scholar] [CrossRef] [PubMed]
  17. Koehler, K.R.; Nie, J.; Longworth-Mills, E.; Liu, X.-P.; Lee, J.; Holt, J.R.; Hashino, E. Generation of Inner Ear Organoids Containing Functional Hair Cells from Human Pluripotent Stem Cells. Nat. Biotechnol. 2017, 35, 583–589. [Google Scholar] [CrossRef] [PubMed]
  18. Mattei, C.; Lim, R.; Drury, H.; Nasr, B.; Li, Z.; Tadros, M.A.; D’Abaco, G.M.; Stok, K.S.; Nayagam, B.A.; Dottori, M. Generation of Vestibular Tissue-Like Organoids From Human Pluripotent Stem Cells Using the Rotary Cell Culture System. Front. Cell Dev. Biol. 2019, 7, 25. [Google Scholar] [CrossRef] [PubMed]
  19. Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell 2007, 131, 861–872. [Google Scholar] [CrossRef]
  20. Choi, J.; Lee, S.; Mallard, W.; Clement, K.; Tagliazucchi, G.M.; Lim, H.; Choi, I.Y.; Ferrari, F.; Tsankov, A.M.; Pop, R.; et al. A Comparison of Genetically Matched Cell Lines Reveals the Equivalence of Human IPSCs and ESCs. Nat. Biotechnol. 2015, 33, 1173–1181. [Google Scholar] [CrossRef]
  21. Ortuño-Costela, M.D.C.; Cerrada, V.; García-López, M.; Gallardo, M.E. The Challenge of Bringing IPSCs to the Patient. Int. J. Mol. Sci. 2019, 20, E6305. [Google Scholar] [CrossRef]
  22. Aasen, T.; Raya, A.; Barrero, M.J.; Garreta, E.; Consiglio, A.; Gonzalez, F.; Vassena, R.; Bilić, J.; Pekarik, V.; Tiscornia, G.; et al. Efficient and Rapid Generation of Induced Pluripotent Stem Cells from Human Keratinocytes. Nat. Biotechnol. 2008, 26, 1276–1284. [Google Scholar] [CrossRef]
  23. Esteban, M.A.; Wang, T.; Qin, B.; Yang, J.; Qin, D.; Cai, J.; Li, W.; Weng, Z.; Chen, J.; Ni, S.; et al. Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells. Cell Stem Cell 2010, 6, 71–79. [Google Scholar] [CrossRef]
  24. Loh, Y.-H.; Agarwal, S.; Park, I.-H.; Urbach, A.; Huo, H.; Heffner, G.C.; Kim, K.; Miller, J.D.; Ng, K.; Daley, G.Q. Generation of Induced Pluripotent Stem Cells from Human Blood. Blood 2009, 113, 5476–5479. [Google Scholar] [CrossRef]
  25. Nakagawa, M.; Koyanagi, M.; Tanabe, K.; Takahashi, K.; Ichisaka, T.; Aoi, T.; Okita, K.; Mochiduki, Y.; Takizawa, N.; Yamanaka, S. Generation of Induced Pluripotent Stem Cells without Myc from Mouse and Human Fibroblasts. Nat. Biotechnol. 2008, 26, 101–106. [Google Scholar] [CrossRef]
  26. Subramanyam, D.; Lamouille, S.; Judson, R.L.; Liu, J.Y.; Bucay, N.; Derynck, R.; Blelloch, R. Multiple Targets of MiR-302 and MiR-372 Promote Reprogramming of Human Fibroblasts to Induced Pluripotent Stem Cells. Nat. Biotechnol. 2011, 29, 443–448. [Google Scholar] [CrossRef]
  27. Li, W.; Zhou, H.; Abujarour, R.; Zhu, S.; Young Joo, J.; Lin, T.; Hao, E.; Schöler, H.R.; Hayek, A.; Ding, S. Generation of Human-Induced Pluripotent Stem Cells in the Absence of Exogenous Sox2. Stem Cells Dayt. Ohio 2009, 27, 2992–3000. [Google Scholar] [CrossRef]
  28. Lin, S.-L.; Chang, D.C.; Chang-Lin, S.; Lin, C.-H.; Wu, D.T.S.; Chen, D.T.; Ying, S.-Y. Mir-302 Reprograms Human Skin Cancer Cells into a Pluripotent ES-Cell-like State. RNA N. Y. N 2008, 14, 2115–2124. [Google Scholar] [CrossRef]
  29. Zhao, Y.; Yin, X.; Qin, H.; Zhu, F.; Liu, H.; Yang, W.; Zhang, Q.; Xiang, C.; Hou, P.; Song, Z.; et al. Two Supporting Factors Greatly Improve the Efficiency of Human IPSC Generation. Cell Stem Cell 2008, 3, 475–479. [Google Scholar] [CrossRef]
  30. Mali, P.; Ye, Z.; Hommond, H.H.; Yu, X.; Lin, J.; Chen, G.; Zou, J.; Cheng, L. Improved Efficiency and Pace of Generating Induced Pluripotent Stem Cells from Human Adult and Fetal Fibroblasts. Stem Cells Dayt. Ohio 2008, 26, 1998–2005. [Google Scholar] [CrossRef]
  31. Yu, J.; Vodyanik, M.A.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J.L.; Tian, S.; Nie, J.; Jonsdottir, G.A.; Ruotti, V.; Stewart, R.; et al. Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science 2007, 318, 1917–1920. [Google Scholar] [CrossRef]
  32. Liao, J.; Wu, Z.; Wang, Y.; Cheng, L.; Cui, C.; Gao, Y.; Chen, T.; Rao, L.; Chen, S.; Jia, N.; et al. Enhanced Efficiency of Generating Induced Pluripotent Stem (IPS) Cells from Human Somatic Cells by a Combination of Six Transcription Factors. Cell Res. 2008, 18, 600–603. [Google Scholar] [CrossRef]
  33. Zhao, H.; Li, Y.; Jin, H.; Xie, L.; Liu, C.; Jiang, F.; Luo, Y.; Yin, G.; Li, Y.; Wang, J.; et al. Rapid and Efficient Reprogramming of Human Amnion-Derived Cells into Pluripotency by Three Factors OCT4/SOX2/NANOG. Differ. Res. Biol. Divers. 2010, 80, 123–129. [Google Scholar] [CrossRef]
  34. Zhu, S.; Li, W.; Zhou, H.; Wei, W.; Ambasudhan, R.; Lin, T.; Kim, J.; Zhang, K.; Ding, S. Reprogramming of Human Primary Somatic Cells by OCT4 and Chemical Compounds. Cell Stem Cell 2010, 7, 651–655. [Google Scholar] [CrossRef]
  35. Ye, L.; Chang, J.C.; Lin, C.; Qi, Z.; Yu, J.; Kan, Y.W. Generation of Induced Pluripotent Stem Cells Using Site-Specific Integration with Phage Integrase. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 19467–19472. [Google Scholar] [CrossRef]
  36. Zhou, W.; Freed, C.R. Adenoviral Gene Delivery Can Reprogram Human Fibroblasts to Induced Pluripotent Stem Cells. Stem Cells Dayt. Ohio 2009, 27, 2667–2674. [Google Scholar] [CrossRef]
  37. Ban, H.; Nishishita, N.; Fusaki, N.; Tabata, T.; Saeki, K.; Shikamura, M.; Takada, N.; Inoue, M.; Hasegawa, M.; Kawamata, S.; et al. Efficient Generation of Transgene-Free Human Induced Pluripotent Stem Cells (IPSCs) by Temperature-Sensitive Sendai Virus Vectors. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 14234–14239. [Google Scholar] [CrossRef]
  38. Fusaki, N.; Ban, H.; Nishiyama, A.; Saeki, K.; Hasegawa, M. 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. 2009, 85, 348–362. [Google Scholar] [CrossRef]
  39. Kaji, K.; Norrby, K.; Paca, A.; Mileikovsky, M.; Mohseni, P.; Woltjen, K. Virus-Free Induction of Pluripotency and Subsequent Excision of Reprogramming Factors. Nature 2009, 458, 771–775. [Google Scholar] [CrossRef]
  40. Woltjen, K.; Michael, I.P.; Mohseni, P.; Desai, R.; Mileikovsky, M.; Hämäläinen, R.; Cowling, R.; Wang, W.; Liu, P.; Gertsenstein, M.; et al. PiggyBac Transposition Reprograms Fibroblasts to Induced Pluripotent Stem Cells. Nature 2009, 458, 766–770. [Google Scholar] [CrossRef]
  41. Si-Tayeb, K.; Noto, F.K.; Sepac, A.; Sedlic, F.; Bosnjak, Z.J.; Lough, J.W.; Duncan, S.A. Generation of Human Induced Pluripotent Stem Cells by Simple Transient Transfection of Plasmid DNA Encoding Reprogramming Factors. BMC Dev. Biol. 2010, 10, 81. [Google Scholar] [CrossRef]
  42. Yu, J.; Hu, K.; Smuga-Otto, K.; Tian, S.; Stewart, R.; Slukvin, I.I.; Thomson, J.A. Human Induced Pluripotent Stem Cells Free of Vector and Transgene Sequences. Science 2009, 324, 797–801. [Google Scholar] [CrossRef]
  43. Yu, J.; Chau, K.F.; Vodyanik, M.A.; Jiang, J.; Jiang, Y. Efficient Feeder-Free Episomal Reprogramming with Small Molecules. PLOS ONE 2011, 6, e17557. [Google Scholar] [CrossRef]
  44. Okita, K.; Matsumura, Y.; Sato, Y.; Okada, A.; Morizane, A.; Okamoto, S.; Hong, H.; Nakagawa, M.; Tanabe, K.; Tezuka, K.; et al. A More Efficient Method to Generate Integration-Free Human IPS Cells. Nat. Methods 2011, 8, 409–412. [Google Scholar] [CrossRef]
  45. Jia, F.; Wilson, K.D.; Sun, N.; Gupta, D.M.; Huang, M.; Li, Z.; Panetta, N.J.; Chen, Z.Y.; Robbins, R.C.; Kay, M.A.; et al. A Nonviral Minicircle Vector for Deriving Human IPS Cells. Nat. Methods 2010, 7, 197–199. [Google Scholar] [CrossRef]
  46. Kim, D.; Kim, C.-H.; Moon, J.-I.; Chung, Y.-G.; Chang, M.-Y.; Han, B.-S.; Ko, S.; Yang, E.; Cha, K.Y.; Lanza, R.; et al. Generation of Human Induced Pluripotent Stem Cells by Direct Delivery of Reprogramming Proteins. Cell Stem Cell 2009, 4, 472–476. [Google Scholar] [CrossRef]
  47. Yakubov, E.; Rechavi, G.; Rozenblatt, S.; Givol, D. Reprogramming of Human Fibroblasts to Pluripotent Stem Cells Using MRNA of Four Transcription Factors. Biochem. Biophys. Res. Commun. 2010, 394, 189–193. [Google Scholar] [CrossRef]
  48. Warren, L.; Manos, P.D.; Ahfeldt, T.; Loh, Y.-H.; Li, H.; Lau, F.; Ebina, W.; Mandal, P.K.; Smith, Z.D.; Meissner, A.; et al. Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified MRNA. Cell Stem Cell 2010, 7, 618–630. [Google Scholar] [CrossRef]
  49. Miyoshi, N.; Ishii, H.; Nagano, H.; Haraguchi, N.; Dewi, D.L.; Kano, Y.; Nishikawa, S.; Tanemura, M.; Mimori, K.; Tanaka, F.; et al. Reprogramming of Mouse and Human Cells to Pluripotency Using Mature MicroRNAs. Cell Stem Cell 2011, 8, 633–638. [Google Scholar] [CrossRef] [PubMed]
  50. Trokovic, R.; Weltner, J.; Nishimura, K.; Ohtaka, M.; Nakanishi, M.; Salomaa, V.; Jalanko, A.; Otonkoski, T.; Kyttälä, A. Advanced Feeder-Free Generation of Induced Pluripotent Stem Cells Directly From Blood Cells. Stem Cells Transl. Med. 2014, 3, 1402–1409. [Google Scholar] [CrossRef]
  51. Schlaeger, T.M.; Daheron, L.; Brickler, T.R.; Entwisle, S.; Chan, K.; Cianci, A.; DeVine, A.; Ettenger, A.; Fitzgerald, K.; Godfrey, M.; et al. A Comparison of Non-Integrating Reprogramming Methods. Nat. Biotechnol. 2015, 33, 58–63. [Google Scholar] [CrossRef]
  52. Kogut, I.; McCarthy, S.M.; Pavlova, M.; Astling, D.P.; Chen, X.; Jakimenko, A.; Jones, K.L.; Getahun, A.; Cambier, J.C.; Pasmooij, A.M.G.; et al. High-Efficiency RNA-Based Reprogramming of Human Primary Fibroblasts. Nat. Commun. 2018, 9. [Google Scholar] [CrossRef]
  53. Wang, A.Y.L. Application of Modified MRNA in Somatic Reprogramming to Pluripotency and Directed Conversion of Cell Fate. Int. J. Mol. Sci. 2021, 22, 8148. [Google Scholar] [CrossRef]
  54. Cabrera, S.; Ji, A.-R.; Frejo, L.; Ramos-Mejia, V.; Romero, T.; Real, P.; Lopez-Escamez, J.A. Generation of Human IPSC Line GRX-MCiPS4F-A2 from Adult Peripheral Blood Mononuclear Cells (PBMCs) with Spanish Genetic Background. Stem Cell Res. 2015, 15, 337–340. [Google Scholar] [CrossRef]
  55. Lamolda, M.; Montes, R.; Simón, I.; Perales, S.; Martínez-Navajas, G.; Lopez-Onieva, L.; Ríos-Pelegrina, R.; del Moral, R.G.; Griñan-Lison, C.; Marchal, J.A.; et al. GENYOi005-A: An Induced Pluripotent Stem Cells (IPSCs) Line Generated from a Patient with Familial Platelet Disorder with Associated Myeloid Malignancy (FPDMM) Carrying a p.Thr196Ala Variant. Stem Cell Res. 2019, 41, 101603. [Google Scholar] [CrossRef]
  56. Cimmino, L.; Neel, B.G.; Aifantis, I. Vitamin C in Stem Cell Reprogramming and Cancer. Trends Cell Biol. 2018, 28, 698–708. [Google Scholar] [CrossRef]
  57. Steinle, H.; Weber, M.; Behring, A.; Mau-Holzmann, U.; Schlensak, C.; Wendel, H.P.; Avci-Adali, M. Generation of IPSCs by Nonintegrative RNA-Based Reprogramming Techniques: Benefits of Self-Replicating RNA versus Synthetic MRNA. Stem Cells Int. 2019, 2019. [Google Scholar] [CrossRef]
  58. Park, I.-H.; Arora, N.; Huo, H.; Maherali, N.; Ahfeldt, T.; Shimamura, A.; Lensch, M.W.; Cowan, C.; Hochedlinger, K.; Daley, G.Q. Disease-Specific Induced Pluripotent Stem Cells. Cell 2008, 134, 877–886. [Google Scholar] [CrossRef]
  59. Francis, K.R.; Wei, L. Human Embryonic Stem Cell Neural Differentiation and Enhanced Cell Survival Promoted by Hypoxic Preconditioning. Cell Death Dis. 2010, 1, e22–e22. [Google Scholar] [CrossRef]
  60. Hu Bao-Yang; Weick Jason P.; Yu Junying; Ma Li-Xiang; Zhang Xiao-Qing; Thomson James A.; Zhang Su-Chun Neural Differentiation of Human Induced Pluripotent Stem Cells Follows Developmental Principles but with Variable Potency. Proc. Natl. Acad. Sci. 2010, 107, 4335–4340. [CrossRef]
  61. Kuruş, M.; Akbari, S.; Eskier, D.; Bursalı, A.; Ergin, K.; Erdal, E.; Karakülah, G. Transcriptome Dynamics of Human Neuronal Differentiation From IPSC. Front. Cell Dev. Biol. 2021, 0. [Google Scholar] [CrossRef] [PubMed]
  62. Israel, M.A.; Yuan, S.H.; Bardy, C.; Reyna, S.M.; Mu, Y.; Herrera, C.; Hefferan, M.P.; Van Gorp, S.; Nazor, K.L.; Boscolo, F.S.; et al. Probing Sporadic and Familial Alzheimer’s Disease Using Induced Pluripotent Stem Cells. Nature 2012, 482, 216–220. [Google Scholar] [CrossRef]
  63. Juopperi, T.A.; Kim, W.R.; Chiang, C.-H.; Yu, H.; Margolis, R.L.; Ross, C.A.; Ming, G.; Song, H. Astrocytes Generated from Patient Induced Pluripotent Stem Cells Recapitulate Features of Huntington’s Disease Patient Cells. Mol. Brain 2012, 5, 17. [Google Scholar] [CrossRef] [PubMed]
  64. Sun, X.; Song, J.; Huang, H.; Chen, H.; Qian, K. Modeling Hallmark Pathology Using Motor Neurons Derived from the Family and Sporadic Amyotrophic Lateral Sclerosis Patient-Specific IPS Cells. Stem Cell Res. Ther. 2018, 9, 315. [Google Scholar] [CrossRef]
  65. Spence, J.R.; Mayhew, C.N.; Rankin, S.A.; Kuhar, M.F.; Vallance, J.E.; Tolle, K.; Hoskins, E.E.; Kalinichenko, V.V.; Wells, S.I.; Zorn, A.M.; et al. Directed Differentiation of Human Pluripotent Stem Cells into Intestinal Tissue in Vitro. Nature 2011, 470, 105–109. [Google Scholar] [CrossRef]
  66. Nakano, T.; Ando, S.; Takata, N.; Kawada, M.; Muguruma, K.; Sekiguchi, K.; Saito, K.; Yonemura, S.; Eiraku, M.; Sasai, Y. Self-Formation of Optic Cups and Storable Stratified Neural Retina from Human ESCs. Cell Stem Cell 2012, 10, 771–785. [Google Scholar] [CrossRef]
  67. Fligor, C.M.; Huang, K.-C.; Lavekar, S.S.; VanderWall, K.B.; Meyer, J.S. Differentiation of Retinal Organoids from Human Pluripotent Stem Cells. Methods Cell Biol. 2020, 159, 279–302. [Google Scholar] [CrossRef]
  68. Lancaster, M.A.; Renner, M.; Martin, C.-A.; Wenzel, D.; Bicknell, L.S.; Hurles, M.E.; Homfray, T.; Penninger, J.M.; Jackson, A.P.; Knoblich, J.A. Cerebral Organoids Model Human Brain Development and Microcephaly. Nature 2013, 501, 373–379. [Google Scholar] [CrossRef] [PubMed]
  69. Chari, D.A.; Chan, D.K. Diagnosis and Treatment of Congenital Sensorineural Hearing Loss. Curr. Otorhinolaryngol. Rep. 2017, 5, 251–258. [Google Scholar] [CrossRef]
  70. Renauld, J.M.; Basch, M.L. Congenital Deafness and Recent Advances Towards Restoring Hearing Loss. Curr. Protoc. 2021, 1, e76. [Google Scholar] [CrossRef]
  71. Sheikh, A.; Bint-e-Zainab; Shabbir, K.; Imtiaz, A. Structure and Physiology of Human Ear Involved in Hearing; IntechOpen, 2022; ISBN 978-1-80355-190-6.
  72. Zhang, W.; Kim, S.M.; Wang, W.; Cai, C.; Feng, Y.; Kong, W.; Lin, X. Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success. Front. Mol. Neurosci. 2018, 11, 221. [Google Scholar] [CrossRef]
  73. Lopez-Escamez, J.A.; Carey, J.; Chung, W.-H.; Goebel, J.A.; Magnusson, M.; Mandalà, M.; Newman-Toker, D.E.; Strupp, M.; Suzuki, M.; Trabalzini, F.; et al. Diagnostic Criteria for Menière’s Disease. J. Vestib. Res. Equilib. Orientat. 2015, 25, 1–7. [Google Scholar] [CrossRef]
  74. Lopez-Escamez, J.A.; Batuecas-Caletrio, A.; Bisdorff, A. Towards Personalized Medicine in Ménière’s Disease. F1000Research 2018, 7, F1000 Faculty Rev-1295. [Google Scholar] [CrossRef]
  75. Gibson, W.P.R. Meniere’s Disease. Adv. Otorhinolaryngol. 2019, 82, 77–86. [Google Scholar] [CrossRef]
  76. Perez-Carpena, P.; Lopez-Escamez, J.A. Current Understanding and Clinical Management of Meniere’s Disease: A Systematic Review. Semin. Neurol. 2020, 40, 138–150. [Google Scholar] [CrossRef] [PubMed]
  77. Frejo, L.; Martin-Sanz, E.; Teggi, R.; Trinidad, G.; Soto-Varela, A.; Santos-Perez, S.; Manrique, R.; Perez, N.; Aran, I.; Almeida-Branco, M.S.; et al. Extended Phenotype and Clinical Subgroups in Unilateral Meniere Disease: A Cross-Sectional Study with Cluster Analysis. Clin. Otolaryngol. Off. J. ENT-UK Off. J. Neth. Soc. Oto-Rhino-Laryngol. Cervico-Facial Surg. 2017, 42, 1172–1180. [Google Scholar] [CrossRef] [PubMed]
  78. Martín-Sierra, C.; Gallego-Martinez, A.; Requena, T.; Frejo, L.; Batuecas-Caletrío, A.; Lopez-Escamez, J.A. Variable Expressivity and Genetic Heterogeneity Involving DPT and SEMA3D Genes in Autosomal Dominant Familial Meniere’s Disease. Eur. J. Hum. Genet. EJHG 2017, 25, 200–207. [Google Scholar] [CrossRef] [PubMed]
  79. Roman-Naranjo, P.; Gallego-Martinez, A.; Soto-Varela, A.; Aran, I.; Moleon, M.D.C.; Espinosa-Sanchez, J.M.; Amor-Dorado, J.C.; Batuecas-Caletrio, A.; Perez-Vazquez, P.; Lopez-Escamez, J.A. Burden of Rare Variants in the OTOG Gene in Familial Meniere’s Disease. Ear Hear. 2020, 41, 1598–1605. [Google Scholar] [CrossRef]
  80. Roman-Naranjo, P.; Moleon, M.D.C.; Aran, I.; Escalera-Balsera, A.; Soto-Varela, A.; Bächinger, D.; Gomez-Fiñana, M.; Eckhard, A.H.; Lopez-Escamez, J.A. Rare Coding Variants Involving MYO7A and Other Genes Encoding Stereocilia Link Proteins in Familial Meniere Disease. Hear. Res. 2021, 409, 108329. [Google Scholar] [CrossRef]
  81. Roman-Naranjo, P.; Parra-Perez, A.M.; Escalera-Balsera, A.; Soto-Varela, A.; Gallego-Martinez, A.; Aran, I.; Perez-Fernandez, N.; Bächinger, D.; Eckhard, A.H.; Gonzalez-Aguado, R.; et al. Defective α-Tectorin May Involve Tectorial Membrane in Familial Meniere Disease. Clin. Transl. Med. 2022, 12, e829. [Google Scholar] [CrossRef]
  82. T, R.; S, C.; C, M.-S.; Sd, P.; A, L.; Ja, L.-E. Identification of Two Novel Mutations in FAM136A and DTNA Genes in Autosomal-Dominant Familial Meniere’s Disease. Hum. Mol. Genet. 2015, 24. [Google Scholar] [CrossRef]
  83. Hoffman, H.J.; Dobie, R.A.; Losonczy, K.G.; Themann, C.L.; Flamme, G.A. Declining Prevalence of Hearing Loss in US Adults Aged 20 to 69 Years. JAMA Otolaryngol. Neck Surg. 2017, 143, 274. [Google Scholar] [CrossRef]
  84. Zheng, G.; Liu, Y.; He, J.; Li, S.; Zhang, Q.; Duan, M.; Yang, J.; Jin, Y. A Comparison of Local Endolymphatic Sac Decompression, Endolymphatic Mastoid Shunt, and Wide Endolymphatic Sac Decompression in the Treatment of Intractable Meniere’s Disease: A Short-Term Follow-Up Investigation. Front. Neurol. 2022, 13, 810352. [Google Scholar] [CrossRef]
  85. De Luca, P.; Cassandro, C.; Ralli, M.; Gioacchini, F.M.; Turchetta, R.; Orlando, M.P.; Iaccarino, I.; Cavaliere, M.; Cassandro, E.; Scarpa, A. Dietary Restriction for The Treatment of Meniere’s Disease. Transl. Med. UniSa 2020, 22, 5–9. [Google Scholar]
  86. Castiglione, A.; Benatti, A.; Velardita, C.; Favaro, D.; Padoan, E.; Severi, D.; Pagliaro, M.; Bovo, R.; Vallesi, A.; Gabelli, C.; et al. Aging, Cognitive Decline and Hearing Loss: Effects of Auditory Rehabilitation and Training with Hearing Aids and Cochlear Implants on Cognitive Function and Depression among Older Adults. Audiol. Neurotol. 2016, 21, 21–28. [Google Scholar] [CrossRef]
  87. Gao, X.; Grayden, D.; McDonnell, M. Unifying Information Theory and Machine Learning in a Model of Electrode Discrimination in Cochlear Implants. PLOS ONE 2021, 16, e0257568. [Google Scholar] [CrossRef]
  88. de Cates, C.; Winters, R. Intratympanic Steroid Injection. In StatPearls; StatPearls Publishing: Treasure Island (FL), 2022. [Google Scholar]
  89. Shin, S.-H.; Byun, S.W.; Park, S.; Kim, E.H.; Kim, M.W.; Lee, H.Y. Optimal First-Line Therapy for Acute Low-Tone Sensorineural Hearing Loss. J. Audiol. Otol. 2021, 25, 209–216. [Google Scholar] [CrossRef]
  90. Goudey, B.; Plant, K.; Kiral, I.; Jimeno-Yepes, A.; Swan, A.; Gambhir, M.; Büchner, A.; Kludt, E.; Eikelboom, R.H.; Sucher, C.; et al. A MultiCenter Analysis of Factors Associated with Hearing Outcome for 2,735 Adults with Cochlear Implants. Trends Hear. 2021, 25, 233121652110375. [Google Scholar] [CrossRef]
  91. Roccio, M.; Senn, P.; Heller, S. Novel Insights into Inner Ear Development and Regeneration for Targeted Hearing Loss Therapies. Hear. Res. 2020, 397, 107859. [Google Scholar] [CrossRef]
  92. He, Z.; Ding, Y.; Mu, Y.; Xu, X.; Kong, W.; Chai, R.; Chen, X. Stem Cell-Based Therapies in Hearing Loss. Front. Cell Dev. Biol. 2021, 9, 730042. [Google Scholar] [CrossRef]
  93. Nacher-Soler, G.; Garrido, J.M.; Rodríguez-Serrano, F. Hearing Regeneration and Regenerative Medicine: Present and Future Approaches. Arch. Med. Sci. AMS 2019, 15, 957–967. [Google Scholar] [CrossRef]
  94. Johnson Chacko, L.; Wertjanz, D.; Sergi, C.; Dudas, J.; Fischer, N.; Eberharter, T.; Hoermann, R.; Glueckert, R.; Fritsch, H.; Rask-Andersen, H.; et al. Growth and Cellular Patterning during Fetal Human Inner Ear Development Studied by a Correlative Imaging Approach. BMC Dev. Biol. 2019, 19, 11. [Google Scholar] [CrossRef]
  95. Filova, I.; Bohuslavova, R.; Tavakoli, M.; Yamoah, E.N.; Fritzsch, B.; Pavlinkova, G. Early Deletion of Neurod1 Alters Neuronal Lineage Potential and Diminishes Neurogenesis in the Inner Ear. Front. Cell Dev. Biol. 2022, 10, 845461. [Google Scholar] [CrossRef]
  96. Song, Z.; Jadali, A.; Fritzsch, B.; Kwan, K.Y. NEUROG1 Regulates CDK2 to Promote Proliferation in Otic Progenitors. Stem Cell Rep. 2017, 9, 1516–1529. [Google Scholar] [CrossRef]
  97. Filova, I.; Dvorakova, M.; Bohuslavova, R.; Pavlinek, A.; Elliott, K.L.; Vochyanova, S.; Fritzsch, B.; Pavlinkova, G. Combined Atoh1 and Neurod1 Deletion Reveals Autonomous Growth of Auditory Nerve Fibers. Mol. Neurobiol. 2020, 57, 5307–5323. [Google Scholar] [CrossRef]
  98. Sherrill, H.E.; Jean, P.; Driver, E.C.; Sanders, T.R.; Fitzgerald, T.S.; Moser, T.; Kelley, M.W. Pou4f1 Defines a Subgroup of Type I Spiral Ganglion Neurons and Is Necessary for Normal Inner Hair Cell Presynaptic Ca2+ Signaling. J. Neurosci. Off. J. Soc. Neurosci. 2019, 39, 5284–5298. [Google Scholar] [CrossRef]
  99. Lahlou, H.; Nivet, E.; Lopez-Juarez, A.; Fontbonne, A.; Assou, S.; Zine, A. Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells. Front. Mol. Neurosci. 2018, 11, 452. [Google Scholar] [CrossRef]
  100. Kurihara, S.; Fujioka, M.; Hirabayashi, M.; Yoshida, T.; Hosoya, M.; Nagase, M.; Kato, F.; Ogawa, K.; Okano, H.; Kojima, H.; et al. Otic Organoids Containing Spiral Ganglion Neuron-like Cells Derived from Human-Induced Pluripotent Stem Cells as a Model of Drug-Induced Neuropathy. Stem Cells Transl. Med. 2022, 11, 282–296. [Google Scholar] [CrossRef]
  101. Boddy, S.L.; Romero-Guevara, R.; Ji, A.-R.; Unger, C.; Corns, L.; Marcotti, W.; Rivolta, M.N. Generation of Otic Lineages from Integration-Free Human-Induced Pluripotent Stem Cells Reprogrammed by MRNAs. Stem Cells Int. 2020, 2020, 3692937. [Google Scholar] [CrossRef]
  102. Chen, J.-R.; Tang, Z.-H.; Zheng, J.; Shi, H.-S.; Ding, J.; Qian, X.-D.; Zhang, C.; Chen, J.-L.; Wang, C.-C.; Li, L.; et al. Effects of Genetic Correction on the Differentiation of Hair Cell-like Cells from IPSCs with MYO15A Mutation. Cell Death Differ. 2016, 23, 1347–1357. [Google Scholar] [CrossRef]
  103. Chen, W.; Jongkamonwiwat, N.; Abbas, L.; Eshtan, S.J.; Johnson, S.L.; Kuhn, S.; Milo, M.; Thurlow, J.K.; Andrews, P.W.; Marcotti, W.; et al. Restoration of Auditory Evoked Responses by Human ES-Cell-Derived Otic Progenitors. Nature 2012, 490, 278–282. [Google Scholar] [CrossRef]
  104. Ronaghi, M.; Nasr, M.; Ealy, M.; Durruthy-Durruthy, R.; Waldhaus, J.; Diaz, G.H.; Joubert, L.-M.; Oshima, K.; Heller, S. Inner Ear Hair Cell-like Cells from Human Embryonic Stem Cells. Stem Cells Dev. 2014, 23, 1275–1284. [Google Scholar] [CrossRef]
  105. Kenna, M.A.; Feldman, H.A.; Neault, M.W.; Frangulov, A.; Wu, B.-L.; Fligor, B.; Rehm, H.L. Audiologic Phenotype and Progression in GJB2 (Connexin 26) Hearing Loss. Arch. Otolaryngol. Head Neck Surg. 2010, 136, 81–87. [Google Scholar] [CrossRef]
  106. Fukunaga, I.; Oe, Y.; Danzaki, K.; Ohta, S.; Chen, C.; Shirai, K.; Kawano, A.; Ikeda, K.; Kamiya, K. Modeling Gap Junction Beta 2 Gene-Related Deafness with Human IPSC. Hum. Mol. Genet. 2021, 30, 1429–1442. [Google Scholar] [CrossRef]
  107. Frejo, L.; Cara, Francisca E; Gallego-Martinez; Lopez-Escamez An Inner Ear Organoid Model of Meniere Disease.; Trieste, Italy, September 2022.
  108. Frejo, L.; Cara, Francisca E; Gallego-Martinez; Lopez-Escamez DTNA and FAM136A Expression in a 3D Inner Ear Organoid Model of Meniere Disease.; Granada, Spain, May 2022.
  109. Nie, J.; Hashino, E. Generation of Inner Ear Organoids from Human Pluripotent Stem Cells. Methods Cell Biol. 2020, 159, 303–321. [Google Scholar] [CrossRef]
  110. Kawasaki, H.; Mizuseki, K.; Nishikawa, S.; Kaneko, S.; Kuwana, Y.; Nakanishi, S.; Nishikawa, S.I.; Sasai, Y. Induction of Midbrain Dopaminergic Neurons from ES Cells by Stromal Cell-Derived Inducing Activity. Neuron 2000, 28, 31–40. [Google Scholar] [CrossRef]
  111. Ying, Q.-L.; Stavridis, M.; Griffiths, D.; Li, M.; Smith, A. Conversion of Embryonic Stem Cells into Neuroectodermal Precursors in Adherent Monoculture. Nat. Biotechnol. 2003, 21, 183–186. [Google Scholar] [CrossRef]
  112. Chen, Y.; Xiong, M.; Dong, Y.; Haberman, A.; Cao, J.; Liu, H.; Zhou, W.; Zhang, S.-C. Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson’s Disease. Cell Stem Cell 2016, 18, 817–826. [Google Scholar] [CrossRef]
  113. Oestreicher, E.; Wolfgang, A.; Felix, D. Neurotransmission of the Cochlear Inner Hair Cell Synapse--Implications for Inner Ear Therapy. Adv. Otorhinolaryngol. 2002, 59, 131–139. [Google Scholar] [CrossRef]
  114. Gunewardene, N.; Bergen, N.V.; Crombie, D.; Needham, K.; Dottori, M.; Nayagam, B.A. Directing Human Induced Pluripotent Stem Cells into a Neurosensory Lineage for Auditory Neuron Replacement. BioResearch Open Access 2014, 3, 162–175. [Google Scholar] [CrossRef]
  115. Matsuoka, A.J.; Morrissey, Z.D.; Zhang, C.; Homma, K.; Belmadani, A.; Miller, C.A.; Chadly, D.M.; Kobayashi, S.; Edelbrock, A.N.; Tanaka-Matakatsu, M.; et al. Directed Differentiation of Human Embryonic Stem Cells Toward Placode-Derived Spiral Ganglion-Like Sensory Neurons. Stem Cells Transl. Med. 2017, 6, 923–936. [Google Scholar] [CrossRef] [PubMed]
  116. Needham, K.; Hyakumura, T.; Gunewardene, N.; Dottori, M.; Nayagam, B.A. Electrophysiological Properties of Neurosensory Progenitors Derived from Human Embryonic Stem Cells. Stem Cell Res. 2014, 12, 241–249. [Google Scholar] [CrossRef] [PubMed]
  117. Chen, J.; Hong, F.; Zhang, C.; Li, L.; Wang, C.; Shi, H.; Fu, Y.; Wang, J. Differentiation and Transplantation of Human Induced Pluripotent Stem Cell-Derived Otic Epithelial Progenitors in Mouse Cochlea. Stem Cell Res. Ther. 2018, 9, 230. [Google Scholar] [CrossRef] [PubMed]
  118. Tang, P.-C.; Alex, A.L.; Nie, J.; Lee, J.; Roth, A.A.; Booth, K.T.; Koehler, K.R.; Hashino, E.; Nelson, R.F. Defective Tmprss3-Associated Hair Cell Degeneration in Inner Ear Organoids. Stem Cell Rep. 2019, 13, 147–162. [Google Scholar] [CrossRef] [PubMed]
  119. MD, J.B. Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss; clinicaltrials.gov, 2018.
  120. Kanzaki, S.; Toyoda, M.; Umezawa, A.; Ogawa, K. Application of Mesenchymal Stem Cell Therapy and Inner Ear Regeneration for Hearing Loss: A Review. Int. J. Mol. Sci. 2020, 21, E5764. [Google Scholar] [CrossRef] [PubMed]
  121. Tang, Z.-H.; Chen, J.-R.; Zheng, J.; Shi, H.-S.; Ding, J.; Qian, X.-D.; Zhang, C.; Chen, J.-L.; Wang, C.-C.; Li, L.; et al. Genetic Correction of Induced Pluripotent Stem Cells From a Deaf Patient With MYO7A Mutation Results in Morphologic and Functional Recovery of the Derived Hair Cell-Like Cells. Stem Cells Transl. Med. 2016, 5, 561–571. [Google Scholar] [CrossRef] [PubMed]
  122. Chen, Y.-C.; Tsai, C.-L.; Wei, Y.-H.; Wu, Y.-T.; Hsu, W.-T.; Lin, H.-C.; Hsu, Y.-C. ATOH1/RFX1/RFX3 Transcription Factors Facilitate the Differentiation and Characterisation of Inner Ear Hair Cell-like Cells from Patient-Specific Induced Pluripotent Stem Cells Harbouring A8344G Mutation of Mitochondrial DNA. Cell Death Dis. 2018, 9, 437. [Google Scholar] [CrossRef] [PubMed]
  123. Fukunaga, I.; Fujimoto, A.; Hatakeyama, K.; Aoki, T.; Nishikawa, A.; Noda, T.; Minowa, O.; Kurebayashi, N.; Ikeda, K.; Kamiya, K. In Vitro Models of GJB2-Related Hearing Loss Recapitulate Ca2+ Transients via a Gap Junction Characteristic of Developing Cochlea. Stem Cell Rep. 2016, 7, 1023–1036. [Google Scholar] [CrossRef] [PubMed]
  124. Hosoya, M.; Fujioka, M.; Sone, T.; Okamoto, S.; Akamatsu, W.; Ukai, H.; Ueda, H.R.; Ogawa, K.; Matsunaga, T.; Okano, H. Cochlear Cell Modeling Using Disease-Specific IPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss. Cell Rep. 2017, 18, 68–81. [Google Scholar] [CrossRef]
  125. Hosoya, M.; Saeki, T.; Saegusa, C.; Matsunaga, T.; Okano, H.; Fujioka, M.; Ogawa, K. Estimating the Concentration of Therapeutic Range Using Disease-Specific IPS Cells: Low-Dose Rapamycin Therapy for Pendred Syndrome. Regen. Ther. 2019, 10, 54–63. [Google Scholar] [CrossRef]
  126. Fujioka, M.; Akiyama, T.; Hosoya, M.; Kikuchi, K.; Fujiki, Y.; Saito, Y.; Yoshihama, K.; Ozawa, H.; Tsukada, K.; Nishio, S.-Y.; et al. A Phase I/IIa Double Blind Single Institute Trial of Low Dose Sirolimus for Pendred Syndrome/DFNB4. Medicine (Baltimore) 2020, 99, e19763. [Google Scholar] [CrossRef] [PubMed]
Preprints 68745 g001
Figure 1. Cell reprogramming of human PBMC. A. Generation of hiPSCs lines by SeV cell reprogramming technology. B. Images of cell reprogramming procedure. Scale bar = 100μm. (Created with BioRender.com).
Figure 1. Cell reprogramming of human PBMC. A. Generation of hiPSCs lines by SeV cell reprogramming technology. B. Images of cell reprogramming procedure. Scale bar = 100μm. (Created with BioRender.com).
Preprints 68745 g001
Preprints 68745 g002
Figure 2. 2D and 3D hPSCs-derived inner ear hair cells protocols. (Created with BioRender.com).
Figure 2. 2D and 3D hPSCs-derived inner ear hair cells protocols. (Created with BioRender.com).
Preprints 68745 g002
Preprints 68745 g003
Figure 3. Schematic representation of 2D differentiation protocol of hPSCs-derived hair cells. A. Protocol of the generation of inner ear hair cells from hPSCs. B. Images obtained by microscopy of hair cell formation. Scale bar at day 0 and 7 = 100μm and at day 10 and 14 = 20μm. OEP: Otic epithelial progenitor. (Created with BioRender.com).
Figure 3. Schematic representation of 2D differentiation protocol of hPSCs-derived hair cells. A. Protocol of the generation of inner ear hair cells from hPSCs. B. Images obtained by microscopy of hair cell formation. Scale bar at day 0 and 7 = 100μm and at day 10 and 14 = 20μm. OEP: Otic epithelial progenitor. (Created with BioRender.com).
Preprints 68745 g003
Preprints 68745 g004
Figure 4. Generation of inner ear organoids from hPSCs (modified from Nie and Hashino 2020 [109]). A. 3D differentiation protocol of hPSCs into inner ear organoids from Koehler et al. [17]. B. Images of inner ear organoids generation. NNE: Non-neural ectoderm. OEDP: Otic-epibranchial progenitor domain. OTIC: Otic Placodes. (Created with BioRender.com).
Figure 4. Generation of inner ear organoids from hPSCs (modified from Nie and Hashino 2020 [109]). A. 3D differentiation protocol of hPSCs into inner ear organoids from Koehler et al. [17]. B. Images of inner ear organoids generation. NNE: Non-neural ectoderm. OEDP: Otic-epibranchial progenitor domain. OTIC: Otic Placodes. (Created with BioRender.com).
Preprints 68745 g004
Preprints 68745 g005
Figure 5. Cellular models of hPSCs-derived 2D and 3D inner ear neurons protocols. NBM: Neurobasal Medium. CDM: Chemically Defined Medium. NIM: Neural Inducing Medium. NM: Neuralizing Medium. (Created with BioRender.com).
Figure 5. Cellular models of hPSCs-derived 2D and 3D inner ear neurons protocols. NBM: Neurobasal Medium. CDM: Chemically Defined Medium. NIM: Neural Inducing Medium. NM: Neuralizing Medium. (Created with BioRender.com).
Preprints 68745 g005
Preprints 68745 g006
Figure 6. Inner ear neurons generation from hiPSCs. A. Differentiation protocol of hPSC-derived inner ear neurons in 2D culture from Boddy et al[101]. B. Images of inner ear neurons culture derived from hiPSC. Scale bar = 100μm. ONP: Otic Neural Progenitor. OSCFM: Otic Stem Cell Full Media. NM: Neuralizing Media. (Created with BioRender.com).
Figure 6. Inner ear neurons generation from hiPSCs. A. Differentiation protocol of hPSC-derived inner ear neurons in 2D culture from Boddy et al[101]. B. Images of inner ear neurons culture derived from hiPSC. Scale bar = 100μm. ONP: Otic Neural Progenitor. OSCFM: Otic Stem Cell Full Media. NM: Neuralizing Media. (Created with BioRender.com).
Preprints 68745 g006
Table 1. Reprogramming methods used in human somatic cells.
Table 1. Reprogramming methods used in human somatic cells.
Type of Vector Integration Factors References
Viral Retrovirus Yes OSKM [19,22,23,24]
OSK [25,26]
OK [27]
Hsa-miR-302ª/b/c/d [28]
Lentivirus Yes OSKM [29]
OSNL [30,31]
OSKMNL [32]
OSN [33,33]
O [34]
Bacteriophage Yes OSKM [35]
Adenovirus No OSKM [36]
Sendai Virus No OSKM [37,38]
Non-viral piggyBac No OSKM [39,40]
Plasmid No OSNL [41]
Episomal Vector No OSKMNL [42,43]
OSKM*L [44]
Minicircle vector No OSNL [45]
Protein No OSKM [46]
mRNA No OSNL [47]
OSKM (L) [48]
microRNA No miR-200c, 302ª/b/c/d,369-3p/5p [49]
O (OCT3/4); S (SOX2); K (KLF4); M (C-MYC); M* (L-MYC); N (NANOG); L (LIN28).
Table 2. Genetic mutations causing inner ear disorders modeled using hPSCs.
Table 2. Genetic mutations causing inner ear disorders modeled using hPSCs.
Gene RefSeq Variant Type of inheritance Model References
MYO7A NM_000260.4 c.1184G>Ayufenc.4118C>T Compound heterozygous Hair Cells [121]
MYO15A NM_016239.4 c.4642G>Ayufenc.8374G>A Compound heterozygous Hair Cells [102]
MERRF/MT-TK NC_012920.1 c.8344A>G Mitochondrial Hair Cells [122]
SLC26A4 NM_000441.2 c.439A>Gyufenc.1229C>Tyufenc.2168A>G Autosomal recessive Supporting Cells [124,125]
GJB2 NM_004004.6 c.235DelC Autosomal recessive / Digenic Supporting Cells [106,123]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated