Rps14 upregulation promotes inner ear progenitor proliferation and hair cell regeneration in the neonatal mouse cochlea

Sensorineural hearing loss a result from hair cell damage, which is irreversible in mammals owing to the lack of hair cell regeneration, but recent researches have shown that Lgr5+ supporting cells are progenitors capable of regenerating hair cells. RPS14 (ribosomal protein S14) is a 40S ribosomal subunit component and is associated with erythrocyte differentiation, and in this study, we used a novel adeno‐associated virus‐inner ear system to upregulate Rps14 expression in cultured hair cell progenitors and observed an enhancement on their ability to proliferate and differentiate into hair cells. Similarly, Rps14 overexpression in the mice cochlea could promote supporting cells proliferation by activating the Wnt signalling pathway. In addition, over‐expressing Rps14 induced hair cells regeneration in the organ of Corti, and lineage tracing showed that the new hair cells had transformed from Lgr5+ progenitors. In conclusion, our analysis reveals the potential role of Rps14 in driving hair cell regeneration in mammalian.

[1]  E. Grassi,et al.  Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness , 2021, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[2]  Q. Fang,et al.  Downregulation of RPS14 inhibits the proliferation and metastasis of estrogen receptor-positive breast cancer cells , 2021, Anti-cancer drugs.

[3]  S. Heller,et al.  Greater epithelial ridge cells are the principal organoid-forming progenitors of the mouse cochlea , 2021, Cell reports.

[4]  A. Griffioen,et al.  Secreted frizzled-related protein 2: a key player in noncanonical Wnt signaling and tumor angiogenesis , 2020, Cancer and Metastasis Reviews.

[5]  A. Doetzlhofer,et al.  LIN28B/let-7 control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling , 2020, Proceedings of the National Academy of Sciences.

[6]  R. Chai,et al.  Hair cell regeneration from inner ear progenitors in the mammalian cochlea. , 2020, American journal of stem cells.

[7]  D. Corey,et al.  Viral vectors for gene delivery to the inner ear , 2020, Hearing Research.

[8]  J. T. Corwin,et al.  EGF and a GSK3 Inhibitor Deplete Junctional E-cadherin and Stimulate Proliferation in the Mature Mammalian Ear , 2020, The Journal of Neuroscience.

[9]  J. Stone,et al.  Atoh1 is required in supporting cells for regeneration of vestibular hair cells in adult mice , 2019, Hearing Research.

[10]  Guisheng Zhong,et al.  AAV-ie enables safe and efficient gene transfer to inner ear cells , 2019, Nature Communications.

[11]  R. Chai,et al.  Frizzled-9+ Supporting Cells Are Progenitors for the Generation of Hair Cells in the Postnatal Mouse Cochlea , 2019, Front. Mol. Neurosci..

[12]  Jung-Bum Shin,et al.  Mechanisms of Hair Cell Damage and Repair , 2019, Trends in Neurosciences.

[13]  J. Bennett,et al.  AAV2.7m8 is a powerful viral vector for inner ear gene therapy , 2019, Nature Communications.

[14]  J. Haug,et al.  scRNA-Seq reveals distinct stem cell populations that drive hair cell regeneration after loss of Fgf and Notch signaling , 2019, eLife.

[15]  R. Chai,et al.  Transduction of Adeno-Associated Virus Vectors Targeting Hair Cells and Supporting Cells in the Neonatal Mouse Cochlea , 2019, Front. Cell. Neurosci..

[16]  D. Tucci,et al.  Global Hearing Loss Prevention. , 2018, Otolaryngologic clinics of North America.

[17]  Shan Sun,et al.  Characterization of Lgr6+ Cells as an Enriched Population of Hair Cell Progenitors Compared to Lgr5+ Cells for Hair Cell Generation in the Neonatal Mouse Cochlea , 2018, Front. Mol. Neurosci..

[18]  R. Nusse,et al.  Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities , 2017, Cell.

[19]  R. Chai,et al.  Characterization of the Transcriptomes of Lgr5+ Hair Cell Progenitors and Lgr5- Supporting Cells in the Mouse Cochlea , 2017, Front. Mol. Neurosci..

[20]  Shan Sun,et al.  Bmi1 Regulates the Proliferation of Cochlear Supporting Cells Via the Canonical Wnt Signaling Pathway , 2017, Molecular Neurobiology.

[21]  J. Karp,et al.  Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. , 2017, Cell reports.

[22]  Ping Chen,et al.  Induction of differentiation of human embryonic stem cells into functional hair-cell-like cells in the absence of stromal cells. , 2016, The international journal of biochemistry & cell biology.

[23]  R. Chai,et al.  Extensive Supporting Cell Proliferation and Mitotic Hair Cell Generation by In Vivo Genetic Reprogramming in the Neonatal Mouse Cochlea , 2016, The Journal of Neuroscience.

[24]  R. Chai,et al.  Wnt activation protects against neomycin-induced hair cell damage in the mouse cochlea , 2016, Cell Death and Disease.

[25]  Michelle C. Chen,et al.  Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9 , 2016, Nature Medicine.

[26]  Tatsunori Sakamoto,et al.  Limited hair cell induction from human induced pluripotent stem cells using a simple stepwise method , 2015, Neuroscience Letters.

[27]  E. Golden,et al.  The RNA-binding protein LIN28B regulates developmental timing in the mammalian cochlea , 2015, Proceedings of the National Academy of Sciences.

[28]  Shan Sun,et al.  Dynamic expression of Lgr6 in the developing and mature mouse cochlea , 2015, Front. Cell. Neurosci..

[29]  R. Chai,et al.  Lgr5+ Cells Regenerate Hair Cells via Proliferation and Direct Transdifferentiation in Damaged Neonatal Mouse Utricle , 2015, Nature Communications.

[30]  J. I. Matsui,et al.  The role of Wnt/β‐catenin signaling in proliferation and regeneration of the developing basilar papilla and lateral line , 2014, Developmental neurobiology.

[31]  K. Hochedlinger,et al.  Lgr5-Positive Supporting Cells Generate New Hair Cells in the Postnatal Cochlea , 2014, Stem cell reports.

[32]  R. Chai,et al.  Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo , 2014, Development.

[33]  Bernd Fritzsch,et al.  Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. , 2013, Developmental biology.

[34]  A. Edge,et al.  Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors , 2013, Proceedings of the National Academy of Sciences.

[35]  A. Groves,et al.  Conditional Deletion of Atoh1 Reveals Distinct Critical Periods for Survival and Function of Hair Cells in the Organ of Corti , 2013, The Journal of Neuroscience.

[36]  G. Corfas,et al.  Inner ear supporting cells: rethinking the silent majority. , 2013, Seminars in cell & developmental biology.

[37]  M. Kelley,et al.  The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea. , 2013, Developmental biology.

[38]  S. Heller,et al.  Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells , 2013, Development.

[39]  H. Okano,et al.  Notch Inhibition Induces Cochlear Hair Cell Regeneration and Recovery of Hearing after Acoustic Trauma , 2013, Neuron.

[40]  M. Kelley,et al.  A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea , 2012, Development.

[41]  Stuart L. Johnson,et al.  Restoration of auditory evoked responses by human ES cell-derived otic progenitors , 2012, Nature.

[42]  A. Edge,et al.  Wnt-Responsive Lgr5-Expressing Stem Cells Are Hair Cell Progenitors in the Cochlea , 2012, The Journal of Neuroscience.

[43]  J. Stone,et al.  Atoh1 expression and function during auditory hair cell regeneration in post-hatch chickens , 2012, Hearing Research.

[44]  Eric J. Liaw,et al.  Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea , 2012, Proceedings of the National Academy of Sciences.

[45]  R. Iozzo,et al.  The canonical Wnt pathway shapes niches supportive of hematopoietic stem/progenitor cells. , 2012, Blood.

[46]  R. Chai,et al.  Dynamic Expression of Lgr5, a Wnt Target Gene, in the Developing and Mature Mouse Cochlea , 2011, Journal of the Association for Research in Otolaryngology.

[47]  B. Ebert,et al.  Ribosomopathies: human disorders of ribosome dysfunction. , 2010, Blood.

[48]  M. Kelley,et al.  Specification of cell fate in the mammalian cochlea. , 2009, Birth defects research. Part C, Embryo today : reviews.

[49]  S. Heller,et al.  Stem/Progenitor Cells Derived from the Cochlear Sensory Epithelium Give Rise to Spheres with Distinct Morphologies and Features , 2009, Journal of the Association for Research in Otolaryngology.

[50]  Hans Clevers,et al.  Lgr5 marks cycling, yet long-lived, hair follicle stem cells , 2008, Nature Genetics.

[51]  A. Wise,et al.  Novel drug delivery systems for inner ear protection and regeneration after hearing loss , 2008, Expert opinion on drug delivery.

[52]  A. Edge,et al.  Hair cell regeneration , 2008, Current Opinion in Neurobiology.

[53]  H. Clevers,et al.  Identification of stem cells in small intestine and colon by marker gene Lgr5 , 2007, Nature.

[54]  D. Cotanche,et al.  Hair cell regeneration in the avian auditory epithelium. , 2007, The International journal of developmental biology.

[55]  C. Birchmeier,et al.  Notch Function in Myogenesis , 2007, Cell cycle.

[56]  N. Segil,et al.  Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells , 2006, Nature.

[57]  H. Clevers,et al.  Wnt, stem cells and cancer in the intestine , 2005, Biology of the cell.

[58]  V. Baladrón,et al.  dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. , 2005, Experimental cell research.

[59]  Mitsuru Sugawara,et al.  Survival of Adult Spiral Ganglion Neurons Requires erbB Receptor Signaling in the Inner Ear , 2004, The Journal of Neuroscience.

[60]  Huawei Li,et al.  Pluripotent stem cells from the adult mouse inner ear , 2003, Nature Medicine.

[61]  D. Taichman,et al.  Characterization of Notch receptor expression in the developing mammalian heart and liver. , 2002, American journal of medical genetics.

[62]  E. Hara,et al.  Id proteins in cell cycle control and cellular senescence , 2001, Oncogene.

[63]  R. Kageyama,et al.  Hes1 is a negative regulator of inner ear hair cell differentiation. , 2000, Development.

[64]  G. Weinmaster,et al.  Notch signalling pathway mediates hair cell development in mammalian cochlea , 1999, Nature Genetics.

[65]  M. Saarma,et al.  Expression patterns of neurotrophin and their receptor mRNAs in the rat inner ear , 1993, Hearing Research.