About My Research
Director of the Tillotson Cell Biology Unit at Mass. Eye and Ear, Dr. Albert Edge’s research is focused on the mechanisms of cellular repair in the nervous system. Specifically, his laboratory works toward replacing both hair cells and first order cochlear neurons of the inner ear lost to a variety of causes, including genetically determined degenerative disorders, noise trauma, and ototoxicity.
Members of his laboratory are investigating endogenous stem cells in the cochlea that can generate hair cells and spiral ganglion neurons in damaged ears. They are attempting to define the molecular pathways for the determination of cell fate from endogenous and embryonic stem cells.The discovery of new pathways that influence the differentiation of inner ear stem cells creates a platform for development of drugs or other procedures to activate endogenous stem cells to replace hair cell or neurons.
Dr. Edge and his laboratory staff have discovered cochlear progenitor cells that express Lgr5, a gene also found in the stem cells of the intestine. Wnt signaling stimulates proliferation of Lgr5-expressing cells and converts them into hair cells. They have also found that Notch signaling inhibits differentiation of hair cells and that inhibition of Notch after hair cell loss in the adult cochlea can induce hair cell regeneration and a partial recovery of hearing.
Dr. Edge also investigates the potential of neural progenitor cells to replace auditory neurons and has developed in vitro and in vivo systems for replacement of damaged cells in the inner ear. In vitro synaptogenesis assays in the laboratory allow screening of molecules that inhibit formation of synapses between the spiral ganglion neurons and hair cells. Inhibitory axon guidance molecules decrease fiber growth to hair cells, while glutamate and neurotrophins enhance new synapse formation. They have taken these findings into the living animal and have shown that neurons derived from stem cells innervate hair cells after direct implantation into ears with hearing loss due to nerve damage. Regeneration of auditory neurons and their connections to hair cells could be a treatment for hearing loss.
- A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss. Nat Commun. 2024 Mar 01; 15(1):1896.
- Auditory Hair Cells and Spiral Ganglion Neurons Regenerate Synapses with Refined Release Properties In Vitro. bioRxiv. 2023 Dec 02.
- Cochlear organoids reveal transcriptional programs of postnatal hair cell differentiation from supporting cells. Cell Rep. 2023 11 28; 42(11):113421.
- Human pluripotent stem cell-derived inner ear organoids recapitulate otic development in vitro. Development. 2023 10 01; 150(19).
- Large-scale annotated dataset for cochlear hair cell detection and classification. bioRxiv. 2023 Sep 01.
- Human pluripotent stem cells-derived inner ear organoids recapitulate otic development in vitro. bioRxiv. 2023 Apr 12.
- Transcriptome-Wide Analysis Reveals a Role for Extracellular Matrix and Integrin Receptor Genes in Otic Neurosensory Differentiation from Human iPSCs. Int J Mol Sci. 2021 Oct 07; 22(19).
- Norrie disease protein is essential for cochlear hair cell maturation. Proc Natl Acad Sci U S A. 2021 09 28; 118(39).
- Hair Cell Generation in Cochlear Culture Models Mediated by Novel ?-Secretase Inhibitors. Front Cell Dev Biol. 2021; 9:710159.
- A Novel Small Molecule Neurotrophin-3 Analogue Promotes Inner Ear Neurite Outgrowth and Synaptogenesis In vitro. Front Cell Neurosci. 2021; 15:666706.
- HIC1 Represses Atoh1 Transcription and Hair Cell Differentiation in the Cochlea. Stem Cell Reports. 2021 04 13; 16(4):797-809.
- Trk agonist drugs rescue noise-induced hidden hearing loss. JCI Insight. 2021 02 08; 6(3).
- An antibody to RGMa promotes regeneration of cochlear synapses after noise exposure. Sci Rep. 2021 02 03; 11(1):2937.
- Altered expression of genes regulating inflammation and synaptogenesis during regrowth of afferent neurons to cochlear hair cells. PLoS One. 2020; 15(10):e0238578.
- Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate. Front Mol Neurosci. 2020; 13:87.
- Lin28 reprograms inner ear glia to a neuronal fate. Stem Cells. 2020 07; 38(7):890-903.
- Increased Type I and Decreased Type II Hair Cells after Deletion of Sox2 in the Developing Mouse Utricle. Neuroscience. 2019 12 01; 422:146-160.
- Increasing the expression level of ChR2 enhances the optogenetic excitability of cochlear neurons. J Neurophysiol. 2019 11 01; 122(5):1962-1974.
- Inner ear organoids: new tools to understand neurosensory cell development, degeneration and regeneration. Development. 2019 09 02; 146(17).
- Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea. Mol Ther. 2019 06 05; 27(6):1101-1113.
- Applications of Lgr5-Positive Cochlear Progenitors (LCPs) to the Study of Hair Cell Differentiation. Front Cell Dev Biol. 2019; 7:14.
- Transcriptional response to Wnt activation regulates the regenerative capacity of the mammalian cochlea. Development. 2018 11 27; 145(23).
- ERBB2 signaling drives supporting cell proliferation in vitro and apparent supernumerary hair cell formation in vivo in the neonatal mouse cochlea. Eur J Neurosci. 2018 11; 48(10):3299-3316.
- In vivo base editing of post-mitotic sensory cells. Nat Commun. 2018 06 05; 9(1):2184.
- Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss. Bioconjug Chem. 2018 04 18; 29(4):1240-1250.
- FANTOM5 CAGE profiles of human and mouse samples. Sci Data. 2017 08 29; 4:170112.
- Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. Nat Commun. 2017 06 06; 8:15790.
- Quantitative imaging analysis of transcanal endoscopic Infracochlear approach to the internal auditory canal. Am J Otolaryngol. 2017 Sep - Oct; 38(5):518-520.
- Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Rep. 2017 02 21; 18(8):1917-1929.
- Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs. Development. 2016 12 01; 143(23):4381-4393.
- Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice. J Neurosci. 2016 09 07; 36(36):9479-89.
- Destabilization of Atoh1 by E3 Ubiquitin Ligase Huwe1 and Casein Kinase 1 Is Essential for Normal Sensory Hair Cell Development. J Biol Chem. 2016 Sep 30; 291(40):21096-21109.
- Sox2 in the differentiation of cochlear progenitor cells. Sci Rep. 2016 Mar 18; 6:23293.
- Endoscopic Transcanal Retrocochlear Approach to the Internal Auditory Canal with Cochlear Preservation: Pilot Cadaveric Study. Otolaryngol Head Neck Surg. 2016 05; 154(5):920-923.
- Comprehensive Expression of Wnt Signaling Pathway Genes during Development and Maturation of the Mouse Cochlea. PLoS One. 2016; 11(2):e0148339.
- Central Gain Restores Auditory Processing following Near-Complete Cochlear Denervation. Neuron. 2016 Feb 17; 89(4):867-79.
- Manipulating cell fate in the cochlea: a feasible therapy for hearing loss. Trends Neurosci. 2015 Mar; 38(3):139-44.
- Optogenetic stimulation of the cochlear nucleus using channelrhodopsin-2 evokes activity in the central auditory pathways. Brain Res. 2015 Mar 02; 1599:44-56.
- Spiral ganglion stem cells can be propagated and differentiated into neurons and glia. Biores Open Access. 2014 Jun 01; 3(3):88-97.
- ß-Catenin is required for hair-cell differentiation in the cochlea. J Neurosci. 2014 May 07; 34(19):6470-9.
- An atlas of active enhancers across human cell types and tissues. Nature. 2014 Mar 27; 507(7493):455-461.
- A promoter-level mammalian expression atlas. Nature. 2014 Mar 27; 507(7493):462-70.
- Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Reports. 2014 Mar 11; 2(3):311-22.
- Inhibition of repulsive guidance molecule, RGMa, increases afferent synapse formation with auditory hair cells. Dev Neurobiol. 2014 Apr; 74(4):457-66.
- An independent construct for conditional expression of atonal homolog-1. Hum Gene Ther Methods. 2014 Feb; 25(1):1-13.
- Ouabain-induced cochlear nerve degeneration: synaptic loss and plasticity in a mouse model of auditory neuropathy. J Assoc Res Otolaryngol. 2014 Feb; 15(1):31-43.
- Generation of hair cells in neonatal mice by ß-catenin overexpression in Lgr5-positive cochlear progenitors. Proc Natl Acad Sci U S A. 2013 Aug 20; 110(34):13851-6.
- Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss. Neurobiol Dis. 2013 Aug; 56:25-33.
- Regenerated synapses between postnatal hair cells and auditory neurons. J Assoc Res Otolaryngol. 2013 Jun; 14(3):321-9.
- Prospects for replacement of auditory neurons by stem cells. Hear Res. 2013 Mar; 297:106-12.
- Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron. 2013 Jan 09; 77(1):58-69.
- An in vitro model of developmental synaptogenesis using cocultures of human neural progenitors and cochlear explants. Stem Cells Dev. 2013 Mar 15; 22(6):901-12.
- Wnt-responsive Lgr5-expressing stem cells are hair cell progenitors in the cochlea. J Neurosci. 2012 Jul 11; 32(28):9639-48.
- Notch signaling alters sensory or neuronal cell fate specification of inner ear stem cells. J Neurosci. 2011 Jun 08; 31(23):8351-8.
- Generating mouse models of degenerative diseases using Cre/lox-mediated in vivo mosaic cell ablation. J Clin Invest. 2011 Jun; 121(6):2462-9.
- TAK1 expression in the cochlea: a specific marker for adult supporting cells. J Assoc Res Otolaryngol. 2011 Aug; 12(4):471-83.
- Primary culture and plasmid electroporation of the murine organ of Corti. J Vis Exp. 2010 Feb 04; (36).
- Beta-catenin up-regulates Atoh1 expression in neural progenitor cells by interaction with an Atoh1 3' enhancer. J Biol Chem. 2010 Jan 01; 285(1):392-400.
- Differentiation of neurons from neural precursors generated in floating spheres from embryonic stem cells. BMC Neurosci. 2009 Sep 24; 10:122.
- Hair cell regeneration. Curr Opin Neurobiol. 2008 Aug; 18(4):377-82.
- Differentiation of inner ear stem cells to functional sensory neurons. Dev Neurobiol. 2008 Apr; 68(5):669-84.
- BMP4 induction of sensory neurons from human embryonic stem cells and reinnervation of sensory epithelium. Eur J Neurosci. 2007 Dec; 26(11):3016-23.
- The potential role of endogenous stem cells in regeneration of the inner ear. Hear Res. 2007 May; 227(1-2):48-52.
- Stem cells for the replacement of inner ear neurons and hair cells. Int J Dev Biol. 2007; 51(6-7):655-61.
- Differential distribution of stem cells in the auditory and vestibular organs of the inner ear. J Assoc Res Otolaryngol. 2007 Mar; 8(1):18-31.
- Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells. Mol Cell Neurosci. 2007 Jan; 34(1):59-68.
- Engraftment and differentiation of embryonic stem cell-derived neural progenitor cells in the cochlear nerve trunk: growth of processes into the organ of Corti. J Neurobiol. 2006 Nov; 66(13):1489-500.
- Identification and characterization of a human monoclonal antagonistic antibody AL-57 that preferentially binds the high-affinity form of lymphocyte function-associated antigen-1. J Leukoc Biol. 2006 Oct; 80(4):905-14.
- Reinnervation of hair cells by auditory neurons after selective removal of spiral ganglion neurons. J Neurobiol. 2006 Mar; 66(4):319-31.
- Stem cells as therapy for hearing loss. Trends Mol Med. 2004 Jul; 10(7):309-15.
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