Albert Edge, PhD
My lab works on regeneration and the complex molecular signaling in cell fate determination. We are interested in sensory biology and the rebuilding of damaged sensory circuits. The hair cells of the cochlea are epithelial cells, specialized for the detection of sound and for the transduction of sound to an electrical signal. The sensitive cells of the inner ear are not replaced after damage in mammals, unlike the sensory cells of lower vertebrates that regenerate spontaneously when lost to injury.
We have shown that a subset of supporting cells in the cochlea, identified by their expression of Lgr5, a gene first identified as a marker for stem cells in the epithelium of the intestine, act as stem cells. These cells are not active under normal conditions but can be recruited by activation of Wnt signaling for regeneration of hair cells. Wnt signaling converts Lgr5 cells to hair cells by stimulating transcription factor Atoh1 a key factor in the determination of hair cell fate. Hair cells can be generated from supporting cells by drug treatments to inhibit Notch resulting in a partial recovery of hearing in the adult cochlea after damage.
We have also been able to determine key steps in differentiation of auditory neurons from embryonic stem cells. Afferent auditory neural fate is controlled by bHLH transcription factor, Ngn1, activated by Sox2 signaling, and we have found that sensory neurons with characteristics of spiral ganglion cells can be induced by drug and growth factor treatment of human ES cells. When grafted into the inner ear of animal models deafened by the ablation of neurons, these neural progenitors can rebuild neural circuits and form synapses with the sensory cells in the adult, where neural loss is irreversible. We have demonstrated partial recovery of hearing in animals deafened by loss of afferent neurons after transplantation of neurons made from embryonic stem cells.
We are exploring the role of epigenetic silencing of transcription factors in the differentiation of hair cells and neurons. Epigenetic changes prevent the activation of these factors in response to Wnt signaling. Epigenetics, combined with gene editing, enable access to specific genes necessary for converting stem cells in the adult ear to hair cells. To accomplish this we study cell fate determination both during development and regeneration. Inhibitors of histone deacetylase increase acetylation of histones and lead directly to the opening of DNA. We use CRISPR and siRNA screening to investigate the expression of genes during differentiation of stem cells to hair cells and neurons to probe for essential genes for differentiation of these cells.
The acquisition of neural and hair cell fate is significant because loss of both neurons and hair cells in the cochlea as a result of exposure to noise, drugs, infection, or aging result in deafness. Regeneration of sensory cells and rebuilding of neural circuits is a potential treatment for hearing loss.
Fujioka M, Tokano H, Fujioka KS, Okano H, Edge ASB. Generating mouse models of degenerative diseases using Cre/lox mediated in vivo mosaic cell ablation. J Clin Invest 121:2462-2469, 2011.
Shi F, Kempfle J, Edge ASB. Wnt responsive Lgr5-expressing stem cells are hair cell progenitors in the cochlea. J Neurosci 32:9639-9648, 2012.
Mizutari K, Fujioka M, Hosoya M, Bramhall N, Okano HJ, Okano H, Edge ASB. Notch inhibition induces cochlear hair cell regeneration and recovery of hearing after acoustic trauma. Neuron 77:58-69, 2013.
Shi F, Hu L, Edge ASB. Hair cell generation by b-catenin overexpression in Lgr5-positive cochlear progenitors. Proc Natl Acad Sci 110:13851-13856, 2013.
Bramhall N, Shi F, Arnold K, Hochedlinger K, Edge ASB. Lgr5-positive supporting cells generate new hair cells in the postnatal cochlea. Stem Cell Reports 2:311-322, 2014.
Cheng YF, Tong M, Edge ASB. Destabilization of Atoh1 by E3 ubiquitin ligase Huwe1 and casein kinase 1 is essential for normal hair cell development. J Biol Chem 291:21096-21109, 2016.
McLean WJ, McLean DT, Eatock RA, Edge ASB. Distinct capacity for differentiation to inner ear cell types by progenitor cells of the cochlea and vestibular organs. Development 143:4381-93, 2016.
Hu L, Lu J, Chiang H, Wu H, Edge ASB, Shi F Diphtheris toxin-induced cell death triggers Wnt-dependent hair cell regeneration in neonatal mice. J Neurosci 36:9479-86, 2016.
Rees HA, Komor AC, Yeh WH, Caetano-Lopes J, Warman M, Edge ASB, Liu DR. Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. Nat Commun 8:15790, 2017.
McLean WJ, Yin X, Lu L, Lenz DR, McLean DT, Langer R, Karp JM, Edge ASB. Clonal expansion of Lgr5-positive cells from mammalian cochlea and high-purity generation of sensory hair cells. Cell Reports 18:1979-1929, 2017.