Head of Group
office : +33 4 13 55 08 94
Y. Cazals (DR, INSERM)
C. Chabbert (CR, CNRS)
J-M Brezun (MCU, AMU)
S. Heller (Stanford, USA)
M. Rivolta (Sheffield, UK)
T. Vandewater (Miami, USA)
Our capacity to hear and hence to communicate depends entirely on our auditory receptors - the sensory hair cells - and their associated primary neurons that reside in the cochlear part of the inner ear. The exclusive sensitivity of the inner ear comes with the risk of damage, for example by noise trauma, ototoxic drug exposure, infections, genetic causes or age-related degeneration. Once lost, the neurosensory cells within the inner ear are not replaced. This in turn results in chronic hearing impairment, a devastating and highly prevalent disorder of infancy and adulthood with widespread implications for the individual and society as a whole. The onset of hearing loss in adult alone ranks among the five leading causes of burden of disease in Europe, entailing enormous socio-economic costs. To date, treatment options are limited and there is no cure for damaged or lost sensory hair cells within the cochlea. The prosthetic treatment with hearing aids and cochlear implants is limited and reaches only one fifth of patients and often fails to improve language comprehension and hence remains an unsatisfactory option.
The major objectives of our study focus on :
- First, on controlling proliferation and differentiation of either murine embryonic stem cells (mESC) and human induced pluripotent stem cells (hiPSCs) towards sensory hair cells and inner ear primary neurons in comprehensive and comparative in vitro approaches.
- Second, to assess the biological activity and potency of mESC and hiPSCs derived otic progenitors in in vitro and in vivo models of sensory hair cell degeneration.
- Finally, the translation of the findings will be applied towards the therapeutic objective aimed at a causal cure of sensorineural hearing loss.
Models & techniques
- Embryonic and adut stem cell cultures
- Primary and explant cultures
- Immunohistochemistry and in situ hybridization
- Confocal & electron microscopy (SEM-TEM)
- qPCR, RNAi and DNA microarray
- Transgenic mouse models
Dinh, C, Goncalves, S, Bas, E, Van De Water,T, Zine, A. (2015). Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma. Front Cell Neurosci, 9:96.
Zine, A (2014). 3D revolution of stem cells: generation of ear sensory epithelia in vitro. Med Sci, 30: 952-954.
Smeti I, Assou S, Savary E, Masmoudi S, Zine A. (2012) Transcriptomic analysis of the developing and adult mouse cochlear sensory epithelia. PLoS One. 7(8): e42987
Smeti, I., Savary, E., Capelle V, Hugnot J.P., Uziel A, Zine, A (2011). Expression of candidate markers for stem/progenitor cells in the inner ears of developing and adult GFAP and nestin promoter-GFP transgenic mice. Gene Expression Patterns. 11:22-32
Jonkamonwiwat, N., Zine, A., Rivolta, M.n (2010). Stem cell based therapy in the inner ear: appropriate donor cell types and routes for transplantation. Curr Drug Targets. 11:888-897.
Abi-Hachem R.N., Zine, A., Van De Water, T.R. (2010). The Injured cochlea as a target for inflammatory processes, initiation of cell death pathways and application of related otoprotectives strategies. Recent Pat CNS Drug Discov. 5:147-163.
Katayama, K., Zine, A., Ota, M., Matsumoto, Y., Inoue, T., Fritzsch, B., & Aruga, J. (2009). Disorganized innervation and neuronal loss in the inner ear of Slitrk6-deficient mice. PLoS One. 4(11): e7786.
Sabourin, J., Ackema, K., Ohayon, D., Guichet, P., Perrin, F., Garces, A., Ripoll, C., Charité, J., Simonneau, L., Kettenmann, H., Zine A, Privat, A., Valmier, J., Pattyn, A & Hugnot, J. (2009). A Mesenchymal-Like Zeb1(+) Niche Harbors Dorsal Radial GFAP(+) Stem Cells in the Spinal Cord. Stem Cells 11:2722-33.
Savary, E., Sabourin, J.C., Santo, J. Hugnot, J.P., Chabbert, C., Van De Water, T.Uziel, A. & Zine, A. (2008). Cochlear stem/progenitor cells from a postnatal cochlea respond to Jagged1 and demonstrate that Notch signaling promotes sphere formation and sensory potential. Mechanisms of Development 125:674-686.
Savary, E, Hugnot, J.P., Chassigneux, Y., Travo, C., Duperray, C., Van De Water T.R & Zine, A (2007). Distinct population of cochlear stem/progenitor cells can be isolated from the postnatal mouse cochlea using side population analysis. Stem Cells 25:332-339.
Zine, A., Uziel, A., Beckmann, J. & Bonny, C (2007). Blocking apoptotic intracellular signaling cascades with cell-permeable peptides. Current Signal Transduction Therapy 2:175-179.
Bonny, C, Borsello, T & Zine, A (2005). Targeting the JNK Pathway for therapeutic protective strategies in the nervous system diseases. Rev Neurosci, 16: 57-67.
Zine, A & Van De Water T.R (2004). The MAPk/JNk signalling pathway offers potential therapeutic targets for The Prevention of acquired deafness. Curr Drug Targets CNS Neurol Disord, 4: 325-332.
Zine, A (2004). Stem cells to repair neurosensory deafness? Med Sci, 5: 518-520.
Wang, J, Van De Water T.R., Bonny, C., De Ribaupierre, F. Puel Jl & A. Zine (2003). A Peptide Inhibitor of C-Jun N-Terminal Kinase (D-JnkI-1) Protects Against Both Aminoglycoside and Acoustic Trauma Induced Auditory Hair Cell Death And Hearing Loss. J Neurosci, 17: 8596-8607.
Zine, A. (2003). Molecular mechanisms that regulate auditory hair cell differentiation in the mammalian cochlea. Molecular Neurobiology, 27: 223-2