Bio


Dr. Nesrine Benkafadar obtained her Pharm.D from the University of Constantine in Algeria. She then joined the Institute for Neurosciences of Montpellier in France, where she completed a master’s degree in Industrial Pharmacy and obtained her Ph.D in Biology and Health. She mainly worked on establishing a functional interaction between oxidative stress, DNA damage and cochlear cell aging. From there, she conducted postdoctoral research in Dr. Stefan Heller’s lab at Stanford University. Her current research is focused on studying the early regenerative triggers in damaged avian cochlea with the overarching goal to characterize the series of events that trigger and execute cochlear hair cell regeneration. Her ultimate goal is to investigate key trigger genes to induce adult mammalian supporting cells in damaged cochlea to reenter the cell cycle toward hair cell regeneration.

Academic Appointments


  • Instructor, Otolaryngology - Head & Neck Surgery Divisions

Honors & Awards


  • MidWinter Meeting Don Henderson Travel Award, Association for Research in Otolaryngology (02/2023)
  • Best Poster Award, Otolaryngology Head and Neck Surgery, Research Day at Stanford Medical School (10/2022)
  • Katharine McCormick Advanced Postdoctoral Scholar Fellowship to Support Women in Academic Medicine, Stanford School of Medicine (04/2022)
  • Discovery Grant, The American Hearing Research Foundation (01/2022)
  • Postdoctoral Fellowship program, Stanford Dean’s Postdoctoral Fellowship (01/2019)
  • Best Poster Award, Otolaryngology Head and Neck Surgery, Research Day at Stanford Medical School (10/2018)
  • Very honorable PhD distinction with unanimous congratulations from the jury, The French National Institute of Health and Medical Research (02/2018)
  • Positive comment of “Benkafadar N et al., EMBO Molecular Medicine” in "News & Views”, EMBO Molecular Medicine, 9: 4-6, by Nonnekens J and Hoeijmakers JH (01/2017)
  • Publication of “Cancers & audition: The end of the double penalty”, Languedoc-Roussillon INSERM Newspaper (12/2016)
  • Best Poster Award, Ageing 2016 Meeting (06/2016)
  • Graduate fellowship program, Foundation of the Future for Medical Research (10/2014)

Boards, Advisory Committees, Professional Organizations


  • Guest Editor, JoVE Methods Collection (2021 - Present)
  • Member, Association for Women in Science - AWIS (2020 - Present)
  • Member, Association for Research in Otolaryngology (2014 - Present)
  • Member, Society for Neuroscience (2013 - Present)

Professional Education


  • PhD, Institute for Neurosciences of Montpellier, FRANCE, Neurobiology and Health Science (2018)
  • Msc, Faculty of Pharmacy. University of Montpellier. FRANCE, Research and development of Pre-clinical products (2014)
  • PharmD, Faculty of Pharmacy. University of Constantine. ALGERIA, Pharmacy (2012)

Patents


  • Nesrine Benkafadar, Florence Francois, Bernard Malfroy-Camine, Jean-Luc Puel and, Jing Wang. "United States Patent WO2020094789A1 METHODS AND COMPOSITIONS FOR PREVENTING AND/OR TREATING AGE-RELATED HEARING LOSS", Institut National de la Santé et de la Recherche Médicale (INSERM) - Universite De Montpellier, May 14, 2020
  • Nesrine Benkafadar, Julien Menardo, Jean-Luc Puel and, Jing Wang. "United States Patent WO2017125429A1 The use of a temporary inhibitor of p53 for preventing or reducing cancer relapse", Institut National de la Santé et de la Recherche Médicale (INSERM) - Universite De Montpellier, Jul 27, 2017

All Publications


  • Topical Delivery of Elastic Liposomal Vesicles for Treatment of Middle and Inner Ear Diseases. ACS applied bio materials Kashfi Sadabad, R., Xia, A., Benkafadar, N., Faniku, C., Preciado, D., Yang, S., Valdez, T. A. 2022

    Abstract

    We present a topical drug delivery mechanism through the ear canal to the middle and inner ear using liposomal nanoparticles without disrupting the integrity of the tympanic membrane. The current delivery method provides a noninvasive and safer alternative to transtympanic membrane injections, ear tubes followed by ear drops administration, and systemic drug formulations. We investigate the capability of liposomal NPs, particularly transfersomes (TLipo), used as drug delivery vesicles to penetrate the tympanic membrane (TM) and round window membrane (RWM) with high affinity, specificity, and retention time. The TLipo is applied to the ear canal and found to pass through the tympanic membrane quickly in 3 h post drug administration. They are identified in the middle ear cavity 6 h and in the inner ear 24 h after drug administration. We performed cytotoxicity in vitro and ototoxicity in vivo studies. Cell viability shows no significant difference between the applied TLipo concentration and control. Furthermore, auditory brainstem response (ABR) reveals no hearing loss in 1 week and 1 month post-administration. Immunohistochemistry results demonstrate no evidence of hair cell loss in the cochlea at 1 month following TLipo administration. Together, the data suggested that TLipo can be used as a vehicle for topical drug delivery to the middle ear and inner ear.

    View details for DOI 10.1021/acsabm.2c00569

    View details for PubMedID 36179346

  • Cell-type identity of the avian utricle. Cell reports Scheibinger, M., Janesick, A., Benkafadar, N., Ellwanger, D. C., Jan, T. A., Heller, S. 2022; 40 (13): 111432

    Abstract

    The avian utricle, a vestibular organ of the inner ear, displays turnover of sensory hair cells throughout life. This is in sharp contrast to the mammalian utricle, which shows limited regenerative capacity. Here, we use single-cell RNA sequencing to identify distinct marker genes for the different sensory hair cell subtypes of the chicken utricle, which we validated in situ. We provide markers for spatially distinct supporting cell populations and identify two transitional cell populations of dedifferentiating supporting cells and developing hair cells. Trajectory reconstruction resulted in an inventory of gene expression dynamics of natural hair cell generation in the avian utricle.

    View details for DOI 10.1016/j.celrep.2022.111432

    View details for PubMedID 36170825

  • Avian auditory hair cell regeneration is accompanied by JAK/STAT-dependent expression of immune-related genes in supporting cells. Development (Cambridge, England) Janesick, A., Scheibinger, M., Benkafadar, N., Kirti, S., Heller, S. 2022

    Abstract

    The avian hearing organ is the basilar papilla that, in sharp contrast to the mammalian cochlea, can regenerate sensory hair cells and thereby recover from deafness within weeks. The mechanisms that trigger, sustain, and terminate the regenerative response in vivo are largely unknown. Here, we profile the changes in gene expression in the chicken basilar papilla after aminoglycoside antibiotic-induced hair cell loss using RNA-sequencing. We identified changes in gene expression of a group of immune-related genes and confirmed with single-cell RNA-sequencing that these changes occur in supporting cells. In situ hybridization was used to further validate these findings. We determined that the JAK/STAT signaling pathway is essential for upregulation of the damage-response genes in supporting cells during the second day after induction of hair cell loss. Four days after ototoxic damage, we identified newly regenerated, nascent auditory hair cells that express genes linked to termination of the JAK/STAT signaling response. The robust, transient expression of immune-related genes in supporting cells suggests a potential functional involvement of JAK/STAT signaling in sensory hair cell regeneration.

    View details for DOI 10.1242/dev.200113

    View details for PubMedID 35420675

  • Cell-type identity of the avian cochlea. Cell reports Janesick, A. n., Scheibinger, M. n., Benkafadar, N. n., Kirti, S. n., Ellwanger, D. C., Heller, S. n. 2021; 34 (12): 108900

    Abstract

    In contrast to mammals, birds recover naturally from acquired hearing loss, which makes them an ideal model for inner ear regeneration research. Here, we present a validated single-cell RNA sequencing resource of the avian cochlea. We describe specific markers for three distinct types of sensory hair cells, including a previously unknown subgroup, which we call superior tall hair cells. We identify markers for the supporting cells associated with tall hair cells, which represent the facultative stem cells of the avian inner ear. Likewise, we present markers for supporting cells that are located below the short cochlear hair cells. We further infer spatial expression gradients of hair cell genes along the tonotopic axis of the cochlea. This resource advances neurobiology, comparative biology, and regenerative medicine by providing a basis for comparative studies with non-regenerating mammalian cochleae and for longitudinal studies of the regenerating avian cochlea.

    View details for DOI 10.1016/j.celrep.2021.108900

    View details for PubMedID 33761346

  • Transcriptomic characterization of dying hair cells in the avian cochlea. Cell reports Benkafadar, N. n., Janesick, A. n., Scheibinger, M. n., Ling, A. H., Jan, T. A., Heller, S. n. 2021; 34 (12): 108902

    Abstract

    Sensory hair cells are prone to apoptosis caused by various drugs including aminoglycoside antibiotics. In mammals, this vulnerability results in permanent hearing loss because lost hair cells are not regenerated. Conversely, hair cells regenerate in birds, making the avian inner ear an exquisite model for studying ototoxicity and regeneration. Here, we use single-cell RNA sequencing and trajectory analysis on control and dying hair cells after aminoglycoside treatment. Interestingly, the two major subtypes of avian cochlear hair cells, tall and short hair cells, respond differently. Dying short hair cells show a noticeable transient upregulation of many more genes than tall hair cells. The most prominent gene group identified is associated with potassium ion conductances, suggesting distinct physiological differences. Moreover, the dynamic characterization of >15,000 genes expressed in tall and short avian hair cells during their apoptotic demise comprises a resource for further investigations toward mammalian hair cell protection and hair cell regeneration.

    View details for DOI 10.1016/j.celrep.2021.108902

    View details for PubMedID 33761357

  • ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation. Molecular neurobiology Benkafadar, N., François, F., Affortit, C., Casas, F., Ceccato, J. C., Menardo, J., Venail, F., Malfroy-Camine, B., Puel, J. L., Wang, J. 2019

    Abstract

    In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated β-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

    View details for DOI 10.1007/s12035-019-1493-6

    View details for PubMedID 30693443

  • New Strategies for Improving the Quality of Life of Cancer Survivors: Reversible p53 Inhibition Journal of Cancer Science & Therapy Benkafadar, N., Coyat, C., Lloyd, R., Puel , J., Wang, J. 2017; 9(6): 490-491
  • Reversible p53 inhibition prevents cisplatin ototoxicity without blocking chemotherapeutic efficacy. EMBO molecular medicine Benkafadar, N., Menardo, J., Bourien, J., Nouvian, R., François, F., Decaudin, D., Maiorano, D., Puel, J., Wang, J. 2017; 9 (1): 7-26

    Abstract

    Cisplatin is a widely used chemotherapy drug, despite its significant ototoxic side effects. To date, the mechanism of cisplatin-induced ototoxicity remains unclear, and hearing preservation during cisplatin-based chemotherapy in patients is lacking. We found activation of the ATM-Chk2-p53 pathway to be a major determinant of cisplatin ototoxicity. However, prevention of cisplatin-induced ototoxicity is hampered by opposite effects of ATM activation upon sensory hair cells: promoting both outer hair cell death and inner hair cell survival. Encouragingly, however, genetic or pharmacological ablation of p53 substantially attenuated cochlear cell apoptosis, thus preserving hearing. Importantly, systemic administration of a p53 inhibitor in mice bearing patient-derived triple-negative breast cancer protected auditory function, without compromising the anti-tumor efficacy of cisplatin. Altogether, these findings highlight a novel and effective strategy for hearing protection in cisplatin-based chemotherapy.

    View details for DOI 10.15252/emmm.201606230

    View details for PubMedID 27794029

    View details for PubMedCentralID PMC5210089

  • Impairment of Visual Function and Retinal ER Stress Activation in Wfs1-Deficient Mice PLOS ONE Bonnet Wersinger, D., Benkafadar, N., Jagodzinska, J., Hamel, C., Tanizawa, Y., Lenaers, G., Delettre, C. 2014; 9 (5)