Our current research examines the molecular mechanisms that maintain the survival and function of hair cells and neurons of the cochlea.

We study how these homeostatic mechanisms operate under normal conditions and how they respond to environmental stressors, particularly to loud sounds. Based on this knowledge, we study if cellular stress could be manipulated for therapeutic purposes to protect against hearing loss.

Our experimental approach involves in vivo functional measurements of hearing, use of various transgenic mouse models, analysis of gene and protein expression, versatile microscopic imaging, organotypic cultures, and viral-mediated gene transfer and drug delivery to the cochlea.

Stress signaling

Recently, we showed how mesencephalic astrocyte-derived neurotrophic factor (MANF) is expressed in the inner ear. We demonstrate how depletion of MANF in the inner ear caused an elevation in hearing thresholds and hair cell pathology dependent on underlying genetic factors. With this evidence we have illuminated how cellular ER-stress, in which MANF plays a role, regulates survival and maintenance of the synapses and the stereocilia of hair cells, required for normal hearing.

In our recent paper (Ikäheimo et al. 2021, Life science alliance) we showed that ER homeostasis maintenance is critical for the normal function of stereocilia bundles and ribbon synapses of cochlear hair cells.

In Herranen et al. 2020 (Cell Death and Disease), we showed that Manf inactivation (ER stress) is critical for the survival of cochlear hair cells.

We have shown the mode of action of JNK/c-Jun stress signaling in the lesioned cochlea. We have provided genetic and pharmacological evidence that inhibition of JNK/c-Jun signaling acutely following noise exposure attenuates hair cell loss (Anttonen, Herranen et al., eNeuro 2016). We have studied the role of JNK/c-Jun, ERK and NF-kB stress pathways in the lateral wall of the cochlea. We have implicated the lateral wall stress response in inflammation, in the sensitivity of hair cells to loud sounds, and in aging (Herranen et al., JARO 2018).

Above: Suggested mechanism how c-Jun activation regulates hair cell death.

Above: Differences in noise vulnerability between mouse strains is demonstrated here by hair cell loss.

Above: Transcriptional activity of NF-kB in the mouse cochlea.



We have recently described the modes of hair cell death and the events of actin cytoskeleton-based wound healing in the lesioned organ of Corti of the cochlea, using serial block-face scanning electron microscopy (SBEM). This method is very suitable for 3D subcellular modelling of the organ of Corti (Anttonen et al., JARO 2014, eNeuro 2017).

Above: RhoA inactivation impairs hair cell development.



We have recently studied regeneration capacity of the inner ear supporting cells. These cells serve as a potential platform for new hair cell formation. We have shown that DNA damage coupled with limited DNA repair capacity forms a critical barrier for the attempts to stimulate supporting cell proliferation in the adult cochlea. These studies were done using viral-mediated gene transfer in organotypic cultures and the analysis of transgenic mouse models in vitro and in vivo (Mdm2, p53) (Laos et al., Aging 2014, Sci Rep 2017).

Above: Stimulation of proliferation is challenging in the post-natal cochlea, as shown in the organotypic culture model.



We have recently shown that the GTPases Cdc42 and RhoA are required for planar cell polarity and normal cytoskeletal development of hair cells and supporting cells of the cochlea. These studies were done using transgenic mouse models in vivo (Anttonen et al., Sci Rep 2012, eNeuro 2017; Kirjavainen et al., Biol Open 2015).

Above: Cdc42 inactivation impairs planar cell polarity in the developing cochlea.