Hair cell regeneration for deafness Deafness is a progressive and irreversible condition in humans. A European study investigated the possibility of inducing regeneration of the inner ear cells to treat deafness. Fundamental Research Health © Andrew Jarman Deafness due to disease, ageing, or birth defects is caused by loss of hair cells in the inner ear, the structure responsible for the detection of equilibrium and sound. Currently, there are no treatments to restore lost hair cells and the gold standard entails the use of hearing aids. To understand the mechanism underlying hair cell regeneration, a deeper understanding of the molecules that control hair cell generation is required. However, hair cell studies in animals have been hampered by the anatomical complexity of the inner ear and the limited cell numbers in this organ. Hair cells from stem cells Scientists of the EU-funded GRNHairCell project proposed to use embryonic stem cells (ESCs) as a platform for in vitro inner ear studies. ESCs constitute an alternative and powerful approach to generate unlimited numbers of hair cells in a simple culture dish without the use of animals. However, low efficiency and reproducibility of hair cell production are issues when using signalling factor cocktails. “Our approach relies on a different methodology that allows for the first time the production of large numbers of hair cells,″ explains project coordinator Dr Andrew Jarman. Dr Aida Costa, the Marie Curie fellow who performed the work, used three proteins – Atoh1, Pou4f3 and Gfi1, which control hair cell development in the embryo. Through genetic manipulation of ESCs to activate expression of these transcriptional regulators, she successfully promoted a direct and robust conversion of stem cells into a hair cell phenotype. “A simple in vitro culture system gave us the opportunity to investigate how these proteins work together in a network to induce the formation of hair cells,″ points out Dr Costa. Using the in vitro culture system, researchers were able to provide important insight into the mechanism of hair cell regeneration. To regenerate lost hair cells in patients with deafness, Atoh1 has been the subject of intense research. However, Atoh1 alone has shown limited regenerative capacity, indicating that other factors are implicated in the process. During the GRNHairCell study, Dr Costa identified Gfi1 as a switch to hair cell commitment and a contributor to Atoh1 transcriptional activity. Moreover, analysis of gene expression and protein-DNA binding activity unveiled important information on the function of these regulatory factors. Clinical significance of the GRNHairCell results Understanding the molecular mechanisms by which Gfi1 is able to change Atoh1 and Pou4f3 transcriptional activity is undoubtedly of great scientific importance. From a clinical perspective, “it is also important to test this particular combination of transcription factors in animals with damaged inner ears to see if we can reverse the damage,″ outlines Dr Costa. Dr Jarman is confident that “although there may be no immediate clinical application of the GRNHairCell study results, the gained knowledge brings us a step closer to comprehending the process of inner ear development and exploiting it in the therapy of deafness. “Identification of the key players in hair cell regeneration could lead to new therapeutic approaches for deafness. Genome-wide studies will also help discover novel proteins implicated in the process and indicate targets of therapeutic value.″ Keywords GRNHairCell, hair cell, deafness, inner ear, Atoh1, Gfi1, Pou4f3
