Conclusions and outlook
Substantial progress has been made in recent years to accumulate tools that potentially can be used, alone or in combination, to develop strategies for hair cell regeneration. Grafting of stem or progenitor cells, viral gene delivery, and manipulations that affect Atoh1 and cell cycle genes have all reached the proof-of-principle stage. At the same time, the accumulated knowledge of organ of Corti function—the integral interplay of OHC-based cochlear amplification, micromechanical movements and the importance of accessory structures such as the tectorial membrane—revealed a plethora of new challenges for cochlear hair cell regeneration. A systematic elaboration of these roadblocks is needed before it will be possible to judge whether mammalian cochlear hair cell regeneration will become a viable treatment option for future generations of people suffering from profound hearing loss.
Nevertheless, these challenges also bring opportunities for new discoveries. For basic science studies, we expect that the next decade will reveal many more aspects of the developmental principles underlying cochlear cell type specification. Exploration of new technologies—for example, the direct conversion of supporting cells in the damaged cochlea into a progenitor cell state—will require more knowledge about transcription factors that define the otic lineage. Likewise, we need to study in much more detail the molecular and cytohistological changes that happen in supporting cells in the organ of Corti after damage. These cells are the key targets of all the manipulations that we have discussed in this perspective. On the translational side, we expect that some of the proof-of-principle studies that we discussed will be refined—for example, by combination of specific strategies such as Atoh1 expression and temporary interference with cell cycle genes. Finally, the ball is in the court of bioengineers and clinician/scientists to develop appropriate devices and methods that will allow us to deliver progenitor cells, gene therapy vectors and drug candidates to the appropriate locations inside the cochlea, so that it will be possible to develop better animal models for regenerative studies. Overall, the task of regenerating cochlear sensory hair cells has not become less challenging, but recent advances now allow us to define the issues that still persist much better than ever before, which is providing a much-needed framework allowing the systematic study of potential treatment options.