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manipulations. This has proven to be fruitful in the cochlea of neonatal rodents in experiments that activate Atoh1 and inhibit Notch simultaneously (Zhao et al., 2011) or activate Atoh1 and Wnt simultaneously (Kuo et al., 2015). These dual approaches acknowledge the complexity of growth regula- tion in mature tissues as well as the critical interactions that occur between pathways.
Transplantation of Cells to
Replace Hair Cells
In the prior section, we discussed strategies for promoting native cells in the damaged organ of Corti to divide or di- rectly transdifferentiate to replace lost hair cells. It is pos- sible, however, that a responsive population may not persist in the adult cochlea. On the other hand, we may fail to find appropriate treatments to stimulate resident cells to regener- ate hair cells. In either case, it will be necessary to adopt an alternative approach and to transplant cells to the inner ear that can replace hair cells. The obvious choice is to transplant stem cells, which have the potential to divide and differenti- ate into a range of mature cell types. Stem cells can be grown in a dish and guided toward a desired cell fate (in this case, hair cell) by certain chemical agents or culture conditions. Stem cells hold great promise for treating several types of pathology, including heart disease, blindness, and leukemia.
Some of the first studies to test the usefulness of differ- ent types of stem cells to replace damaged hair cells were performed with pluripotent stem cells or neural stem cells derived from mouse embryos. Li et al. (2003) conditioned mouse embryonic stem cells with various compounds in cul- ture to drive them to differentiate hair cell-like features. On transplantation into the embryonic chicken ear, conditioned cells incorporated into hair cell epithelia and acquired hair cell-like properties. Fujino et al. (2004) found that neural stem cells introduced into cultured inner ear organs from rats integrated into the sensory epithelia of vestibular organs but not the cochlea. Subsequently, Oshima et al. (2010) iden- tified treatments that drive induced pluripotent stem cells (derived from fibroblasts) to differentiate advanced features of hair cells in culture, including hair bundles and mecha- notransduction currents. More recently, stem cells from hu- man embryos were found to be capable of forming hair cell- like cells in culture (Ronaghi et al., 2014).
The true test of the therapeutic usefulness of a stem cell is whether it can become integrated into the organ of Corti, become innervated by the auditory nerve, differentiate ma-
ture features, and survive. Introduction of stem cells into the organ of Corti is a challenge because the organ is surround- ed by a fluid-filled cavity that is embedded within the tem- poral bone and is easily disrupted by surgical intervention. It would seem very difficult to place transplanted cells into the organ of Corti given the tiny nature and delicacy of the tissue and the fact that fluid barriers would need to be dis- rupted. Nonetheless, several approaches for cell delivery are under investigation. Scientists have introduced embryonic stem cells into the fluids of the organ of Corti (scala media) and into the perilymphatic spaces surrounding the scala me- dia (Coleman et al., 2006; Hildebrand et al., 2005). Although some stem cells seem to persist in these spaces and integrate into some tissues around them, there is little evidence that stem cells integrate into the organ of Corti. However, Parker et al. (2007) reported that neural stem cells injected into the noise-damaged cochlea became incorporated into the sen- sory epithelium. Clearly, more studies are needed to identify ways to coax stem cells to integrate into damaged hair cell epithelia, acquire mature features, and restore function.
Clinical Considerations
Although progress toward hair cell regeneration has been significant given the limited time elapsed since its discov- ery, several challenges remain to determine how effective hair cell replacement could be for improving hearing in hu- mans. For instance, we do not know how many hair cells of each type must be regenerated to adequately restore hearing in impaired individuals. Although we know that inner hair cells are critical, we can only guess how well they will restore hearing in the absence of outer hair cells. Many forms of hearing loss are caused by selective destruction of outer hair cells; regeneration of outer hair cells alone could be helpful in such patients. Furthermore, we lack the capability to ac- curately test which type of cells need repair in patients. This assessment requires development of more cell-specific and noninvasive diagnostic procedures. In addition, high-reso- lution imaging of the inner ear, enabling quantitative assess- ment of each cell type, would be very helpful and is currently under investigation. Although there are challenges to restor- ing hair cells after damage in mammals, many hurdles have already been conquered, with promising research on the ho- rizon to introduce a potential treatment for hearing loss.
Acknowledgments
The authors extend their gratitude to Glen MacDonald and Linda Howarth, who provided images for this article.
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