Faizaan Khan

Background:  One of the most common sensory impairments is hearing loss, which is often caused by permanent damage to hair cells¹. Sensorineural hearing loss leads to increased rates of hospitalization and deaths, as well as higher healthcare costs. In the United States alone, 50% of those in their 60s and 80% of those over 85 suffer severe hearing loss that impacts their daily communication². Mammalian inner ear hair cells lack the ability to regenerate like their non-mammalian counterparts, leading to irreversible hearing loss³. Current treatment modalities fail to address the underlying cause of sensorineural hearing loss which is the death and impairment of cochlear hair cells, and there is no approach to obtain large numbers of hair cells⁴.

Research Objectives:  This work aims to critically review literature that examined cellular processes crucial for the regeneration of cochlear hair cells. The results of these studies suggests that these factors in combination could be essential for developing therapies for sensorineural hearing loss.

Methods:  ​A critical review of literature on hair cell regeneration was conducted using the PubMed database. The search process combined terms including “Hair Cell Regeneration” and “LGR5+ Cells” to understand foundational knowledge and advances in this field. MeSH subheadings in PubMed were also used to refine the search.

Results:  Leucine-Rich Repeat Containing G Protein-Coupled Receptor 5 (LGR5) expressing cells have been identified as progenitors capable of regenerating cochlear hair cells and reversing sensorineural hearing loss⁴. The expression of Wnt responsive genes, including LGR5, increases in response to hair cell damage, leading to possible innate regeneration⁵. Furthermore, the role of Notch1 in LGR5-positive cells during inner ear development has been explored, revealing its stage-dependent, unidirectional role⁶. The super elongation complex (SEC) has also been implicated in the proliferation and differentiation of LGR5 progenitors⁷. The potential for manipulating gene expression, such as Gfi1, Pou4f3, and Atoh1 to regenerate new cells that undergo maturation was also discovered⁸.

Conclusion:  Literature reviewed provides insights into the mechanisms underlying cochlear hair cell regeneration. The findings have significant implications for clinical practice and research, offering hope for the development of novel treatments. They also broaden our understanding of the mechanisms involved in hair cell regeneration, opening avenues for future investigations. Based on these findings, future studies may further develop innovative approaches to combat sensorineural hearing loss.

1. Works Cited:
2. Xia M, Ma J, Sun S, Li W, Li H. The biological strategies for hearing re-establishment based on the stem/progenitor cells. Neuroscience Letters. 2019/10/15/ 2019;711:134406. doi:https://doi.org/10.1016/j.neulet.2019.134406
3. Cunningham LL, Tucci DL. Hearing Loss in Adults. New England Journal of Medicine. 2017;377(25):2465-2473. doi:10.1056/NEJMra1616601
4. Wagner EL, Shin J-B. Mechanisms of Hair Cell Damage and Repair. Trends in Neurosciences. 2019/06/01/ 2019;42(6):414-424. doi:https://doi.org/10.1016/j.tins.2019.03.006
5. McLean WJ, Yin X, Lu L, et al. Clonal Expansion of Lgr5-Positive Cells from Mammalian Cochlea and High-Purity Generation of Sensory Hair Cells. Cell Reports. 2017/02/21/ 2017;18(8):1917-1929. doi:https://doi.org/10.1016/j.celrep.2017.01.066
6. Smith-Cortinez N, Yadak R, Hendriksen FGJ, et al. LGR5-Positive Supporting Cells Survive Ototoxic Trauma in the Adult Mouse Cochlea. Original Research. Frontiers in Molecular Neuroscience. 2021;14
7. Jiang H, Zeng S, Ni W, Chen Y, Li W. Unidirectional and stage-dependent roles of Notch1 in Wnt-responsive Lgr5+ cells during mouse inner ear development. Frontiers of Medicine. 2019/12/01 2019;13(6):705-712. doi:10.1007/s11684-019-0703-y
8. Chen Y, Qiang R, Zhang Y, et al. The Expression and Roles of the Super Elongation Complex in Mouse Cochlear Lgr5+ Progenitor Cells. Original Research. Frontiers in Cellular Neuroscience. 2021;15
9. Chen Y, Gu Y, Li Y, et al. Generation of mature and functional hair cells by co- expression of Gfi1, Pou4f3, and Atoh1 in the postnatal mouse cochlea. Cell Reports. 2021/04/20/ 2021;35(3):109016. doi:https://doi.org/10.1016/j.celrep.2021.109016