Study examines the possibility of promoting hair cell regeneration using cellular reprogramming

Approximately 430 million people worldwide suffer from disabling hearing loss. In the United States, approximately 37.5 million adults report hearing problems. Hearing loss can occur when part of the ear or nerves that transmit sound information to the brain do not work in the usual way.

For example, damaged hair cells in the inner ear can lead to hearing loss. “These cells allow the brain to detect sounds,” said Dr. Amrita Iyer, first author of a new paper published in eLife. Iyer was a graduate student in the lab of Dr. Andrew Groves, Professor and Vivian L. Smith Chair in Neuroscience and Molecular and Human Genetics at Baylor College of Medicine, while working on this project.

Hair cells are generated during normal development, but this ability is gradually lost after birth as mammals mature.

When hair cells are lost in mature animals, the cells cannot be regenerated naturally, which can lead to permanent hearing loss. In the present study, we took a closer look at the possibility of promoting hair cell regeneration in mature animals using cellular reprogramming. Our approach involved the overexpression of various combinations of transcription factors.”

Dr. Amrita Iyer, first author

Transcription factors promote the expression of some genes and prevent the expression of others. By altering the gene expression pattern, the researchers hoped to bring the cells to a state in which they would regenerate hair cells in mature animals in much the same way as happens during development.

“We compared the reprogramming efficiency of the hair cell transcription factor ATOH1 alone or in combination with two other hair cell transcription factors, GFI1 and POU4F3, in mouse nonsensory cells in the cochlea, the part of the l inner ear that supports hearing.” Iyer said. “We did this at two time points – eight days after birth and 15 days after birth, assessing the extent of hair cell regeneration in mice.”

To study the structure of hair cell bundles generated by reprogramming, Iyer collaborated with Dr. Yeohash Raphael’s lab at the University of Michigan to perform scanning electron microscopy imaging on the cochlea of ​​mice conditionally overexpressing these transcription factors. . The images clearly showed that the hair cell bundles were consistent with what is seen on inner hair cells during development. Other studies have shown that these cells also have certain characteristics suggesting that they are capable of detecting sound.

“We found that although expression of ATOH1 with the hair cell transcription factors GFI1 and POU4F3 can increase the efficiency of hair cell reprogramming in older animals compared to ATOH1 alone or GFI1 plus ATOH1, hair cells generated by reprogramming at eight days of age—even with three hair cell transcription factors—are significantly less mature than those generated by reprogramming on the first postnatal day,” Iyer said. “We suggest that the reprogramming with multiple transcription factors is better able to access the hair cell differentiation gene regulatory network, but that additional interventions may be required to produce mature, fully functional hair cells.”

These findings are essential to advance the current understanding of the process of hair cell regeneration in the mammalian inner ear. From a therapeutic perspective, transcription factor-mediated reprogramming and the underlying biology associated with its function may help refine current gene therapy approaches for the long-term treatment of hearing loss.

Other contributors to this work include Ishwar Hosamani, John D. Nguyen, Tiantian Cai, Sunita Singh, Melissa M. McGovern, Lisa Beyer, Hongyuan Zhang, Hsin-I Jen, Rizwan Yousaf, Onur Birol, Jenny J. Sun, Russell S. Ray, Yehoash Raphael and Neil Segil. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Southern California, and University of Michigan.

The project was supported by the following grants: RO1 DC014832, R21 OD025327, DC015829, and an award from the Hearing Restoration Project Consortium of the Hearing Health Foundation. The project was also funded by a CPRIT Core Facility Support Award (CPRIT-RP180672), NIH grants (P30 CA125123, S10 RR024574, S10OD018033, S10OD023469, S10OD025240, and P30EY002520), the R. Jamison and Betty Williams Chair, the University of Michigan College of Engineering and NSF grant #DMR-1625671.