zebrafish

Single-Cell RNA Sequencing Reveals More Clues for Hair Cell Regeneration

By Mark E. Lush, Ph.D., and Daniel C. Diaz

Sensorineural hearing loss in mammals can often be attributed to damage or destruction of the delicate hair cells located within the inner ear. The microscopic hairlike projections on the surface of these cells are the key structure responsible for converting sound waves to electrical signals that travel to the brain through the auditory nerve. Unlike mammals, other vertebrates such as fish, birds, and reptiles routinely regenerate sensory hair cells during homeostasis and following injury. By studying the genetic program of hair cell regeneration in nonmammalian vertebrate organisms, researchers may discover therapeutic targets for treating hearing loss in humans.

The lateral line is a sensory system that allows aquatic vertebrates to orient themselves by detecting water motion. The lateral line organs (neuromasts), distributed on the head and along the body, contain approximately 60 cells, composed of central sensory hair cells surrounded by support cells and an outer ring of mantle cells. Using single-cell RNA sequencing, we combined some of the less well-defined clusters and identified major neuromast cell types, shown in this illustration, ranging from support cells to mature sensory hair cells. Credit: The lab of Tatiana Piotrowski, Ph.D., Stowers Institute for Medical Research, Kansas City

The lateral line is a sensory system that allows aquatic vertebrates to orient themselves by detecting water motion. The lateral line organs (neuromasts), distributed on the head and along the body, contain approximately 60 cells, composed of central sensory hair cells surrounded by support cells and an outer ring of mantle cells. Using single-cell RNA sequencing, we combined some of the less well-defined clusters and identified major neuromast cell types, shown in this illustration, ranging from support cells to mature sensory hair cells. Credit: The lab of Tatiana Piotrowski, Ph.D., Stowers Institute for Medical Research, Kansas City

One such organism, the zebrafish, has emerged as a powerful model for studying sensory hair cell regeneration. Like other fish, zebrafish contain a network of sensory hair cells throughout their body to detect changes in water movement. The hair cells are located in small organs in the skin called neuromasts, which also contains cell types that are remarkably similar to those found in the mammalian inner ear. To study the genetic program of hair cell regeneration in zebrafish, we sequenced the RNA of individual cells within neuromasts, allowing us to classify cell types based on their gene expression signature. This included cells transitioning from support cells to fully mature sensory hair cells, thereby identifying new genes that are expressed during hair cell development. In addition, we characterized the role of the growth factor fgf3, and found that it acts to inhibit hair cell progenitor proliferation. Our results were published in the journal eLife on Jan. 25, 2019. Future work will examine the function of these genes in sensory hair cell regeneration.

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Mark E. Lush, Ph.D., and Daniel C. Diaz both work in the lab of Tatjana Piotrowski, Ph.D., at Stowers Institute for Medical Research in Kansas City. Piotrowski is a member of the Hearing Restoration Project, which helped fund this study.

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Understanding a Pressure Relief Valve in the Inner Ear

By Ian Swinburne, Ph.D.

The inner ear senses sound to order to hear as well as sensing head movements in order to balance. Sounds or body movements create waves in the fluid within the ear. Specialized cells called hair cells, because of their thin hairlike projections, are submerged within this fluid. Hair cells bend in response to these waves, with channels that open in response to the bending. The makeup of the ear’s internal fluid is critical because as it flows through these channels its contents encode the information that becomes a biochemical and then a neural signal. The endolymphatic sac of the inner ear is thought to have important roles in stabilizing this fluid that is necessary for sensing sound and balance.

This study helps unravel how a valve in the inner ear's endolymphatic sac acts to relieve fluid pressure, one key to understanding disorders affected by pressure abnormalities such as Ménière’s disease.

This study helps unravel how a valve in the inner ear's endolymphatic sac acts to relieve fluid pressure, one key to understanding disorders affected by pressure abnormalities such as Ménière’s disease.

While imaging transparent zebrafish, my team and I found a pressure-sensitive relief valve in the endolymphatic sac that periodically opens to release excess fluid, thus preventing the tearing of tissue. In our paper published in the journal eLife June 19, 2018, we describe how the relief valve is composed of physical barriers that open in response to pressure. The barriers consist of cells adhering to one another and thin overlapping cell projections that are continuously remodeling and periodically separating in response to pressure.

The unexpected discovery of a physical relief valve in the ear emphasizes the need for further study into how organs control fluid pressure, volume, flow, and ion homeostasis (balance of ions) in development and disease. It suggests a new mechanism underlying several hearing and balance disorders characterized by pressure abnormalities, including Ménière’s disease.

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Here is a time-lapse video of the endolymphatic sac, with the sac labeled “pressure relief valve” at 0:40.

2017 Ménière’s Disease Grants scientist Ian A. Swinburne, Ph.D., is conducting research at Harvard Medical School. He was also a 2013 Emerging Research Grants recipient.

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