A scientific study from the Stowers Institute of Medical Research is issued in the Journal Developmental Cell. It focuses on the regeneration of hair cells in fish and reveals an important component of this secret weapon in fish. According to the study, the “support cells” cause the regeneration of the sensory hair cells in fish.
The inner ear sensory hair cells succumb to age or injuries. The older an individual gets, the less likely is he to hear well. Interestingly, humans are one-upped by fish here. Fishes have hair cells in their sensory system that dots their bodies and forms the lateral line. They discern the movement of water with these cells. These cells are readily regenerated, by support cells, if damaged or death occurs. These support cells surround centrally-located hair cells in each garlic-shaped sensory organ or neuromast.
Intriguingly, mammals also have supports cells. However, they don’t respond to hair cell death in a similar manner. In order to develop an insight into how mammalian support cells might be coaxed into regenerating hair cells, the researchers analyzed how zebrafish support cells respond to hair cell loss.
Zebrafish are particularly acquiescent to studies of regeneration. This is because their transparent embryos and larvae render developmental processes visible and accessible experimentally.
What did the researchers do?
The larvae of zebrafish were treated with the antibiotic neomycin that kills the hair cells. Afterward, the researchers monitored support cell proliferation in regenerating neuromasts for three days using time-lapse movies.
As per the team, these single cell lineage analyses were immensely time-consuming but very informative as well. The research team kept the record of every individual support cell’s location and behavior across different time-lapse frames.
It was found that approximately half of the dividing support cells differentiated into hair cells, while the rest opted for self-renewal. Self-renewal is an equally important fate as it ensures the maintenance of a reserve force leading to regenerative action. The researchers also noticed that the lineage fate of support cells hinged on where they were located in the neuromast. The self-renewing cells were found clustered at opposite poles. However, the differentiating cells were distributed in a random, circular pattern close to the center.
These distinct locations of support cells strongly indicate differences in gene expression. Thus, the research team explored some of the genes and signaling pathways involved as well.
A study of gene expression
A study of gene expression patterns showed that members of the Notch and Wnt pathways were expressed in different parts of the neuromast. The Notch members were expressed in the center and the Wnt members at the poles. The researchers used an inhibitor to determine how the two pathways regulate each other. The inhibitor turned off Notch signaling in neuromasts. This halt was similar to neomycin-induced hair cell death. After the inhibition, the scientists observed a transient upregulation of Wnt ligands, in the neuromast center, along with support cell proliferation. The majority of the proliferating cells developed into hair cells.
Thus, it was determined that Notch directly suppresses differentiation of support cells into hair cells. Moreover, it indirectly inhibits proliferation by keeping Wnt in check. Previously, it was believed that Wnt had to be down-regulated to initiate regeneration. However, this study proves that the loss of Notch signaling is likely to trigger the regeneration.
The research was partially supported by the Hearing Health Foundation through it’s Hearing Restoration Project (HRP). It emphasizes collaborations across several institutions to extend new therapies for hearing loss. By continuing to enlighten the details of hair cell regeneration in zebrafish, the study provides other HRP scientists with candidate genes and molecular pathways to probe in other models. It strengthens their goal of providing insight that could someday make human inner ear hair cells readily replaceable.