Researchers at John Hopkins University have identified a pair of proteins that control when hair cells form in mammalian ears, to great precision. The research team believes these proteins may help restore hearing in people with irreversible deafness.
"Scientists in our field have long been looking for molecular signals that trigger the formation of hair cells," notes Professor Angelika Doetzlhofer from the John Hopkins University School of Medicine, USA. "These hair cells play an important role when it comes to hearing loss. Knowing how they develop will help us understand how damaged hair cells can be replaced".
Approximately 90% of all cases of genetic hearing loss are due to hair cell problems. These can regenerate in other mammals, but not in humans. Doetzlhofer and her team went in search of signaling substances in the spiral-shaped cochlea.
Of the proteins investigated, two stood out in particular: Activin A and follistatin. Activin A values increased in areas where progenitor cells were transformed into hair cells. In follistatin, the opposite seemed to be the case. Here, only small amounts of the protein were present in the outermost part of the cochlea and only high amounts in the innermost part of the cochlea. Activin A moved in waves inwards, follistatin in outward waves.
Professor Doetzlhofer elaborates: "We knew that activin A and follistatin act in opposite ways in their natural setting to regulate cells. Based on our discoveries, we assume that the two proteins perform a tightrope act with precursor cells in order to control the orderly formation of hair cells along the spiral cochlea."
In order to find out how exactly the two proteins coordinate the development of hair cells, the researchers examined their respective properties in detail. First, they increased the release of activin A in mice, leading to the early transformation of progenitor cells and the premature appearance of hair cells in the cochlea. Hair cells formed late and scattered disorganized in different rows of the cochlea in mice that were trained to overproduce follistatin or not produce activin A at all.
"The interplay between activin A and follistatin is so precise in development that any disruption can have a negative effect on the organization of the cochlea," notes Doetzlhofer. "It's like a house: if the foundation is not laid correctly, everything that is built on it is affected”.
The researchers found that an overproduction of follistatin leads to unorganized hair cells because high amounts of the protein cause a more frequent division of precursor cells. A higher amount of progenitor cells is converted into internal hair cells in a random way.
The scientists in Doetzlhofer’s team note that their studies on the development of hair cells - although still in the stage of basic research - offer possibilities to treat deafness caused by damaged hair cells. Doetzlhofer says: "We want to apply the knowledge about the development of hair cells in order to improve treatment strategies against hearing loss or to open new possibilities".
Meenakshi Prajapati-DiNubila, Ana Benito-Gonzalez, Erin Jennifer Golden, Shuran Zhang, Angelika Doetzlhofer. A counter gradient of Activin A and follistatin instructs the timing of hair cell differentiation in the murine cochlea. eLife, 2019; 8 DOI: 10.7554/eLife.47613