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Hair Cell Regeneration—Overcoming the Challenges

 

by Neil Bauman, Ph.D.

Question: What are some of the challenges facing researchers in their quest for hair cell regeneration? Are they unlocking the secrets that make hair cells “tick”?

Answer: Twenty years ago, hair cell regeneration was unheard of. Fifteen years ago it was still in the realm of science fiction. Today, scientists are hard at work to make it a reality.

Research into hair cell regeneration has made tremendous strides in the past few years. However, researchers still face enormous challenges before hair cell regeneration becomes a reality in the lives of hard of hearing people.

Work on hair cell regeneration began in earnest in 1986 when researchers discovered that after being exposed to loud sounds, birds have the remarkable ability to regenerate and replace dead hair cells and return their hearing to near normal levels in just 28 days.1 However, this is not true for mammals, including human beings. The question is, “Why can’t humans also regenerate damaged hair cells?” That is the question scientists are scrambling to answer.

Unfortunately, hair cell regeneration is not as simple as it might seem. Human ears are very complex organs (perhaps the most complex of all the organs in the body apart from the brain). It should be no surprise then, that hair cell regeneration is also a complex process. The following is a greatly simplified version of some of the challenges researchers face in their quest for hair cell regeneration in humans.

The sensory part of the cochlea contains two types of cells—hair cells and supporting cells. The hair cells detect sound and are thus essential to hearing. Hair cells are embedded in the top of support cells, which help nourish and support them.

In order to restore hearing when hair cells die, any surviving support cells need to receive the correct signals to be “turned on” to do two things—progress through the cell cycle and divide into two new daughter cells (the process of mitosis), then some of these new daughter cells (or even some of the original support cells) need to change themselves into hair cells (called transdifferentiation).2

Currently, researchers have discovered one of the genes that triggers this differentiation process in support cells. Dr. Raphael found that by inserting the Math1 gene into support cells, they change into hair cells. If they do not have the Math1 gene, they remain support cells.3 Thus, it is apparent that the Math1 gene is one necessary transcription factor that causes this to take place.4 (A transcription factor is just a protein [gene] that switches other genes into life.5)

For example, mice deficient in Math1 fail to develop hair cells. In contrast, in one study, when researchers introduced Math1 into the cochleas of rats, they were able to produce several hundred new hair cells.6 Research is continuing on the molecular chain of events that causes support cells do this.

Getting support cells to produce new hair cells is one challenge. Getting them to stop when the right number of hair cells exists is another challenge. Too many hair cells cause hearing problems just like too few. Researchers have found that factors such as Hes1 and Hes5 are needed to turn hair cell production off or there will be a superabundance of hair cells. Researchers have also discovered that in mice that are deficient in the cell cycle inhibitor p27(Kip1), hair cells are initially overproduced. Later, a massive degeneration of hair cells occurs, leading to hearing loss.7 Thus, regulating hair cell production is critical to hearing success.

Another challenge is getting the hair cells to grow in the proper places. In one study using guinea pig ears, researchers grew new hair cells, but “found new hair cells growing in areas where hair cells are typically absent.”8 In other words, researchers need to find out how to get the hair cells to grow only in the right places—not anywhere they please.

Yet another challenge was finding a way to introduce the specific genes they needed into the support cells to turn on hair cell production. They hit on using a virus (adenovirus) to place the “turn on” gene in the cochlea. This appears to work. However, at this time there is nothing to stop this virus from infecting other cells and making them proliferate in the wrong places throughout the body. Dr. Raphael, who is working on this problem, says hopefully, “As long as the amount you inoculate is small, the spread to other organs is minimal, and the risk of systemic toxicity is almost zero.”9 Much more work still needs to be done to guarantee that this process truly will be safe for use in humans.

Still another challenge is getting the newly grown hair cells to “mature.” It appears that the regenerated hair cells researchers are producing are immature. They have evolved to a stage just before the transduction apparatus is functional.10 These hair cells must develop appropriate ion channels for transduction11 before they can accept sound signals for transmission to the brain. Perhaps there is a “maturing” gene(s) that they have yet to discover.

How hair cells generate nerve impulses in response to sound signals is an amazing process. Here’s how scientists think this takes place. Each bundle of between 20 to 300 stereocilia (tiny hair-like structures) protrude from the top surface of the hair cell (hence the name “hair cell”) and are arranged by height with the tallest in the center and the shortest to the sides.

Incoming sounds set up waves in the cochlea that bend the stereocilia at their point of attachment, but only in one of two directions; either towards the tallest or towards the shortest edge of the hair bundle.

A microscopic elastic filament, called a tip link, connects the top of each stereocilium to the side of its tallest neighbor. This tip link serves as a handle to open and close the cell’s transduction channel doors.

When stereocilia bend toward their tallest neighbors this tip link stretches, which tugs transduction channel gates open to admit cations. This leads to the release of neurotransmitters from the cell’s base, which send sound signals to the brain. When the stereocilia bundle bends towards the short stereocilia, the tip links between them slacken, closing the channel doors and no signal is sent.12

Until every last bit of this delicate tip link transduction-channel apparatus is in place and fully operational, the hair cell can’t generate an ionic signal in response to sound. Thus getting hair cells to fully mature is another critical step in the hair cell regeneration process.

Last, but not least, fully-mature hair cells are still totally useless unless they are hooked up to the auditory nerves. In studies that have induced new hair cells to grow in adult guinea pigs, researchers have found that, fortunately, nerve fibers grow to and hook up to some (but, not all, for some reason) of the new hair cells.13 Research is continuing into growth factors (called trophic factors) which are thought to attract nerve fibers to the hair cells.14

This gives a tiny glimpse into a few of the complexities of regenerating hair cells in mammals. When all these challenges (and many others) have been overcome, perhaps then, human hair cell regeneration will help lift the curse of hearing loss. Until then, researchers diligently continue to delve into the mysteries of the hair cells buried deep in our inner ears.

__________________

1 Dooling, Ryals. ~1997. Recovery of Hearing Following Hair Cell Regeneration. http://www.bsos.umd.edu/psyc/dooling/HCL.html. pp. 1-2.

2 Lopez-Schier, Hernan. 2004. Neurobiology: On Regeneration of Sensory Epithelia. In: ScienceWeek. http://scienceweek.com/2004/sa040326-3.htm. p. 2.

3 Pobojewski, Sally. 2003. Gene Therapy Grows New Auditory Hair Cells in Mammals. Phoenix Rising. http://www.phoenixrising.ca/detail.asp?ArtID=79. p. 1.

4 Bermingham-McDonogh, Olivia. 2003. Hair Cell Regeneration: Wing Our Way Towards a Sound Future. Current Opinion in Neurobiology. 13:119-126. http://www.current-opinion.com. p. 123.

5 Deaf Defying. January 31, 1998. In: The Economist. p. 4.

6 Hair Cell Regeneration. 2004.http://hearinglossweb.com/Medical/cures/hair/hair.htm. p. 2.

7 Bermingham-McDonogh, Olivia. 2003. Hair Cell Regeneration: Wing Our Way Towards a Sound Future. Current Opinion in Neurobiology. 13:119-126. http://www.current-opinion.com. p. 123.

8 Pobojewski, Sally. 2003. Gene Therapy Grows New Auditory Hair Cells in Mammals. Phoenix Rising. http://www.phoenixrising.ca/detail.asp?ArtID=79. p. 2.

9 Ibid. p. 2.

10 Mack, Alison. Deep in the Land of Listening. Hopkins Medical News. Fall, 1995. http://oscar.med.jhu.edu/mome/news/Gillespie.html. p. 3.

11 Bermingham-McDonogh, Olivia. 2003. Hair Cell Regeneration: Wing Our Way Towards a Sound Future. Current Opinion in Neurobiology. 13:119-126. http://www.current-opinion.com. p. 119.

12 Mack, Alison. Deep in the Land of Listening. Hopkins Medical News. Fall, 1995. http://oscar.med.jhu.edu/mome/news/Gillespie.html. p. 2.

13 Pobojewski, Sally. 2003. Gene Therapy Grows New Auditory Hair Cells in Mammals. Phoenix Rising. http://www.phoenixrising.ca/detail.asp?ArtID=79. p. 1.

14 Rubel, Edwin. 2000. Inner Ear Hair Cell Regeneration.http://depts.washington.edu/hearing/Hair%20Cells.html. p. 3.

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