HLAA Convention 2009 Research Symposium: Hair Cell Regeneration

By Bonnie O'Leary

August 2009

Editor: It's that time of year again! The start of Hearing Loss Convention Season! As is normally the case, HLAA kicks off the activity in June. Char and I didn't attend this year, but super reporters extraordinaire Cheryl Heppner and Bonnie O'Leary from NVRC will be providing detailed coverage of the activities.

More coverage of this great convention is at: http://www.hearinglossweb.com/res/hlorg/shhh/cn/2009/2009.htm

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Cochlear Regeneration: A Treatment for Severe Hearing Loss in Our Lifetime?
Presented by George A. Gates, M.D., Medical Director, Deafness Research Foundation

This all-morning event was introduced by George A. Gates, MD, medical director of the Deafness Research Foundation. Providing background for what was to come, Dr. Gates talked about regenerative medicine in general, and stated that cochlear regeneration might not happen for another 5 or 10 years, perhaps longer. Two determining factors: funding and luck.

What is Generation and Regeneration?

All mammals originate from a single cell, the fertilized ovum, which is the ultimate stem cell. Throughout our lives, some of our tissues are regularly replaced as they wear out, such a blood cells, bone, skin, and so on. The discovery by Drs. Cotanche and Rubel in 1987 that birds regenerate their inner ears after damage opened a new field of science.

Regeneration requires cells to enter the cell cycle, divide, and exit the cycle on cue. Possible factors that control this process are continually being evaluated. Too many cells could be as bad as too few, and there are unresolved issues about how to start and stop the cycle, which cells to stimulate, and how to control their interactions with existing cells.

Regenerative medicine is a new field. Growing tissues in culture, such as skin or cartilage, and implanting them is evolving. Inner ear regeneration involves more than 30 cell types with complex associations. So far, the best guess among experts is that inner ear regeneration will require injecting material into the ear.

Hearing regeneration will require accurate cell and functional diagnoses. Probable first candidates will have recent onset deafness from a specific cause such as ototoxicity. The timeline for clinical application is still unknown and may be decades away. The hearing regeneration initiative will require $50 million over ten years to bring inner ear regeneration to the point of developing and testing an agent or multiple agents. A consortium of key laboratories under the aegis of DRF is involved in the initiative.

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Hair Cell Regeneration: Where Are We and How Did We Get Here?
Presented by Douglas Cotanche, Ph.D., Boston University

Dr. Douglas Cotanche was next to speak. He started his presentation with some familiar statistics. Nearly 35 million Americans suffer from measurable hearing impairment and related speech disorders. Hearing loss affects more people than epilepsy, multiple sclerosis, spinal injury, stroke, Huntington's and Parkinson's diseases combined. Two million Americans are completely deaf, and one in 1,000 children are born severely to profoundly deaf, half of those due to hereditary causes.

Most hearing loss is caused by damage to the hair cells, the sensory cells in the cochlea, or by a loss of the auditory neurons in the cochlear spiral ganglion (auditory neuropathy). Current therapies for hearing loss include cochlear implants, hearing aids, and sign language.

The goal of the research is to develop a biological cochlear implant. How? Through producing functional hair cells and nerves by inducing regeneration in the cochlear or by transplanting stem cells into the damaged cochlea.

Background

In 1967, Bob Ruben showed that hair cells are produced only during a limited time during mouse cochlear development, embryonic days 13-15. After this, no new cells are generated. Thus, any loss of hair cells in a mature mammalian ear leads to permanent hearing loss.

In 1987, studies from Dr. Cotanche's lab showed that mature birds could regenerate their cochlear hair cells following noise damage and obtain a functional recovery. So if birds can do it, why can't we?

Inside the Bird's Ear

Inside the human cochlea is the Organ of Corti, which is where our sensory hair cells live. Ninety five percent are inner hair cells and 5% are outer cells. The outer cells monitor the inner cells. What is known as "cocktail party syndrome" (blocking out background noise) is achieved by the outer cells. But birds have a mosaic of hair cells, whereas humans have 4 rows of hair cells.

In birds, new cells will grow in four to six days and will be perfectly restored in four to six weeks. How does this happen? Where were the new hair cells coming from? Using DNA synthesis in regenerating ears showed that the new hair cells were arising from former supporting cells that had re-entered the cell cycle, divided and produced new cells that then differentiated into new hair cells and supporting cells.

After a bird's hair cells have been damaged, they regenerate using one of two methods - rapid response or extensive repair. But both methods utilize the same program for making new hair cells. Also the cell cycle knows when to stop and produces only enough new hair cells and supporting cells to replace those that were lost. Hair cell regeneration does not occur in the normal, undamaged ear.

What About Humans?

It is assumed that humans are more complex, and that maybe there are human genes that don't want to be regenerated. This means that scientists have to discover ways to change that, to restore regenerative capacity using genetic manipulation. Gene therapy is another possible way to induce new hair cell production. Stem cell transplantation is a way to induce replacement of lost or damaged inner ear cells.

Experiments on mature mice and guinea pigs involve inducing hair cell loss and cochlear damage through the use of loud noise. Mouse neural stem cells are injected into the cochlea and allowed to integrate for four to six weeks. Then cochleas are examined to see where the stem cells have gone and what cell types they have become. Stem cells become hair cells, nerves and glia.

As promising as this is, it would be seven to 15 years before approval of generative therapies is given for humans, even after clinical trials.

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Can We Regenerate the Mammalian Auditory System?

Neil Segil, Ph.D., Director of the Division of Cell Biology and Genetics, House Ear Institute

Neil Segil, Ph.D., Director of the Division of Cell Biology and Genetics at the House Ear Institute explained that there are two strategies for hair cell regeneration:  (1) repair from the outside, which would involve transplantation of hair cells, their progenitors, or stem cells, and (2) repair from the inside, which would involve stimulation of stem cells or progenitors present in the damaged ear. 

Repairing from the outside could be mechanically difficult, and it's also possible that stem cells could become cancer cells, so identification of cells would have to be done ahead of time.  In general, the sensitivity of hair cells is almost problematic because so much can cause them to break down.   And to regenerate hair cells, doctors will need to replace specific supporting cells, the right number of cells and in the right position. 

There is also the developmental approach, which is to study how cells develop and regulate themselves in embryo.  We know that cells stop dividing in utero at some point and never divide again, so the study of the cell cycle, and the master regulators that determine the cycle, is important.    Research shows that when DNA is duplicated in synthesis phase and distributed to other cells, the onset of p27 expression, a cell cycle regulator, correlates with cell cycle exit and somehow stops cell replication. 

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