Inner Ear Hair Cell Regeneration — Maybe We Can Know More

The evidence that manipulating both Wnt and notch signalling has the potential to regenerate hair cells while preserving supporting cell population continues to grow. The caveat is that much of this work is in very young animals so it remains to be seen what translates to adults.

A new paper by Albert Edge and Fuxin Shi and colleagues (http://www.jneurosci.org/content/36/36/9479.abstract) suggests that there is a threshold level of Wnt signalling required for regeneration and that inhibiting notch signalling increases the size of the effect.

SIGNIFICANCE STATEMENT Sensory HCs of the inner ear do not regenerate in the adult, and their loss is a major cause of deafness. We found that HCs regenerated spontaneously in the newborn mouse after diphtheria toxin (DT)-induced, but not neomycin-induced, HC death. Regeneration depended on activation of Wnt signaling, and regeneration in DT-treated ears correlated to a higher level of Wnt activation than occurred in nonregenerating neomycin-treated ears. This is significant because insufficient regeneration caused by a failure to reach a threshold level of signaling, if true in the adult, has the potential to be exploited for development of clinical approaches for the treatment of deafness caused by HC loss.

This comes on the heels of a series of papers by Huwei Li and colleagues that explore the interactions of Wnt and Notch signalling:

http://www.jneurosci.org/content/36/33/8734.abstract
http://www.nature.com/articles/srep29418
http://www.pnas.org/content/112/1/166.long

Based on earlier publications, Li was almost certainly a postdoc in Heller's lab at Harvard when Heller was at Harvard; Li's lab is quite prolific in the last couple of years.

This is promising, but it is not clear how perfectly the multiple pathways must be understand (and there are more then two - Edge has a new paper about another pathway regulating Atoh1: http://www.ncbi.nlm.nih.gov/pubmed/27542412).

 

I get the impression that a lot of progress is made in China.
http://www.nature.com/articles/srep29418
Was received in October 2015
http://www.jneurosci.org/content/36/33/8734
Was received in January 2016
That to me looks like a steady progress.
This is what @Aaron123 already pointed out and think it is very interesting what these researchers are doing.

 

So they are combining treatments?

 

All I'm saying is people probably thought shooting a laser into your eye to correct your vision was crazy. Soon cell therapy will be the norm.

 

Nobody thinks cells therapy is crazy, we're no longer in the 90's

 

What I understand is that they are a small step closer to mimic what happens in the developing ear. So no uncontrolled haircell regeneration. Orderly, so the new haircells are not "all over the place" inside the inner ear. Also no depletion of support cells.

This is my level of understanding. Very, very basic.
But if these group of scientists keep going at the same pace? Who knows

 

Shooting lasers Into your eyes has caused a lot of problems for a lot of people. Many people have been left with double vision, haloes, dry eyes etc. There are several high profile campaigns on this issue especially in the UK.

 

My father is a biomedical engineer and he trusted those lasers to correct his vision. It's all the rave here in the states.

 

I found this on the internet: (deals with hair cell regeneration in balance organ).
https://www.sciencedaily.com/releases/2016/09/160908084147.htm
Quote: "Subsequently, supporting cells very rapidly fill in the space of the dead sensory hair cells."
Does anyone know if this also happens in the inner ear? Will dead hair cells be replaced with supporting cells?
I understand that dead cells are "taken away". But are they replaced by supporting cells, or another type of cell?

 

This research sounds unsense to me because my hair cells were poisened by antibiotics and now I have modarate H. Maybe little amounts of supporting cells cover to hair cells I think.

 

This research is about the balance organ. I understand there already is limited hair cell regeneration in this organ. But if researchers understand why and improve this, perhaps this can be translated to processes in the inner ear.

Like other dead cells in our body are taken away (I believe this process has a name, but can't remember what name) I would think that dead hair cells also would be taken away completely. But with what are they replaced? They need to be replace with something, otherwise the structure of the inner ear would collapse.

 

Hmm. I missed this detail. So this is why I sense right direction
I think Atoh-1 project will explain some important details about that. We just need some timeç

 

Won't they just be replaced with glial scar tissue?

 

Scar tissue yes (http://bmb.oxfordjournals.org/content/63/1/25.full); glial scar tissue no (talking about hair cells not glia).

 

@Reinier

Thats like saying if you shave your head, your scalp and skull must protrude out to replace it.

 

I forgot about the endolymph and perilymph. You cannot have "holes" after hair-cell death.
Now I even got more questions
I will just patiently continue to read and take in information.
I am not in a rush.

I am not sure what you mean.

 

This one hasn't been posted before (at least not to my knowledge), so I thought it might be interesting for you guys.

http://www.ncbi.nlm.nih.gov/pubmed/23165382

By the way, this is the paper that inspired the Baumgartners to conduct their hearing loss trial in Florida.

 

A girl at my church is getting stem cell treatment for her ammune system. Basically to replace all the bad cells that genetically are not working anymore with good healthy ones. Evidently this is a standard practice now.

It seems just over the past year cell therapy has exploded.

 

Perhaps another step toward diagnosing hidden hearing loss:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162726#pone-0162726-g001

Toward a Differential Diagnosis of Hidden Hearing Loss in Humans

M. Charles Liberman, Michael J. Epstein, Sandra S. Cleveland, Haobing Wang, Stéphane F. Maison

Abstract
​

Recent work suggests that hair cells are not the most vulnerable elements in the inner ear; rather, it is the synapses between hair cells and cochlear nerve terminals that degenerate first in the aging or noise-exposed ear. This primary neural degeneration does not affect hearing thresholds, but likely contributes to problems understanding speech in difficult listening environments, and may be important in the generation of tinnitus and/or hyperacusis. To look for signs of cochlear synaptopathy in humans, we recruited college students and divided them into low-risk and high-risk groups based on self-report of noise exposure and use of hearing protection. Cochlear function was assessed by otoacoustic emissions and click-evoked electrocochleography; hearing was assessed by behavioral audiometry and word recognition with or without noise or time compression and reverberation. Both groups had normal thresholds at standard audiometric frequencies, however, the high-risk group showed significant threshold elevation at high frequencies (10–16 kHz), consistent with early stages of noise damage. Electrocochleography showed a significant difference in the ratio between the waveform peaks generated by hair cells (Summating Potential; SP) vs. cochlear neurons (Action Potential; AP), i.e. the SP/AP ratio, consistent with selective neural loss. The high-risk group also showed significantly poorer performance on word recognition in noise or with time compression and reverberation, and reported heightened reactions to sound consistent with hyperacusis. These results suggest that the SP/AP ratio may be useful in the diagnosis of “hidden hearing loss” and that, as suggested by animal models, the noise-induced loss of cochlear nerve synapses leads to deficits in hearing abilities in difficult listening situations, despite the presence of normal thresholds at standard audiometric frequencies.

 

And helps nobody. What good is a diagnosis of hidden hearing loss if there are no treatments for it.... I'm bringing up the obvious!

 

It's actually quite important to have a test for hidden hearing loss in order to actually do the work to find a treatment. As the authors say in closing "Future clinical trials of such regenerative therapies will require objective measures of cochlear synaptopathy to identify candidates and to track treatment efficacy."

Moreover, in the context of younger people in particular they say: "Noise damage early in life likely accelerates the age-related further loss of hair cells and cochlear neurons, even in the absence of further ear abuse [8, 39]. Clarification of the true risks of noise, and the true prevalence of noise-induced damage, are important to public policy on noise abatement, to raising general consciousness about the dangers of ear abuse and to preventing a dramatic rise in hearing impairment in the future." A test for hidden hearing loss that is as easy to administer as standard audiometry would be valuable even prior to the existence of a treatment if leads to earlier identification of hearing issues and to greater awareness that damage exists prior to being seen on a standard hearing test.

 

I still wonder if it is "as simple" as this:
Initial stage of noise induced hearing loss is the hidden hearing loss. Loss of synapses and neurons.
The next level is loss of hair cells. This does show on the rudimentary audiogram.
This would mean there still are very many people on this planet that have lost hair cells in the inner ear due to wear and tear.

Good news that perhaps they can develop a more robust method to determine what is damaged. That is after all what you need to do first.

I wonder at which stage Liberman and group of scientists are. Are they already investigating treatments, or just suggesting what could work?
I realise this is ongoing research. Just wondering.

 

Yes, the problem with tinnitus, hyperacusis and hearing loss is that there even aren't proper diagnostic protocols in place yet. These unfortunately have to be developed first.

At some moments you realise how prehistoric our current methods are regarding an immensely important sensory function; hearing. This is one of these moments. Clinically, we really aren't very much further than the "hot sliced bread on the ears, and with God's grace it will be fine" solution advised by a doctor from Wales 600 years ago (Okay, they meanwhile introduced pure-tone audiometry... which... still doesn't tell quite much as it appears now).

Seeing the pace upon which improvements in understanding are made though, I stay positive we might be seeing huge improvements in the situation described above in the near future.

 

Liberman is investigating neurotrophins as a treatment if I'm not mistaken.

http://hyperacusisfocus.org/2015/09...trophins-a-potential-hyperacusis-treatment-2/

 

Sorry for my ignorance, is it about spiral ganglions or an other nerve supplied zone ?

 

No idea.

 

From the article:
http://www.psypost.org/2016/09/rese...hearing-loss-college-age-human-subjects-44892

“Hidden hearing loss,” on the other hand, refers to synaptopathy, or damage to the connections between the auditory nerve fibers and the sensory cells, a type of damage which happens well before the loss of the sensory cells themselves. Loss of these connections likely contributes to difficulties understanding speech in challenging listening environments, and may also be important in the generation of tinnitus (ringing in the ears) and/or hyperacusis (increased sensitivity to sound). Hidden hearing loss cannot be measured using the standard audiogram; thus, the Mass. Eye and Ear researchers set out to develop more sensitive measures that can also test for cochlear synaptopathy."

Pretty interesting. I guess it shows that tinnitus probably comes from both loss of hearing cells and damage between the cells and the brain.

 

link to the article?

 

Already posted, including a link to the paper:
https://www.tinnitustalk.com/posts/203098/

 

Whoops.
http://www.psypost.org/2016/09/rese...hearing-loss-college-age-human-subjects-44892

I put the link back into the original post.

I sort of wonder if strengthening the nerve connection between the ears and the brain can help, it that is possible.