Inner Ear Hair Cell Regeneration — Maybe We Can Know More

OTOSTEM — Result In Brief
https://cordis.europa.eu/result/rcn/221335_en.html

OTOSTEM tested two therapeutic approaches to treat hearing loss: A cell-based treatment introducing stem/otic progenitor cells into the cochlea, and a drug-based treatment to protect or regenerate sensory hair cells.

Researchers utilised various stem cell sources to obtain otic progenitor cells (OPCs). These included native stem cells from foetal and adult human otic tissues, and embryonic or induced pluripotent stem cells. The generated OPCs had to fulfil certain criteria such as in vitro expansion and differentiation into sensory hair cells, supporting cells or otic neuronal cell types.

OTOSTEM developed protocols with morphogens or small molecule compounds that induce and determine otic cell fate. OPCs were tested for biological function and absence of tumorigenicity in various ex vivo and in vivo assays. Through comparison of OPC phenotype and gene expression, OTOSTEM partners identified native human stem cells as the stem cell source with the highest otic differentiation potential.

Functionality of the generated otic or neuronal cell types was validated in in vitro experiments. Electrophysiological monitoring demonstrated that transplanted cells resembled those of mouse cochlear hair cells. Human otic neuronal progenitors were tested in preclinical animal models of auditory neuropathy. Hearing restoration was achieved and preserved for more than 30 weeks after transplantation with no adverse effects.

Currently, there is no quantitative cell-based assay for testing drugs specifically toxic to the ear (ototoxicity) in humans, thus even approved drugs bear the risk of causing hearing loss. To address this, and facilitate drug safety studies, the OTOSTEM consortium designed drug screening assays. This ‘hearing loss in a dish model’ employed otic progenitor cell-like cells derived from human induced pluripotent stem cells. The human assay was used for medium-throughput testing of more than 2 000 pharmacological active compounds including FDA-approved drugs. Surprisingly, several of these drugs were identified to be ototoxic.

The OTOSTEM consortium has developed novel compounds with otoprotective and otoregenerative activity. Otoprotective compounds prevent death of human ear hair cells. Otoregenerative drugs induce replacement of lost sensory cells. The OTOSTEM findings are of outmost commercial significance to the largely unexplored but growing market of otoprotective and regenerative drugs.

Given the association of hearing impairment with neurodevelopment in young, and dementia in older people, there is an imminent unmet need for clinically validated therapies. Industrial partners envisage that the OTOSTEM models can be incorporated into the drug discovery pipeline to enable the identification of new and better drugs to treat hearing loss. As Dr Avci outlines, “With the support of the Seventh Framework Programme, we significantly advanced the development of novel therapies against hearing loss and we are eager to continue our success within the H2020 programme.

 

This is about the wrong kind of hair cells, but interesting nonetheless. It is science after all. It's about unexpected discoveries not too unlike those of Penicillin.

Turning hair into a biomedical nanomaterial
https://www.nanowerk.com/spotlight/spotid=50317.php
A key challenge in developing materials for biomedical engineering is their biocompatibility. Of course, it would be ideal if high-performance biomaterials could directly be obtained from patients themselves.

This is exactly what a team of scientists in China has now demonstrated. They discovered that the hierarchical micro- and nanostructures of human hair can be turned into hierarchical micro- and nanoparticles with a simple top-down procedure and be used as a novel type of biomaterial for medical applications.

This strategy of preparing biomaterials from abundant human hair might provide a potent tool for producing autogenous materials from patients themselves to overcome the drawbacks of synthetic materials.

"Our study began with a very interesting coincidence," Zhang recounts. "When we were preparing a sample for electron microscopy scanning, a piece of hair dropped on the object stage. Coincidentally, we observed the beautiful hierarchical structure in this piece of hair. Our major research interest is discovering new materials for solving biomedical problems, and materials obtained from the human body might be very suitable to address these challenges. Looking back at the whole research process, I think curiosity has motivated us to conduct this work."

From a chemical perspective, hair is mainly composed of melanins and keratins – two polymers that are ideal materials for biomedical applications. Keratin-based biomaterials display superior performances in bone regeneration, hemostasis, and cell protection. Pigments of melanin, a kind of functional polymer existing in most life forms, have versatile functions in regulating redox equilibrium, photothermal conversion, and dynamic coloration.

In their experiments the team found that, compared with commercialized carriers, such as liposomes or albumin nanoparticles, the hair particles exhibited negligeable immunogenicity and intrinsic blood compatibility.

"Due to the satisfactory photothermal conversion of melanin, both hair micro- and nanoparticles showed high and continuable photothermal conversion ability, and this feature made them ideal materials to achieve photothermal therapy," says Zhang. "Furthermore, these biomaterials displayed attentional abilities on light absorption and free radical scavenging. We also found that, when made into sunscreen, they could prevent skin from UV-induced damage. The aqueous dispersion of these particles could also relieve symptoms of cataracts, rescue mice from vein thrombosis, and suppress tumor growth."

In their next research stage, the team will further investigate the bio-safety and durability of these materials. In the present study, all hair samples were used immediately after collection. However, translating an eventual hair-based hierarchical biomaterial from conceptional work into clinical applications, exploring and optimizing the standard conditions of hair collection, transportation and storage would be an inevitable step.

"Advances in medicine in the areas of genomics, proteomics, tissue engineering, and regenerative medicine are occurring at a rate that was previously unthinkable," Zhang concludes. "The purpose of our research is to discover high-performance biomaterials through interdisciplinary methods and help facilitate their successful introduction into clinical applications."

 

I wrote about professor Hudspeth earlier. He was in the news today, so I thought I would post a small note here. He has been awarded with the Kavli Prize, a gold medal and 1 million dollars in cash prize. I would say that's well deserved, for his 50 years of foundational work in the field of auditory science.

A. James Hudspeth to receive Kavli Prize in Neuroscience
https://www.rockefeller.edu/news/22736-james-hudspeth-receive-kavli-prize-neuroscience/

When Hudspeth began his studies in the late 1960s, very little was known about hearing beyond basic anatomy and physiology. Hudspeth revealed the role of the receptor cells of the inner ear, as well as the role and development of hair cells, which translate sound-induced mechanical actions into electrical signals for transmission to the brain. He also showed how sound is amplified by thousands of these hair cells covering the cochlea, a conch-shell-shaped cavity in the inner ear. Recently, Hudspeth has begun exploring the possibility of using hair cell regeneration as treatment for hearing loss. His studies of the neural mechanisms of hearing are facilitated by a specially designed microscope that can record a million measurements a second, with subnanometer resolution.

 

The dream team? It turns out Hudspeth will be sharing the prize with Robert Fettiplace, university of Wisconsin-Madison, and Christine Petit who is on the scientific advisory board of Sensorion.

Here is a short summary of their work.

"James Hudspeth has provided the major framework for our understanding of the process that transduces sound into neural signals. Extending from each hair cell is a bundle of fine processes that act as sensors. Hudspeth used ingenious methods to reveal how sound-induced vibrations, which set the hair bundle in motion, evoke an electrical response in the hair cells through a direct mechanical connection between the hair bundle and ion channels. He also revealed how sound signals, which can be extremely small, are amplified within the inner ear."

(This so called cochlear amplifier is technically named electromotility and I was reading up on it just the other day. Fascinating stuff! Only the outer hair cells exhibit this motile property. No other cell type in the human body has this property. Not even the muscle cells, because the method by which you excite them is different. Hair cells are sensory cells, and sensory cells don't normally have motile properties.)

"Robert Fettiplace has made fundamental contributions to our understanding of sound transduction and demonstrated that each hair cell in the cochlea of the inner ear is sensitive to a specific range of sound frequencies. His experiments revealed that hair cells are organized along the cochlea in a pattern that reflects their frequency selectivity. Using sensitive physiological measurements and theoretical modeling, he discovered that this selectivity reflects an intrinsic electrical property of the cell, set by the density and kinetics of its ion channels that induce a resonance at a particular frequency."

"Christine Petit has explored the genetics of hereditary deafness in humans and identified more than twenty genes that are required for hearing and inner ear development. She elucidated the mechanisms through which these mutations cause hearing deficits, thus illuminating the unique biology of hair cells and informing deafness diagnosis and counseling. Several of the genes she identified form major components of the hair cell mechanotransduction machinery."

2018 Kavli Prize Winners - NEUROSCIENCE

"Collectively the breakthroughs made by this year’s Kavli Prize laureates have unveiled the molecular and cellular mechanisms that underlie hearing and deafness."

"The work of the 2018 prizewinners may even have a practical application in future through gene therapy, or regeneration of hair cells in the inner ear to replace those that become damaged over time.

Medical applications aside, the Kavli Neuroscience Prize of 2018 honours curiosity-driven basic research that advances our understanding of hearing."

Full story here:
http://kavliprize.org/prizes-and-laureates/prizes/2018-kavli-prize-neuroscience

The Kavli Prize is presented every two years. Who knows who will be honored with the Kavli Prize and what for in the year 2020...