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November 7, 2017

Stem Cell Restoration of Hearing Loss Might Be a Double-Edged Sword

Hair cells in a chicken hearing organ. The nucleus is purple and hair bundles are highlighted green. [Kelvin Y. Kwan/Rutgers University-New Brunswick]

  • Stem cells have been a boon to biological research, allowing researchers to visualize and develop potential therapies for diseases where intervention has hit a wall. However, not all stem cell therapies are as simple as adding undifferentiated cells to damaged areas, allowing natural biological processes to take hold. For instance, inner ear stem cells can be converted to auditory neurons that could reverse deafness, but the process can also make those cells divide too quickly, posing a cancer risk—this according to recent findings from a study led by investigators at Rutgers University-New Brunswick.        

    Results from the new study, published recently in Stem Cell Reports  (“NEUROG1 Regulates CDK2 to Promote Proliferation in Otic Progenitors”), should open up new avenues of research for stem cells and guide potential therapeutic interventions.

    "It's a cautionary tale," explained senior study investigator Kevin Kwan, Ph.D., assistant professor in the department of cell biology and neuroscience in the School of Arts and Sciences at Rutgers. "People say, 'we'll just put stem cells in and we're going to replace lost neurons.' We're saying that 'yes, we can make neurons,' but you have other side effects that are unanticipated, such as increased proliferation of stem cells. So, this will guide us toward a better strategy for cell replacement therapies." 

  • Click Image To Enlarge +
    A stem cell–derived neuron grafted onto a mouse cochlea in the inner ear that lacked neurons. The new neuron is marked red, hair cells that convert sounds into neural signals are green, and hair bundles are blue. [Kelvin Y. Kwan/Rutgers University-New Brunswick]

    Hair cells within the inner ear convert sound into neural signals that are relayed to the brain by spiral ganglion neurons. Hearing loss from overexposure to noise causes hair cell loss, severe damage to neuronal processes, and slow degeneration of auditory neurons. The neurons do not regenerate once they are lost.

    "Hearing loss impacts about 15% of the American population—probably more," Dr. Kwan noted. "Over the years, you don't realize that you're not hearing well until you get tested. We're one of the few labs trying to figure out how to address the hearing loss issue."

    In the current study, the scientists overexpressed a gene called NEUROG1 to turn inner ear stem cells into auditory neurons.

    “Using an immortalized multipotent otic progenitor (iMOP) cell line that can self-renew and differentiate into otic neurons, NEUROG1 was enriched at the promoter of cyclin-dependent kinase 2 (Cdk2) and neurogenic differentiation 1 (NeuroD1) genes,” the authors wrote. “Changes in H3K9ac and H3K9me3 deposition at the Cdk2 and NeuroD1 promoters suggested epigenetic regulation during iMOP proliferation and differentiation. In self-renewing iMOP cells, overexpression of NEUROG1 increased CDK2 to drive proliferation, while knockdown of NEUROG1 decreased CDK2 and reduced proliferation. In iMOP-derived neurons, overexpression of NEUROG1 accelerated the acquisition of neuronal morphology, while knockdown of NEUROG1 prevented differentiation.”

    Dr. Kwan added that the overexpression of NEUROG1 “leads to increased cell division, and NEUROG1 is used in other stem cells to make other types of neurons. Scientists in other fields should be aware that when using this factor they'll probably also increase cell proliferation.”

    Interestingly, the Rutgers team also discovered that chromatin—DNA studded with histone proteins—influences how NEUROG1 functions. Changes in chromatin may help reduce unwanted stem cell proliferation and can be achieved by adding drugs to experimental cultures.

    "Ideally, we would change the chromatin state before we start overexpressing NEUROG1 and prevent unwanted stem cell proliferation," Dr. Kwan concluded.

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