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Scientists find a simpler way to make sensory hearing cells

Scientists from the USC Stem Cell laboratories of Neil Segil and Justin Ichida are whispering the secrets of a simpler way to generate the sensory cells of the inner ear. Their approach uses direct reprogramming to produce sensory cells known as “hair cells,” due to their hair-like protrusions that sense sound waves. The study was published today in the journal eLife.

“We’ve succeeded in directly reprogramming a variety of mouse cell types into what we’re calling induced hair cell-like cells, or iHCs,” said Ph.D. student Louise Menendez, the study’s lead author. “This allows us to efficiently generate large numbers of iHCs to identify causes and treatments for hearing loss.”

The scientists successfully reprogrammed three different types of mouse cells to become iHCs. The first two types were embryonic and adult versions of connective tissue cells, known as fibroblasts. The third was a different type of inner ear cell, known as a supporting cell.

To achieve reprogramming, the scientists exposed fibroblasts and supporting cells to a cocktail of four transcription factors, which are molecules that help convey the instructions encoded in DNA. The scientists identified this cocktail by testing various combinations of 16 transcription factors that were highly active in the hair cells of newborn mice.

“The four key ingredients turned out to be the transcription factors Six1, Atoh1, Pou4f3, and Gfi1,” said Menendez.

The resulting iHCs resembled naturally occurring hair cells in terms of their structure, electrophysiology, and genetic activity. The iHCs also possessed several other distinct characteristics of hair cells, including vulnerability to an antibiotic known to cause hearing loss.

“Hair cells are easy to damage, and currently impossible to repair in humans,” said Segil, a professor in the Department of Stem Cell Biology and Regenerative Medicine, and the USC Tina and Rick Caruso Department of Otolaryngology—Head and Neck Surgery, and one of the corresponding authors of the study. “Aging, loud noises, and certain chemotherapy drugs and antibiotics can all lead to the permanent loss of hair cells, which is the leading contributor to hearing loss worldwide.”

iHCs have the potential to accelerate hearing loss research in at least two important ways, according to Ichida, who is the John Douglas French Alzheimer’s Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, and the other corresponding author of the study.

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Fat check: Researchers find explanation for stress’ damage in brown fat

In their search for what triggers the damaging side-effects caused by acute psychological stress, Yale researchers found an answer by doing a fat check.

In the face of psychological stress, an immune system response that can significantly worsen inflammatory responses originates in brown fat cells, the Yale team reports June 30 in the journal Cell.

Since the hormones associated with stress, cortisol and adrenaline, generally decrease inflammation, it has long puzzled researchers how stress can worsen health problems such as diabetes and autoimmune disease as well as depression and anxiety.

“In the clinic, we have all seen super-stressful events that make inflammatory disease worse, and that never made sense to us,” said Dr. Andrew Wang, assistant professor of internal medicine and immunobiology, and corresponding author of the study.

Cortisol and adrenaline, hormones released in the classic “flight or fight” stress response, generally suppress the immune system, not activate it. These hormones also initiate a massive metabolic mobilization that provides fuel to the body as it addresses threats.

The scientists found that it was an immune system cell—the cytokine interleukin-6 (IL-6)—that triggers inflammation in times of stress. IL-6 has also been shown to play a role in autoimmune diseases, cancer, obesity, diabetes, depression and anxiety.

Wang and colleagues began to study the role of IL-6 in stress after a simple observation: When the researchers drew blood from mice, a very stressful procedure, the blood showed elevated levels of the cytokine.

In a series of experiments in mice, designed by Hua Qing and Reina Desrouleaux in Wang’s lab, the researchers found that IL-6, which is usually secreted in response to infections, was induced by stress alone and worsened inflammatory responses in the stressed animals.

And to their surprise, they found that in times of stress IL-6 was secreted in brown fat cells, which are most known for their roles in regulating metabolism and body temperature. When signals from the brain to brown fat cells are blocked, stressful events no longer worsened inflammatory responses.

“This was a completely unexpected finding,” said Qing, a postdoctoral associate at Yale School of Medicine.

The researchers reasoned that IL-6 must play another role in the “fight or flight” response besides triggering inflammation. They learned it also helps prepare the body to increase production of glucose in anticipation of threats. The brown fat cell response causes IL-6 levels to peak well after the metabolic production of glucose and the release of cortisol and adrenaline. This may explain why stress can trigger inflammation even while immune-suppressing hormones are being released, the researchers said.

Blocking IL-6 production not only protected stressed mice from inflammation, it also made them less agitated when placed in a stressful environment.

Wang and his team also suspect IL-6 may play a role in mental health disorders such as depression and anxiety. Wang observes that many of symptoms of depression, such as loss of appetite and sex drive, mimic those caused by infectious diseases such as the flu—so-called “sickness behaviors”—that can be triggered by IL-6.

Existing drugs designed to treat autoimmune diseases such as rheumatoid arthritis block the activity of IL-6. Preliminary findings suggest these drugs may help alleviate symptoms of depression, the authors note. There is also preliminary evidence that IL-6 may also play a role in diabetes and obesity as well.

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Researchers find on-off switch for inflammation related to overeating

Researchers at Yale have identified a molecule that plays a key role in the body’s inflammatory response to overeating, which can lead to obesity, diabetes, and other metabolic diseases. The finding suggests that the molecule could be a promising therapeutic target to control this inflammation and keep metabolic diseases in check.

The study appears on June 29 in the Proceedings of the National Academy of Sciences.

When a person overeats, the body stores excess calories in the form of fat in the adipose tissue, or body fat, said lead author Xiaoyong Yang of Yale School of Medicine. As the amount of calories consumed continues to increase, this leads to inflammation in adipose tissue and the release of fatty acids into other tissues, including the liver and muscles.

“This is dangerous,” Yang said, “and leads to metabolic disorders like diabetes.”

Researchers were aware that overeating led to inflammation and metabolic diseases, but until now, they did not know the precise way that the body’s immune cells, such as macrophages—which react to excess calorie consumption—contributed to this process. The new research by Yang and team zeroed in on a pathway called O-GIcNAc signaling, which activates when a person overeats, instructing the cells to limit inflammation.

Inflammation happens when the body’s immune system reacts to injury or threat, and involves increased blood flow, capillary dilation, and an influx of white blood cells.

“The body is smart,” said Yang, associate professor of comparative medicine and of cellular & molecular physiology. “It tries to protect against inflammation when fat builds up in the body. We discovered a key pathway that quenches inflammation caused by overnutrition.”

In particular, the researchers found that OGT (O-GIcNAc transferase), an enzyme that activates GIcNAc signaling, was responsible for activating the body’s pro-inflammatory response by turning on or off a specific signaling pathway in macrophages.

“The macrophage can be a good guy or a bad guy,” Yang said. “It becomes a bad guy in overnutrition, secreting a lot of inflammatory factors. In other contexts, it’s a good guy and has an anti-inflammatory effect. We found out that OGT tries to stop the macrophage from becoming a bad guy—to stop the pro-inflammatory response.”

Their finding suggests that OGT could be a target for new therapies to suppress inflammation and improve health.

The study also sheds light on the workings of glutamine and glucosamine, nutritional supplements recommended by doctors for arthritis and inflammation of the joints, Yang said. While researchers have known that these supplements promote O-GlcNAc signaling and reduce inflammation, they did not know how this process worked.

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