PIEZO2

Scientists have known for years that a lattice of blood vessels nourishes cells in the retina that allow us to see -- but it's been a mystery how the intricate structure is created. Now, researchers have found a new type of neuron that guides its formation. The discovery could one day lead to new therapies for diseases that are related to impaired blood flow in the eyes and brain. Scientists have known for years that a lattice of blood vessels nourishes cells in the retina that allow us to see -- but it's been a mystery how the intricate structure is created. Now, researchers at UC San Francisco have found a new type of neuron that guides its formation. The discovery, described in the May 23, 2024, issue of Cell, could one day lead to new therapies for diseases that are related to impaired blood flow in the eyes and brain. "This is the first time anyone has seen retinal neurons using direct contact with blood vessels as a way of guiding them to form these precise 3-D lattices," said Xin Duan, PhD, an associate professor of ophthalmology and senior author of the study. "This brings us closer to the possibility of repairing them when they're damaged or rerouting them when they weren't built right in the first place." A protein that senses the presence of nearby cells The researchers worked with newborn mice, whose eyes still need several weeks to develop fully. Kenichi Toma, PhD, labeled the retinal neurons closest to the blood vessels with a protein that glows green under ultraviolet light so he could observe the lattice as it was forming. The team then identified a subset of neurons, called perivascular neurons, which contact and then surround growing blood vessels, directing them to form the lattice. These perivascular neurons produce a protein called PIEZO2 that enables them to sense when they are touching another cell. Perivascular neurons in mice that were unable to produce PIEZO2 could not maintain contact with blood vessels, and they grew in a tangled, disorganized way that disrupted blood flow. Starved for oxygen, the surrounding nerve cells degraded, and the mutant mice were more vulnerable to stroke-like injuries. Duan found that these neurons guide the formation of a similar network of blood vessels in the cerebellum, a part of the brain that is involved in coordination, language, and sense perception. "The fact that we see this same pattern repeated in the brain means that damage to this lattice might have a role in multiple neurodegenerative diseases," Toma said. The team collaborated with developmental biologist Arnold Kriegstein, MD, PhD, to confirm that perivascular retinal neurons also exist in humans. 3-D view shows how the lattice forms Most research to date on the connection between the vascular and nervous systems has been limited by technology that only allows scientists to take two-dimensional pictures. But Duan and Toma benefited from a new technique, using multiphoton microscopy, that Tyson Kim, MD, PhD, an assistant professor of ophthalmology, had developed to make 3-D images of retinal blood networks without disturbing the eye. Kim helped Toma create revolving movies that captured the lattice from every angle and showed how it broke down in the absence of PIEZO2. "We had been wanting to collaborate for some time, and this was the perfect opportunity," Kim said. "It was really a confluence of what we're each passionate about." A new way to protect neurons The discoveries could inspire new ways of treating neurodegenerative diseases by ensuring that neurons, which demand a lot of energy, maintain a healthy blood supply. "There are lots of people trying to understand the ways we can grow neurons," Duan said. "But how in the world do we grow the intricate networks of blood vessels required to support them? That's the question we're trying to answer."

Targeting a receptor responsible for our sense of touch and temperature, which researchers have now found to be present in our colon, could provide a new avenue for treating chronic pain associated with gastrointestinal disorders such as irritable bowel syndrome. A team examining the colon identified the presence of Piezo2, the subject of the 2021 Nobel Prize in Physiology or Medicine, now known to be responsible for sensing light touch on our skin. Targeting a receptor responsible for our sense of touch and temperature, which researchers have now found to be present in our colon, could provide a new avenue for treating chronic pain associated with gastrointestinal disorders such as irritable bowel syndrome. A team examining the colon, led by Professor Hongzhen Hu at Washington University and Professor Nick Spencer at Flinders University, identified the presence of Piezo2, the subject of the 2021 Nobel Prize in Physiology or Medicine, now known to be responsible for sensing light touch on our skin. "In discovering that this receptor is also in our gut, there's the potential that selectively targeting these channels could be used for long-term silencing of pain sensations from internal organs, without the need for frequent consumption of opiate pain medications," says Professor Spencer, a Matthew Flinders Professor in the College of Medicine and Public Health. Professor Nick Spencer said, "Chronic pain from internal organs, such as the gut or bladder, is notoriously difficult to treat. Opiates, including morphine and their derivates have been commonly used to treat a variety of types of pain but visceral pain doesn't respond well to the treatment and the drugs are highly addictive with a multitude of side effects." The authors say the availability of selective pain medications for the gut has been hindered by a lack of understanding about how sensory nerves communicate pain sensations from the gut to the brain. "It was previously known that many different ion channels are located on the 'pain-sensing' neurons that communicate from the gut to the brain, but our study, published in the journal Neuron, has now identified the major ion channel in the colon that responds to mechanical stimulation leading to the sensation of pain," says Professor Spencer. "Furthermore, we have discovered that the major ion channel that responds to this mechanical pain is a member of the Piezo ion channel, specifically Piezo2. "From this knowledge we can focus on targeting these channels to silence the pain sensations and hopefully produce a treatment for visceral pain, common in conditions such as irritable bowel syndrome, endometriosis or abdominal cancers, while avoiding the devastating side effects of opioids." The research was funded by grants from the US National Institutes of Health and the National Health and Medical Research Foundation.

New finding could lead to better drug treatments for chronic itch conditions, like eczema. Scientists at Scripps Research have identified a protein in sensory nerves that works as a key detector of itch -- specifically the "mechanical" itch stimulus of crawling insects, wool fibers, or other irritating objects that touch the skin. The discovery, published June 22, 2022, in Nature, is the first identification of a sensor for mechanical itch rather than chemically-triggered itch. It could lead to better treatments for itch conditions such as eczema and psoriasis. "These findings help us untangle the complexity of itch sensation, and suggest that PIEZO1 inhibitors could be very useful clinically," says study senior author Ardem Patapoutian, PhD, a professor in the Department of Neuroscience at Scripps Research, and a Howard Hughes Medical Institute investigator. Itch is a distinct sensation with its own nerve circuitry and evolutionary purpose -- likely to alert organisms to potentially harmful chemicals, insects and parasites. Researchers over the past decade or so have identified itch-specific subsets of spinal neurons that extend nerve fibers into the skin and are sensitive to chemical triggers of itch such as the allergy mediator histamine. But so far, relatively little has been discovered about the circuitry of mechanical itch. PIEZO1's role in mechanical itch was unexpected. Patapoutian won a share of last year's Nobel Prize for Medicine or Physiology for his lab's pioneering research on PIEZO1 and its sister-protein PIEZO2. These unique, propeller-shaped "mechanosensor" ion channels are embedded in the outer membranes of many cell types. They become activated when mechanically distorted, opening their ion channels and triggering various downstream events. Since 2010, Patapoutian and colleagues have shown that PIEZO2 is a key mechanosensor for light touch, the feeling of the positioning of the body and limbs, and the urge to urinate -- all via nerves in various tissues and organs. By contrast, the researchers have found that PIEZO1 has a variety of non-sensory roles throughout the body, for example in blood vessels and red blood cells. While their initial studies suggested that PIEZO1 was not expressed in sensory neurons, other recent investigations have suggested that it is expressed at low levels in some subsets of these neurons. In the new study, Patapoutian and his team, including study first author Rose Hill, PhD, a postdoctoral research associate, followed up on this surprising lead. In experiments in mice, they confirmed that PIEZO1 is expressed, and appears to be a functional, mechanical pressure-sensitive ion channel protein in two different types of sensory neuron that were already implicated in chemical itch. Mice with an overactive form of PIEZO1 were markedly more sensitive to itch sensations. By contrast, mice lacking PIEZO1 in their sensory neurons scratched themselves far less when stimulated on the skin with filaments that normally would trigger strong itch sensations. The researchers also showed that a PIEZO1-blocking compound alleviates scratching behaviors in mice with the equivalent of eczema. "We did see a dramatic effect on itch with this compound, and though it wasn't specific enough against PIEZO1 to develop into a drug, we hope eventually to develop a much more PIEZO1-specific compound for treating itch conditions," Hill says. Curiously, the absence or enhancement of PIEZO1 activity in mice caused at least a small reduction or increase of scratching due to chemical itch triggers such as histamine -- implying that mechanical and chemical itch signals are indeed transmitted in some cases by the same sensory neurons. The researchers are now investigating whether variants of the PIEZO1 gene in the human population are related to itch sensitivity. The Patapoutian lab published a paper in 2018 showing that a mildly overactive form of PIEZO1, which also has the effect of making red blood cells relatively resistant to malaria parasites, is present in about a third of people of African ancestry. "PIEZO1 transduces mechanical itch in mice" was co-authored by Rose Hill, Meaghan Loud, Adrienne Dubin, Brooke Peet, and Ardem Patapoutian. Funding was provided by the Howard Hughes Medical Institute, the National Institutes of Health (R35 NS105067), and the Helen Hay Whitney Foundation.