Monell scientists identify elusive taste stem cells

Scientists at the Monell Center have identified the location and certain genetic characteristics of taste stem cells on the tongue. The findings will facilitate techniques to grow and manipulate new functional taste cells for both clinical and research purposes.

"Cancer patients who have taste loss following radiation to the head and neck and elderly individuals with diminished taste function are just two populations who could benefit from the ability to activate adult taste stem cells," said Robert Margolskee, M.D., Ph.D., a molecular neurobiologist at Monell who is one of the study’s authors.

Taste cells are located in clusters called taste buds, which in turn are found in papillae, the raised bumps visible on the tongue’s surface.

Two types of taste cells contain chemical receptors that initiate perception of sweet, bitter, umami, salty, and sour taste qualities. A third type appears to serve as a supporting cell.

A remarkable characteristic of these sensory cells is that they regularly regenerate. All three taste cell types undergo frequent turnover, with an average lifespan of 10-16 days. As such, new taste cells must constantly be regenerated to replace cells that have died.

For decades, taste scientists have attempted to identify the stem or progenitor cells that spawn the different taste receptor cells. The elusive challenge also sought to establish whether one or several progenitors are involved and where they are located, whether in or near the taste bud.

Drawing on the strong physiological relationship between oral taste cells and endocrine (hormone producing) cells in the intestine, the Monell team used a marker for intestinal stem cells to probe for stem cells in taste tissue on the tongue.

Stains for the stem cell marker, known as Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5), showed two patterns of expression in taste tissue. The first was a strong signal underlying taste papillae at the back of the tongue and the second was a weaker signal immediately underneath taste buds in those papillae.

The Monell scientists hypothesize that the two levels of expression could indicate two different populations of cells. The cells that more strongly express Lgr5 could be true taste stem cells, whereas those with weaker expression could represent those stem cells that have begun the transformation into functional taste cells.

Additional studies revealed that the Lgr5-expressing cells were capable of becoming any one of the three major taste cell types.

The findings are published online in the journal Stem Cells.

"This is just the tip of the iceberg," said senior author Peihua Jiang, Ph.D., also a Monell molecular neurobiologist. "Identification of these cells opens up a whole new area for studying taste cell renewal, and contributes to stem cell biology in general."

Future studies will focus on identifying the factors that program the Lgr5-expressing cells to differentiate into the different taste cell types, and explore how to grow these cells in culture, thus providing a renewable source of taste receptor cells for research and perhaps even clinical use.

(Image: Getty)

Pioneering research helps to unravel the brain’s vision secrets

A new study led by scientists at the Universities of York and Bradford has identified the two areas of the brain responsible for our perception of orientation and shape.

Using sophisticated imaging equipment at York Neuroimaging Centre (YNiC), the research found that the two neighbouring areas of the cortex — each about the size of a 5p coin and known as human visual field maps — process the different types of visual information independently.

The scientists, from the Department of Psychology at York and the Bradford School of Optometry & Vision Science established how the two areas worked by subjecting them to magnetic fields for a short period which disrupted their normal brain activity. The research which is reported in Nature Neuroscience represents an important step forward in understanding how the brain processes visual information.

Attention now switches to a further four areas of the extra-striate cortex which are also responsible for visual function but whose specific individual roles are unknown.

The study was designed by Professor Tony Morland, of York’s Department of Psychology and the Hull York Medical School, and Dr Declan McKeefry, of the Bradford School of Optometry and Vision Science at the University of Bradford. It was undertaken as part of a PhD by Edward Silson at York.

Researchers used functional magnetic resonance imaging (fMRI) equipment at YNiC to pinpoint the two brain areas, which they subsequently targeted with magnetic fields that temporarily disrupt neural activity. They found that one area had a specialised and causal role in processing orientation while neural activity in the other underpinned the processing of shape defined by differences in curvature.

(Photo: Image courtesy of Brian A. Wandell, Serge O. Dumoulin and Alyssa A. Brewer)

Cats and humans suffer from similar forms of epilepsy

Epilepsy arises when the brain is temporarily swamped by uncoordinated signals from nerve cells. Research at the Vetmeduni Vienna has now uncovered a cause of a particular type of epilepsy in cats. Surprisingly, an incorrectly channelled immune response seems to be responsible for the condition, which closely resembles a form of epilepsy in humans. The work is published in the current issue of the Journal of Veterinary Internal Medicine.

There is something sinister about epilepsy: the disease affects the very core of our being, our brain. Epileptic attacks can lead to seizures throughout the body or in parts of it. Clouding of consciousness or memory lapses are also possible. The causes are still only partially understood but in some cases brain tumours, infections, inflammations of the brain or metabolic diseases have been implicated.

Epilepsy is not confined to humans and many animals also suffer from it. Together with partners in Oxford and Budapest, Akos Pakozdy and his colleagues at the University of Veterinary Medicine, Vienna have managed to identify the cause of a certain form of epilepsy in cats, in which the body’s own immune system attacks particular proteins in the cell membranes of nerve cells. The symptoms include twitching facial muscles, a fixed stare, chewing motions and heavy dribbling. Based on their clinical experience, the researchers believe that this form of epilepsy is fairly widespread in cats. Interestingly, a highly similar type of epilepsy occurs in humans: an inflammation in the brain, known as limbic encephalitis, leads to epileptic seizures that generally manifest themselves in the arm and the facial muscles on only one side of the body.

Pakozdy and his colleagues have found antibodies in the blood of epileptic cats that react to proteins in the cell membranes of nerve cells. The proteins form the building blocks of ion channels that are involved in the production of nerve signals. The same ion channels are affected in the corresponding human form of epilepsy. They control the membrane’s permeability to potassium ions based on the electric potential across the membrane, thereby helping generate the rapid nerve signals of the so-called action potential.

Immunotherapy for cats?
If the immune system attacks components of these ion channels, the production of nerve signals is disrupted. There is an increased release of neurotransmitters, which leads directly to the symptoms of epilepsy. Previous work – in another group – on human patients has shown that normal anti-epilepsy medication has hardly any effect on this form of epilepsy. However, immunotherapy has proven to be relatively effective. Pakozdy’s work now shows that “limbic encephalitis in cats has the same cause as it does in humans, where the origins have been known for years. It is important that cats with epilepsy are diagnosed early, so that the correct form of therapy can be started. We believe this will dramatically increase the chances of a successful treatment. It seems as though epileptic cats might benefit from treatment with immune preparations.”

(Image: Thinkstock)

Autism Speaks Through Gene Expression

Autism spectrum disorders affect nearly 1 in 88 children, with symptoms ranging from mild personality traits to severe intellectual disability and seizures. Understanding the altered genetic pathways is critical for diagnosis and treatment. New work to examine which genes are responsible for autism disorders will be presented at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

“Autism is the most inheritable of neurodevelopmental disorders,” explains Rajini Rao of Johns Hopkins University in Baltimore, Md., “but identifying the underlying genes is difficult since no single gene contributes more than a tiny fraction of autism cases.” Rather, she continues, “mutations in many different genes variably affect a few common pathways.”

A team of scientists at Johns Hopkins and Tel Aviv University in Israel looked at genetic variations in DNA sequence in the ion transporter NHE9 and found that autism-associated variants in NHE9 result in a profound loss of transporter function. “Altering levels of this transporter at the synapse may modulate critical proteins on the cell surface that bring in nutrients or neurotransmitters such as glutamate,” says Rao. “Elevated glutamate levels are known to trigger seizures, possibly explaining why autistic patients with mutations in these ion transporters also have seizures.”

A unique aspect of the team’s approach was that they exploited decades of basic research done in bacteria and yeast to study a complex human neurological disorder. First, the group at Tel Aviv University, led by Nir Ben-Tal, built structural models of NHE9 using a bacterial relative as a template, allowing the Rao laboratory at Johns Hopkins to use the simple baker’s yeast for screening the mutations. In the future, as genomic information becomes readily available for everyone, such easy, inexpensive, and rapid screening methods will be essential to evaluate rare genetic variants in autism and other disorders.

Rao and her team are optimistic about the potential benefits of their latest findings. “Although the research is still at an early stage, drugs that target the cellular pathways regulated by NHE9 could compensate for its loss of function and lead to potential therapy in the future,” Rao says. “These findings add a new candidate for genetic screening of at-risk patients that may lead to better diagnosis or treatment of autism.”

Propping Open the Door to the Blood Brain Barrier

The treatment of central nervous system (CNS) diseases can be particularly challenging because many of the therapeutic agents such as recombinant proteins and gene medicines are not easily transported across the blood-brain barrier (BBB). Focused ultrasound can be used to “open the door” of the blood brain barrier. However, finding a way to “prop the door open” to allow therapeutics to reach diseased tissue without damaging normal brain tissue is the focus of a new study by a team of researchers at the Institute of Biomedical Engineering at National Taiwan University presenting at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

The group is investigating the feasibility of using heparin, a common anticoagulant, to enhance the delivery of therapeutic macromolecules using ultrasound into the brain. Heparin could be employed to increase treatment efficacy in patients with different types of CNS diseases under the guidance of medical imaging system providing new hope in these challenging cases. Initial results show that heparin does have the potential to optimize therapeutic delivery with ultrasound, acting as a “doorstop,” allowing drugs to better permeate the BBB and enhancing treatment success.

“A higher acoustic pressure and longer sonication, and/or a higher dose of microbubbles may increase the delivery of drugs or tracers into the sonicated brain tissue,” explains Kuo-Wei Lu, a member of the research team, “but side-effects, such as microhemorrhage, can also increase dramatically. The results of this study indicate that heparin may offer a safer way can to enhance the delivery of therapeutics to patients with CNS diseases.”

With these encouraging results, the next step for the team is to develop a focused ultrasound system with Magnetic Resonance Imaging (MRI) guidance to establish suitable parameters needed for patient clinical trials. “Focused ultrasound sonication is a noninvasive technology capable of localized and transient BBB opening for the delivery of CNS therapeutics,” Lu states. “We hope by developing suitable parameters and using chemical enhancers like heparin, this can be a valuable tool in the treatment of patients with CNS diseases, opening the door to better patient outcomes.”

(Image: Ben Brahim Mohammed)

Joslin Scientists Generate First Human Induced Pluripotent Stem Cells from Patients with Maturity Onset Diabetes of the Young

Joslin scientists report the first generation of human induced pluripotent stem cells from patients with an uncommon form of diabetes, maturity onset diabetes of the young (MODY). These cells offer a powerful resource for studying the role of genetic factors in the development of MODY and testing potential treatments. The findings appear in the Journal of Biological Chemistry.

Human induced pluripotent stem cells (hiPSCs) are adult cells that have been genetically reprogrammed to exhibit the characteristics of embryonic stem cells, including the ability to differentiate into specialized cell types. The generation of hiPSCs, which was first reported in 2006, was a major scientific breakthrough with the potential to increase understanding of many diseases and aid in drug development.

Maturity onset diabetes of the young (MODY) is a form of diabetes that mainly affects individuals age 25 or younger and accounts for about 1 to 5 percent of all diabetes cases in the United States. Unlike type 1 and type 2 diabetes, which are polygenic and result from alterations in genetic and environmental factors, MODY is a monogenic disease that results from mutations in a single gene. To date, eight types of MODY and eleven MODY genes have been identified. Some types of MODY produce only mild symptoms and are often treated solely with oral diabetic medications.

Joslin Diabetes Center is one of a limited number of research institutes with the capability to generate hiPSCs from patients with diabetes. The cells used to produce the hiPSCs were obtained from patients with five different types of MODY at Joslin Diabetes Center and Haukeland University Hospital, Bergen, Norway. The MODY-hiPSCs are morphologically, molecularly and functionally indistinguishable from human pluripotent stem cells (hPSCs).

As a monogenic disease, MODY provides “a valuable opportunity to directly study in more detail the genetic mechanisms underlying the disease and not be influenced by other factors, such as insulin resistance,” says senior author Rohit N. Kulkarni, M.D., Ph.D., a Principal Investigator in the Section on Islet Cell and Regenerative Biology at Joslin and Associate Professor of Medicine at Harvard Medical School.

The scientists will first induce the MODY-hiPSCs to differentiate towards beta cells and in the process learn more about the potential blocks in their ability to differentiate. Using the iPSC-derived beta cells, they plan to study how MODY genes regulate the insulin secretory function. “Generating hiPSCs is an important step forward because we cannot obtain beta cells from living patients. These cells will allow us to do many experiments that otherwise would not be possible,” says Dr. Kulkarni.

The scientists also plan to explore ways to correct the genetic defect and use the beta cells derived from the “repaired” hiPSCs to test various treatments. “If we find medications that improve beta cell function, we can go back to the clinic and use them to treat patients,” says Dr. Kulkarni. “It will allow us to tailor treatments to a patient’s unique characteristics and provide personalized medicine to diabetes patients.”

New stroke gene discovery could lead to tailored treatments

A study led by King’s College London has identified a new genetic variant associated with stroke. By exploring the genetic variants linked with blood clotting – a process that can lead to a stroke – scientists have discovered a gene which is associated with large vessel and cardioembolic stroke but has no connection to small vessel stroke.

Published in the journal Annals of Neurology, the study provides a potential new target for treatment and highlights genetic differences between different types of stroke, demonstrating the need for tailored treatments.

Approximately 152,000 people in Britain have a stroke each year, costing the UK over £8.2 billion. While there are thought to be 1.2 million stroke survivors in the UK, more than half have been left with disabilities that affect their daily lives.

A stroke occurs when the blood supply to the brain is cut off, often due to a blood clot blocking an artery that carries blood to the brain, which then leads to brain cell damage. Coagulation (blood clotting) abnormalities, particularly easy clotting of the blood, are therefore common contributing factors in the development of stroke.

Dr Frances Williams, Senior Lecturer from the Department of Twin Research and Genetic Epidemiology at King’s and lead author of the paper, said: ‘Previous studies have demonstrated the influence of genetic factors on the components of coagulation. The goal of this study was to extend these observations to determine if they were further associated with different types of stroke.’

The research was carried out in three stages. The first consisted of a genome-wide association study (GWAS) in 2100 healthy volunteers which identified 23 independent genetic variants that were involved in coagulation. The second stage examined the 23 variants in 4200 stroke and non-stroke cases from centres across Europe (Wellcome Trust Case Control Consortium 2 and MORGAM collections) and found that a particular mutation on the ABO gene was significantly associated with stroke.

Stage three of the study used the MetaStroke cohort, a project of the International Stroke Genetics Consortium which comprises 8900 stroke cases recruited from centres in the Europe, USA and Australia, whose DNA has been collected and undergone GWA scan. It was confirmed that a variant in the ABO blood type gene was associated with stroke, a finding specific to large vessel and cardioembolic stroke.

Dr Williams said: ‘The discovery of the association between this genetic variant and stroke identifies a new target for potential treatments, which could help to reduce the risk of stroke in the future. It is also significant that no association was found with small vessel disease, as this suggests that stroke subtypes involve different genetic mechanisms which emphasises the need for individualised treatment.’