Uterine stem cells used to treat diabetes

Wednesday, 18 September 2013

Islamabad, Sep 19 (Newswire): Controlling diabetes may someday involve mining stem cells from the lining of the uterus, Yale School of Medicine researchers report in a new study published in the journal Molecular Therapy.

The team treated diabetes in mice by converting cells from the uterine lining into insulin-producing cells.

The endometrium or uterine lining, is a source of adult stem cells. These cells generate uterine tissue each month as part of the menstrual cycle. Like other stem cells, however, they can divide to form other kinds of cells.

The Yale team's findings suggest that endometrial stem cells could be used to develop insulin-producing islet cells, which are found in the pancreas. These islet cells could then be used to advance the study of islet cell transplantation to treat people with diabetes.

Led by Yale Professor Hugh S. Taylor, M.D., the researchers bathed endometrial stem cells in cultures containing special nutrients and growth factors. Responding to these substances, the endometrial stem cells adopted the characteristics of beta cells in the pancreas that produce insulin. Over the course of a three-week incubation process, the endometrial stem cells took on the shape of beta cells and began to make proteins typically made by beta cells. Some of these cells also produced insulin.

After a meal, the body breaks food down into components like the sugar glucose, which then circulates in the blood. In response, beta cells release insulin, which allows the body's cells to take in the circulating glucose. In this study, Taylor and his team exposed the mature stem cells to glucose and found that, like typical beta cells, the cultured cells responded by producing insulin. The team then injected diabetic mice with the mature, insulin-making stem cells. The mice had few working beta cells and very high levels of blood glucose.

Mice that did not receive the stem cell therapy continued having high blood sugar levels, developed cataracts and were lethargic. In contrast, mice that received the cell therapy were active and did not develop cataracts, but the animals' blood sugar levels remained higher than normal.

Taylor said that the next step in the research will be to verify how long this treatment remains effective. "We will also investigate how changing the nutrient bath or increasing the dose of injected cells could make this treatment more effective," he said. "Endometrial stem cells might prove most useful for Type 1 diabetes, in which the immune system destroys the body's own insulin-producing cells. As a result, insulin is not available to control blood glucose levels."

Other Yale authors on the study included Xavier Santamaria, Elfi E. Massasa, Yuzhe Feng, and Erin Wolff.

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Fail-safe system may lead to cures for inherited disorders

Islamabad, Sep 19 (Newswire): Scientists at the University of California, San Diego School of Medicine have uncovered a previously unknown fail-safe (compensatory) pathway that potentially protects the brain and other organs from genetic and environmental threats.

The discovery could provide new ways to diminish the negative consequences of genetic mutations and environmental toxins that cause neurological diseases and other maladies.

Messenger ribonucleic acid (mRNA) is an essential molecule that "reads" genetic information contained within the human genome, and based on this information, generates proteins essential for life. A key inherent feature of mRNA is its "stop signal," which tells cellular machinery to stop reading the mRNA because it has produced a full-length protein. Importantly, in some aberrant mRNAs, the stop signal is displayed too early, resulting in the production of a shorter-than-normal protein. Some of these short proteins can be highly toxic to cells. To avoid their production, cells use a quality control pathway called nonsense-mediated mRNA decay or NMD, which rapidly degrades "bad" mRNAs with early stop signals.

In the research, Miles Wilkinson, PhD, professor of reproductive medicine and a member of the UCSD Institute for Genomic Medicine, and colleagues, revealed that NMD is important for the normal development of the brain and the nervous system. Jozef Gecz, PhD, professor of pediatrics at the University of Adelaide, showed that when NMD doesn't work correctly, neurological conditions arise, ranging from mental retardation and attention-deficit disorder to schizophrenia and autism. These conditions are likely due to the production and accumulation of short proteins in the brain.

Like all components of the body, the NMD pathway is vulnerable to insults, such as environmental toxins or gene mutations. "If such events prevent the NMD pathway from working, there will be an accumulation of short proteins, some of which are likely toxic, resulting in bad consequences to the individual," Wilkinson said.

In their present work, Wilkinson and colleagues report the discovery that human cells have evolved a way to overcome attacks on the NMD pathway. If any molecule of the pathway is injured, the cell sends reinforcement molecules to compensate for the loss.

"These reinforcements are not sent out from all cells of our body but only selectively in certain cells; in some cases they appear to be sent from cells that need reinforcements the most," Wilkinson said.

"This is an important feature of this compensatory ("buffering") response that could potentially be relevant for clinical application," Wilkinson said. "To appreciate this, one first needs to realize that a very large proportion of people with genetic diseases -- one-third, in fact -- have a faulty gene with a mutation that leads to an early stop signal. As a consequence, most of these genes will give rise to an mRNA that is degraded by NMD and hence the encoded protein is never made. A key point is that a proportion of these mutant proteins -- although shorter than normal -- is actually still functional. So, if clinicians could inhibit NMD, this would potentially ameliorate the symptoms of some of these diseases because this treatment would increase the production of these short, but still functional, proteins."

"Unfortunately, a global NMD blockade would also lead to the production of lots of other short proteins, some of which would be toxic," Wilkinson noted. As a result, "in the past, there has been little interest in 'NMD-inhibition therapy.'" The new discovery makes NMD-inhibition therapy much more attractive because the tissue-specific compensatory response has the potential to greatly dampen the side effects.

"By choosing a branch of the NMD pathway that is subject to compensation only in the appropriate tissues, a highly selective effect can potentially be achieved" said Wilkinson.

"For example, there is a need to come up with better treatments for cystic fibrosis -- a heritable chronic lung disease -- that is currently being treated in some patients with drugs that act by blocking recognition of the premature stop signal in the mutant CFTR gene," he said.

"There has been some success with this approach, but there are concerns with side effects." The finding that NMD is buffered by a tissue-specific regulatory system means that one could design a different type of drug -- a tissue-specific NMD-inhibition drug -- that increases the level of the CFTR protein primarily in its main cellular site of action: the lung. "This could potentially increase the efficacy and drastically reduce the side effects of NMD-inhibition drugs" says Wilkinson.

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Team discovers treatable mechanism responsible for often deadly response to flu

Islamabad, Sep 19 (Newswire): Researchers at The Scripps Research Institute have found a novel mechanism by which certain viruses such as influenza trigger a type of immune reaction that can severely sicken or kill those infected.

This severe immune reaction -- called a "cytokine storm" -- floods the tiny air sacs of the lungs with fluid and infection-fighting cells, blocking off airways and damaging body tissues and organs. Cytokine storms are believed to have played a major role in the staggering mortality of the 1918-1919 worldwide influenza pandemic, as well as in the more recent swine flu and bird flu outbreaks.

In a new study published in the journal Cell, a team of Scripps Research scientists have pinpointed the cells that orchestrate cytokine storms, opening up entirely new possibilities for treatment of the condition.

"In the new research, we show directly for the first time that the damaging effects of cytokine storm are distinct from the impact of virus replication and pathological changes in infected cells," said Scripps Research Professor Hugh Rosen, MD, PhD, who led the study with Scripps Research Professor Michael B.A. Oldstone, MD. "The findings provide a new paradigm for understanding influenza and could point the way to new therapies."
"This study has greatly increased our understanding of the biological basis of cytokine storm, opening the door to development of new treatments for this potentially fatal immune reaction," said James M. Anderson, MD, PhD, director of the National Institutes of Health (NIH) Division of Program Coordination, Planning, and Strategic Initiatives, which provided funds for the work.

"This research is an excellent example of scientific discovery facilitated by the NIH Common Fund's Molecular Libraries and Imaging program and of the potential that this discovery provides for targeted new therapies."

Influenza and many other viruses destroy cells, especially the cells that line the alveoli (tiny air sacs) that exchange gases in the lung. In response, the body generates cytokines (small cell-signaling protein molecules) and brings in a variety of immune cells in an attempt to limit infection. Normally, the production of cytokines is kept in check by the body, but in some cases cytokine production goes into overdrive and results in a dangerous cytokine storm.

Using advanced chemical and genetic approaches that allow tracking and modulation of receptor function in real time, the Scripps Research team set out to determine the role of a receptor S1P1 (molecule on the surface of a cell that binds to molecules, triggering a certain biological effect) for a specific molecule known as Sphingosine-1-phosphate (S1P). S1P1 has been a topic of investigation in Rosen's lab, in part due to its connection to autoimmune disease.
Unexpectedly, the team found that manipulating the S1P1 receptors in the endothelial cells -- the thin layer of cells lining the interior surface of blood vessels -- in the lung affected cytokine release. Previously, scientists had assumed that cytokine release occurred through virus-infected cells or other cells lining the lungs.

Next, the scientists wanted to see if they could alter the course of cytokine storm in mice infected with the human pandemic influenza strain that resulted in a severe flu season in 2009 (H1N1 2009). Using a molecule that bound to the S1P1 receptor, the team was able to "downregulate" the immune reaction, allowing enough immune response to fight the virus, while at the same time diminishing or even eliminating the cytokine storm and improving survival rate from infection.

"It had been thought for a long time that all injury from influenza was due to the virus itself, consequently, and rationally, the focus was on developing antiviral drugs," said Oldstone. "The surprise in our findings was that by modulating the S1P1 receptors, we could protect the infected host, a target not subject to the rapid mutational escape of the virus, and therefore less subject to resistance."

A number of companies including Novartis, Actelion, and Receptos have S1P1 modulators in clinical trials. The Receptos compounds were discovered by the Rosen and Roberts laboratories in the Scripps Research Institute Molecular Screening Center, supported by the NIH Common Fund.

"Now that we know where cytokines come from and have isolated the specific receptor-based mechanism, it is likely that a single oral dose of a compound can be developed that will provide protection from cytokine storm early in infection," said Rosen, who added that previous studies from his lab suggested that such a drug could be used in conjunction with Tamiflu, a common antiviral medication used to treat influenza.

Oldstone noted that future research on the S1P1 receptor could help identify which individuals are most susceptible to cytokine storms and would be most likely to benefit from a drug targeting this mechanism.

The joint first authors of the study, "Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection," were Scripps Research postdoctoral fellows John Teijaro and Kevin Walsh. Additional authors included Stuart Cahalan, Daniel M. Fremgen, Edward Roberts, Fiona L. Scott, Esther Martinborough, and Robert J. Peach.

The study was supported by grants from the United States Public Health Service and the National Institute of Allergy and Infectious Diseases, part of the NIH, and the NIH Common Fund.

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