Supercharging stem cells to create new therapies

A new method for culturing stem cells has been developed, which sees the highly therapeutic cells grow faster and stronger. Stem cell therapy is showing promising signs for transplant patients, and the IL-17 treated stem cells should be even more effective at preventing and treating inflammation in transplant recipients -- particularly controlling rejection in transplant patients. 

The research, which was published in the international journal, Stem Cells, is expected to eventually lead to new treatments for transplant patients.
Kisha Sivanathan, a PhD student in the University of Adelaide's School of Medicine and the Renal Transplant Unit at the Royal Adelaide Hospital, says this is an exciting breakthrough in stem cell research.
"Adult mesenchymal stem cells, which can be obtained from many tissues in the body including bone marrow, are fascinating scientists around the world because of their therapeutic nature and ability to cultivate quickly. These stem cells have been used for the treatment of many inflammatory diseases but we are always looking for ways in which to increase stem cells' potency," says Ms Sivanathan, lead author on the study.
"Our research group is the first in the world to look at the interaction between mesenchymal stem cells and IL-17, a powerful protein that naturally occurs in the body during times of severe inflammation (such as during transplant rejection).
"We discovered that when cultured mesenchymal stem cells are treated with IL-17 they grow twice as fast as the untreated stem cells and are more efficient at regulating the body's immune response," she says.
Stem cell therapy is showing promising signs for transplant patients and according to Ms Sivanathan, the IL-17 treated stem cells should be even more effective at preventing and treating inflammation in transplant recipients -- particularly controlling rejection in transplant patients.
"Current drugs (immunosuppressant drugs) used to help prevent a patient rejecting a transplant suppress the whole immune system and can cause severe side effects, like cancer. However, stem cell therapy (used in conjunction with immunosuppressant drugs) helps patients 'accept' transplants while repairing damaged tissue in the body, resulting in less side effects," says Ms Sivanathan.
"We are yet to undertake clinical trials on the IL-17 treated stem cells but we anticipate that because this treatment produces more potent stem cells, they will be more effective than the untreated stem cells," she says.
 

Journal Reference:

1. Kisha Nandini Sivanathan, Darling M. Rojas-Canales, Christopher M. Hope, Ravi Krishnan, Robert P. Carroll, Stan Gronthos, Shane T. Grey, Patrick T. Coates. Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. STEM CELLS, 2015; DOI: 10.1002/stem.2075 

Courtesy: ScienceDaily
 

Live imaging reveals how wound healing influences cancer

Scientists have known for some time that inflammation is one of the ten hallmarks of cancer. Cancer has also been described as a "wound that does not heal." Now researchers have studied the 'see-through' larvae of zebrafish to reveal how wound healing leads to melanoma. 

"Our results provide direct visual evidence of a physical link between wound-associated inflammation and the development of skin cancer," says EMBO Member Paul Martin, professor at Bristol University and the University of Cardiff. "White blood cells, in particular neutrophils, that typically serve as part of the body's built-in immune system are usurped by nearby precancerous skin cells in a way that leads to the proliferation of tumour cells in our zebrafish model experimental system of human melanoma."
Scientists have known for some time that inflammation is one of the ten hallmarks of cancer. Cancer has also been described as a "wound that does not heal." However details about how physical damage to body tissues might influence the progress of cancer have remained scarce.
The researchers used genetically modified larvae of zebrafish to watch the relationship between wound-associated inflammation and melanoma as the cancer took hold in the living fish. The cellular events and changes were observed by live imaging with a special confocal laser-scanning microscope.
In further experiments, the researchers were also able to show that a specific type of signaling molecule released by neutrophils, prostaglandin E2, is part of the signal that drives the splurge of cell growth linked to the cancer in their experimental system. High levels of neutrophils were also detected in human clinical samples of melanomas that had been obtained from individuals whose cancers had open ulcers. Importantly, neutrophils were linked to increased proliferation of melanoma cells and poor survival, which suggests that these findings in fish may have considerable relevance to cancer patients.
The authors note that the findings of the study may have implications for cancer surgery. Minimally invasive surgery is beneficial to cancer patients in many situations and often the preferred treatment. However, particularly in cases where all cancerous tissue cannot be removed, the inflammatory response might influence the remaining cancer cells in the body. "Our studies to date suggest that several strategies might improve outcomes for patients including the possible use of therapeutics to dampen damage-induced inflammatory responses," adds Martin.
Further work is in progress to better understand the relationship between the inflammatory response and skin cancer in the zebrafish model system. Studies are also needed to investigate what therapeutic or other strategies might bring better interventions for patients who have adverse tissue inflammation due to planned (for example biopsy or surgery) or unplanned (e.g. ulceration) tissue damage.
 

Journal Reference:

1. N. Antonio, M. L. Bonnelykke-Behrndtz, L. C. Ward, J. Collin, I. J. Christensen, T. Steiniche, H. Schmidt, Y. Feng, P. Martin. The wound inflammatory response exacerbates growth of pre-neoplastic cells and progression to cancer. The EMBO Journal, 2015; DOI: 10.15252/embj.201490147 

Courtesy: ScienceDaily
 

Novel HIV vaccine regimen provides robust protection in non-human primates

A new study shows than an HIV-1 vaccine regimen, involving a viral vector boosted with a purified envelope protein, provided complete protection in half of the vaccinated non-human primates (NHPs) against a series of six repeated challenges with simian immunodeficiency virus (SIV), a virus similar to HIV that infects NHPs.

Based on these pre-clinical data, the HIV-1 version of this vaccine regimen is now being evaluated in an ongoing Phase 1/2a international clinical study sponsored by Crucell Holland B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson.
"We previously showed that adenovirus vector-based HIV-1 vaccine candidates offered partial protection against SIV when given alone," said lead author Dan H. Barouch, M.D., Ph.D., director of the Center for Virology and Vaccine Research at BIDMC and professor of medicine at Harvard Medical School. The paper describes two new studies in which investigators evaluated the protective efficacy of an adenovirus serotype 26 (Ad26) vectored vaccine boosted with a purified envelope protein.
The results demonstrate that viral vector priming plus protein boosting resulted in complete protection in half of the vaccinated animals. "This shows improvement over our previous results," said Barouch, who is also a steering committee member of the Ragon Institute of MGH, MIT, and Harvard. "Moreover, protection correlated with the magnitude and polyfunctionality of antibody responses. The data show the potential utility of envelope protein boosting following Ad26 priming."
"Bringing the global HIV epidemic under control requires new tools, bold strategies and collaboration among a number of stakeholders," said Hanneke Schuitemaker, one of the study authors and vice president, Viral Vaccines Discovery and Translational Medicine, Janssen. "In line with our company's commitment to address global health needs, we are committed to working with leading experts to develop a preventative HIV vaccine and our team is excited to advance this program into human clinical studies."
 

Journal Reference:

1. Dan H. Barouch, Galit Alter, Thomas Broge, Caitlyn Linde, Margaret E. Ackerman, Eric P. Brown, Erica N. Borducchi, Kaitlin M. Smith, Joseph P. Nkolola, Jinyan Liu, Jennifer Shields, Lily Parenteau, James B. Whitney, Peter Abbink, David M. Ng’ang’a, Michael S. Seaman, Christy L. Lavine, James R. Perry, Wenjun Li, Arnaud D. Colantonio, Mark G. Lewis, Bing Chen, Holger Wenschuh, Ulf Reimer, Michael Piatak, Jeffrey D. Lifson, Scott A. Handley, Herbert W. Virgin, Marguerite Koutsoukos, Clarisse Lorin, Gerald Voss, Mo Weijtens, Maria G. Pau, and Hanneke Schuitemaker. Protective efficacy of adenovirus-protein vaccines against SIV challenges in rhesus monkeys. Science, 2 July 2015 DOI: 10.1126/science.aab3886

 Courtesy: ScienceDaily

Prion trials and tribulations: Finding the right tools and experimental models

Prions are fascinating, enigmatic, and might teach us not only about rare prion diseases like Creutzfeld-Jakob disease, mad cow disease, or scrapie, but also about other more common neurodgenerative diseases. Two studies report progress with novel tools and paradigms to study prion disease. 

Prion protein, shown in red, can become infectious and cause neurodegenerative disease. Here four nerve cells in a mouse illustrate how infectious prion protein moves within cells along neurites -- wire-like connections the nerve cells use for communicating with adjacent cells.

Credit: NIAID, CC-BY

Several research groups have recently succeeded in generating infectious prions with prion protein produced by bacteria in test tubes under consistent and controlled conditions. Such synthetic prions are a critical tool to study how prions cause disease in general and to test the "protein-only" hypothesis, which states that the mutant prion protein itself can trigger the disease by co-opting other prion proteins to form aggregates that are toxic to nerve cells. Jiyan Ma, from the Van Andel Research Institute in Grand Rapids, USA, and colleagues tested whether the properties of synthetically generated prions are the same as those of natural disease-causing prions, and whether the disease caused by synthetic prions is identical to naturally occurring prion disease.
They demonstrate that similar to the classical disease-causing prions, synthetic prions are infectious in a concentration-dependent way, and are able to cause prion disease in normal mice not only by direct injection into the brain (which is the easiest but not a naturally occurring way of prion transmission) but also by other routes. The researchers also show that the synthetic prions induced pathological changes typical for classic prion disease, including the dissemination of disease-specific prion protein accumulation and the route and mechanism of invasion of nerve cells in the brain. They conclude that their results "demonstrate the similarity of synthetically generated prion to the infectious agent in TSEs [transmissible spongiform encephalopathies, another term for prion diseases] and provide strong supporting evidence for the prion hypothesis."
About 15% of human prion disease is heritable and caused by dominant mutations in the human PRP gene. The mutations are thought to predispose the resulting PRP protein proteins to adapt the disease conformation and trigger the cascade that kills nerve cells. Much of the study of inherited human prion disease in mice has focused on mixing mutant human prions--isolated from human patients or produced by transgenic mice carrying the mutant human gene--with normal mouse prions in order to establish whether the mutant human prions are infectious, i.e. whether they can change normal proteins to the disease-associated conformation (or shape).
John Collinge, from University College London, UK, and colleagues answered a crucial question regarding such studies, namely whether superimposition of pathogenic human PrP mutation into mouse PrP (which is similar but not identical) will have the same structural consequences as occur in the human brain. They focused on a specific mutation underlying an inherited form of human prion disease called Gerstmann-Sträussler-Scheinker (GSS) disease. This mutation causes an amino-acid substitution (proline-to-leucine) in the prion protein, human PrP 102L for short. In the brain of patients with GSS disease, this mutant prion (GSS-102L) co-exists with a heterogeneous mixture of normal PrP and other PrP derivatives, which it somehow manages to co-opt into forming aggregates that are toxic to the nerve cells.
To characterize the transmission capabilities of the GSS-associated prions, the researchers tested whether the ability of GSS P102L to cause prion disease in mice depended on what other types of prion proteins and derivatives were present. They examined whether GSS P102L prions could infect transgenic mice that express human mutant 102L PrP, human normal PrP, or normal mouse PrP. Injecting a pure preparation of GSS P102L prions into the brains of the three different types of mice, they found that GSS P102L prions can only infect transgenic mice expressing human 102L PrP, i.e. those carrying the identical mutant human gene. Mice expressing normal human PrP or normal mouse PrP were completely resistant to infection with GSS-102L prions.
"Collectively," the researchers say, their data "establish that GSS-102L prions which replicate with high efficiency in a host expressing human PrP 102L are unable to propagate using wild-type [normal] human PrP or wild-type mouse PrP as substrate." These results differ from the reported transmission properties of prions generated in GSS-P102L challenged mice expressing mouse PrP 101L (the equivalent mutation in the closely related but not identical mouse PrP): such prions readily infect animals expressing normal human or normal mouse PrP. Commenting on the discrepancy, the researchers suggest that the superimposition of the human on the mouse mutation might have generated experimental prion strains with different transmission characteristics from those of authentic human prion strains. Overall, they conclude that "future transgenic modeling of infectious prion diseases should focus exclusively on expression of mutant human PrP, as other approaches may generate novel experimental prion strains that are unrelated to human disease."
Better tools and better paradigms to study prion diseases should help the understanding of how these diseases spread and devastate mammalian brains, and eventually lead to efficient treatment and prevention strategies.
 

Journal References:

1. Xinhe Wang, Gillian McGovern, Yi Zhang, Fei Wang, Liang Zha, Martin Jeffrey, Jiyan Ma. Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion. PLOS Pathogens, 2015; 11 (7): e1004958 DOI: 10.1371/journal.ppat.1004958
2. Emmanuel A. Asante, Andrew Grimshaw, Michelle Smidak, Tatiana Jakubcova, Andrew Tomlinson, Asif Jeelani, Shyma Hamdan, Caroline Powell, Susan Joiner, Jacqueline M. Linehan, Sebastian Brandner, Jonathan D. F. Wadsworth, John Collinge. Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS. PLOS Pathogens, 2015; 11 (7): e1004953 DOI: 10.1371/journal.ppat.1004953 

Courtesy: ScienceDaily