Mouse model of human immune system inadequate for stem cell … – Medical Xpress

August 22, 2017 Credit: Martha Sexton/public domain

A type of mouse widely used to assess how the human immune system responds to transplanted stem cells does not reflect what is likely to occur in patients, according to a study by researchers at the Stanford University School of Medicine. The researchers urge further optimization of this animal model before making decisions about whether and when to begin wide-scale stem cell transplants in humans.

Known as "humanized" mice, the animals have been engineered to have a human, rather than a murine, immune system. Researchers have relied upon the animals for decades to study, among other things, the immune response to the transplantation of pancreatic islet cells for diabetes and skin grafts for burn victims.

However, the Stanford researchers found that, unlike what would occur in a human patient, the humanized mice are unable to robustly reject the transplantation of genetically mismatched human stem cells. As a result, they can't be used to study the immunosuppressive drugs that patients will likely require after transplant. The researchers conclude that the humanized mouse model is not suitable for studying the human immune response to transplanted stem cells or cells derived from them.

"In an ideal situation, these humanized mice would reject foreign stem cells just as a human patient would," said Joseph Wu, MD, PhD, director of Stanford's Cardiovascular Institute and professor of cardiovascular medicine and of radiology. "We could then test a variety of immunosuppressive drugs to learn which might work best in patients, or to screen for new drugs that could inhibit this rejection. We can't do that with these animals."

Wu shares senior authorship of the research, which will be published Aug. 22 in Cell Reports, with Dale Greiner, PhD, professor in the Program in Molecular Medicine at the University of Massachusetts Medical School, and Leonard Shultz, PhD, professor at the Jackson Laboratory. Former postdoctoral scholars Nigel Kooreman, MD, and Patricia de Almeida, PhD, and graduate student Jonathan Stack, DVM, share lead authorship of the study.

"Although these mice are fully functional in their immune response to HIV infection or after transplantation of other tissues, they are unable to completely reject the stem cells," said Kooreman. "Understanding why this is, and whether we can overcome this deficiency, is a critical step in advancing stem cell therapies in humans."

"Humanized mice are critical preclinical models in many biomedical fields helping to bring basic science into the clinic, but as this work shows, it is critical to frame the question properly," said Greiner. "Multiple laboratories remain committed to advancing our understanding and enhancing the function of engrafted human immune systems."

Greiner and Shultz helped to pioneer the use of humanized mice in the 1990s to model human diseases and they provided the mice used in the study.

Understanding stem cell transplants

The researchers were studying pluripotent stem cells, which can become any tissue in the body. They tested the animals' immune response to human embryonic stem cells, which are naturally pluripotent, and to induced pluripotent stem cells. Although iPS cells can be made from a patient's own tissues, future clinical applications will likely rely on pre-screened, FDA-approved banks of stem cell-derived products developed for specific clinical situations, such as heart muscle cells to repair tissue damaged by a heart attack, or endothelial cells to stimulate new blood vessel growth. Unlike patient-specific iPS cells, these cells would be reliable and immediately available for clinical use. But because they won't genetically match each patient, it's likely that they would be rejected without giving the recipients immunosuppressive drugs.

Humanized mice were first developed in the 1980s. Researchers genetically engineered the mice to be unable to develop their own immune system. They then used human immune and bone marrow precursor cells to reconstitute the animals' immune system. Over the years subsequent studies have shown that the human immune cells survive better when fragments of the human thymus and liver are also implanted into the animals.

Kooreman and his colleagues found that two varieties of humanized mice were unable to completely reject unrelated human embryonic stem cells or iPS cells, despite the fact that some human immune cells homed to and were active in the transplanted stem cell grafts. In some cases, the cells not only thrived, but grew rapidly to form cancers called teratomas. In contrast, mice with unaltered immune systems quickly dispatched both forms of human pluripotent stem cells.

The researchers obtained similar results when they transplanted endothelial cells derived from the pluripotent stem cells.

A new mouse model

To understand more about what was happening, Kooreman and his colleagues created a new mouse model similar to the humanized mice. Instead of reconstituting the animals' nonexistent immune systems with human cells, however, they used immune and bone marrow cells from a different strain of mice. They then performed the same set of experiments again.

Unlike the humanized mice, these new mice robustly rejected human pluripotent stem cells as well as mouse stem cells from a genetically mismatched strain of mice. In other words, their newly acquired immune systems appeared to be in much better working order.

Although more research needs to be done to identify the cause of the discrepancy between the two types of animals, the researchers speculate it may have something to do with the complexity of the immune system and the need to further optimize the humanized mouse model to perhaps include other types of cells or signaling molecules. In the meantime, they are warning other researchers of potential pitfalls in using this model to screen for immunosuppressive drugs that could be effective after human stem cell transplants.

"Many in the fields of pluripotent stem cell research and regenerative medicine are pushing the use of the humanized mice to study the human immune response," said Kooreman. "But if we start to make claims using this model, assuming that these cells won't be rejected by patients, it could be worrisome. Our work clearly shows that, although there is some human immune cell activity, these animals don't fully reconstitute the human immune system."

The researchers are hopeful that recent advances may overcome some of the current model's limitations.

"The immune system is highly complex and there still remains much we need to learn," said Shultz. "Each roadblock we identify will only serve as a landmark as we navigate the future. Already, we've seen recent improvements in humanized mouse models that foster enhancement of human immune function."

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These Six Startups From Y Combinator’s Demo Day 1 Are Ready to Transform Our World – Futurism

A Room Full of Ideas

Great ideas,given the proper support, can change the world. Thats one of the reasons seed funding provider Y Combinator helps innovative startups acquire the financial resources they need to put their ideas into action. Since 2005, theyvefunded about 1,500 startups, and two times every year, they present some of those companies to investors via a three-day event known as Demo Day.

For the firstdayof Y Combinators Summer 2017Demo Day event, the startup accelerator presented 50 companies that all have remarkable potential. While you can check them all out on TechCrunch,the following six startups earn our vote as the most futuristic of them all.

Founded by a group of medical doctors and biomedical research scientists, Forever Labs combines two of the most advanced fields in modern medicine: stem cells and anti-aging research.

The startups current staff of 20 doctors wants to take a different approach to fighting age-related diseases by cryogenically freezing stem cells that can be used to combat such diseases when a person is older.

According to the company, stem cell storage couldgrow into a $56 billion market, and the figure doesnt seem outlandish considering the rapid pace at which anti-aging studies and stem cell research have been advancing lately.

Sunuisanother startup with a health-focus, only instead of combatting aging, their goal is to help those who suffer from visual impairments.

The company wants to help blind people navigate streets without having to depend on a cane or a guide dog. To do this, the startup has developed a sonar bracelet or smartwatch that vibrates to alert visually impaired people of nearby objects.

Sunu band combines sonar or echolocation with gentle precise vibrations to inform the user about objects or obstacles within their environment, according to the companys website. After beta-testing the device for six months, Sunu says it managed to reduce the chances that their vision-impaired users got into accidents by 90 percent.

Not all of the startups featured at Demo Day were focused on health and medicine, though this next one combines materials engineering withtextile science.

Kestrel Materialshas designed a fabric thats a step-up from breathable and waterproof types, and their goal is simple enough: reduce the need for bulky layers. To do this, the startup has created an adaptive material that reacts to cold and warmth.

When exposed to cold surroundings, the fabric flexes and creates air pockets that trap heat and keep people warm. During warmer weather, the air pockets collapse and prevent heat from being trapped in the clothing. Since the material uses common fibers, such as nylon and polyester, the applications for such an adaptive fabric are as plentiful as the styles of clothes people wear.

Few things scream future quite likeflying cars, and the next two startups are looking to extend their reach into that space.

First is Skyways, a startup based in Austin, Texas, thats building vertical take-off and landing (VTOL) delivery drones. While they arent exactly the kinds of flying cars you may expect to one day operate yourself, delivery drones like Skyways are positioned to be just as big a part of that flying future.

Skyways drones are capable of hauling loads of up to roughly 20 kilograms (45 pounds), and the company wants to use them to provide the military with a transportation service that doesnt put peoples lives at risk.

Now, this startup takes flying cars to the next level.

Pykawants to make autonomous single-person aircraft a part of our reality, and theyve already built a 181 kilogram (400 pound) one that can fly itself.

While theyre ironing out the tons of regulations requiredfor commercial use of this transportation system, Pykas taken on a side gig in New Zealand as an autonomous crop duster.

Speaking of autonomous tech and farming, thisstartup wants to employ robots as vegetable farmers.

Modular Science, as their name suggests, is into building modular machines for agriculture, and one of their products is a specialized plant-farming robot. The companys goal is to automate 99 percent of the vegetable farming process in the next six months.

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UTMB lung experiment flies into space – Austin American-Statesman

GALVESTON

Two hundred and fifty miles above the Earths surface, scientists have begun testing the limits of human biology. In the sterile environment of the International Space Station, cells are being prodded to grow and multiply.

The goal is to grow human body parts, without the rest of the human attached.

The experiment sounds like a plot for a science fiction movie. But its actually one of the newest experiments to be conducted on the space station. The experiment, launched this month, was designed by a University of Texas Medical Branch team.

Researchers aim to study how stem cells develop in a zero-gravity environment. The results could lead to new possibilities to help with long-distance space flight and terrestrial medical treatments, said Joan Nichols, a professor of internal medicine, and microbiology and immunology and the associate director of the Galveston National Laboratory.

The experiment was developed over the past five years. It was launched as part of the payload aboard a SpaceX Dragon Cargo ship. The ship carried 6,400 pounds of equipment, experiments and supplies, including a freezer with Blue Bell ice cream cups.

Nichols and her team spent the week before the launch in Florida, preparing the experiment. It went off without a hitch, and the capsule arrived at the space station.

Everything went smoothly, Nichols said.

Nichols has studied lungs and their development on a cellular level for 15 years. The lab, which is focused on studying how lungs grow and heal, is no stranger to pushing scientific boundaries. In 2015, researchers from the lab successfully transplanted a bioengineered lung into a living pig.

Over time, the limits of growing cells on Earth has become apparent, she said. Studies have already shown that stems cells grow and multiply better in a zero-gravity environment than they do down below, she said.

The results could be used to develop treatments for problems astronauts develop on a long space flight, such as lung disease or traumatic injury.

Weve discovered what our limits are for doing large tissue constructs is the fact that the stem cells dont proliferate very well, Nichols said. Stem cells stay stemmy in space, she said, they dont mature and become other types of cells as fast.

If the cells stay stemmier and produce better, thats a huge thing that we cant do here on Earth, Nichols said. It will answer some questions about these cells.

Nichols and her team will be in communication with NASA and the astronauts on the space station over the six-week course of the experiment. While tests are done in space, her team will replicate the experiment at the Galveston National Laboratory, to provide a control sample to compare the results.

Being able to expand the UTMB program to the stars has been a dream come true, Nichols said.

Being at Kennedy and Cape Canaveral, and working at the lab there, at the building where all the Apollo missions happened I grew up with that, Nichols said. We worked hard and there were really long days, but it really was the most amazing experience ever.

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Stem Cell Treatments for Lung Diseases Advance – Healthline – Healthline

Two new studies look at using stem cells from lungs to combat fibrosis and other lung-related diseases.

Stem cell treatments for lung diseases may have taken a big step forward according to a pair of studies published earlier this month.

In one animal study, researchers did transbronchial biopsies, sending miniscule tweezers down the throats of rats in order to obtain lung cells.

The researchers were able to culture tens of millions of cells and inject them into rats that had a condition similar to idiopathic pulmonary fibrosis.

Rats that received the injected cells showed less lung inflammation and overall healthier lung cells than those that didnt receive the cells.

Both studies, published in the journals Respiratory Research and Stem Cells Translational Medicine, built upon research into stem cell therapies for heart diseases, and less successful work on lung diseases like emphysema.

Both offer new hope for fibrosis patients, whose current treatment options are medications to reduce symptoms, or a lung transplant.

The new research raises the possibility of reversing the impacts of fibrosis and similar diseases that cause lung inflammation, which gradually damages lung tissue and makes internal organs less able to transfer oxygen to the blood.

Its also the first time stem cells have been gathered and reproduced using the minimally invasive biopsy method, researchers said.

Lung stem cells are most often obtained surgically.

That requires putting the patient on a ventilator and cutting out a small piece of lung, said Dr. Jason Lobo, an assistant professor at the University of North Carolina School of Medicine, and co-author of the new papers.

Using the method employed by the researchers, Lobo told Healthline, medical professionals can tweeze out a few cells and send patients home the same day.

However, minimally invasive may be a relative term.

Its not as invasive as opening up your chest, but if youve ever had a tube stuck down your throat, you wouldnt call it noninvasive, Dr. Norman Edelman, senior scientific advisor to the American Lung Association, told Healthline.

But Edelman calls the new research exceedingly interesting.

Stem cells are hot, he said. People are doing a lot of interesting things with stem cells, and I expect eventually theyll hit on something, and maybe this it.

Edelman cautions, however, that theres been a long history of stem therapy for lung diseases, most of it not very satisfactory.

He points specifically to work using stem cells to fight emphysema. He said the therapies havent been proven to be successful, but have led to a number of clinics outside the United States providing Americans with stem cell treatments not yet approved by the U.S. Food and Drug Administration (FDA).

The American Lung Association has cautioned against these unregulated stem cell therapies.

Lots of interesting things in rats and mice dont turn out, said Edelman, who wasnt involved in the latest studies.

But he expects the University of North Carolina researchers would go through all the necessary safeguards when they start testing in humans and not offer it as something more than experimental.

Lobo said they hope to have FDA approval to begin human trials by the end of the year. Those would start within six months after the approval.

We might have to do more mouse trials, but the last time we met with the FDA, we got the feeling they werent leaning that way, Lobo said.

They would join about a dozen other clinical trials looking into the use of various types of stem cells to combat pulmonary fibrosis.

Stem cells are young enough that they can still grow up to become any number of specialized cells, potentially including mature lung tissue cells.

Other research into stem cell therapies has largely focused on mesenchymal stromal cells, which have immunosuppressive qualities but arent necessarily obtained from lungs.

Lobo and his co-authors focused on resident lung cells, which they figured would more easily graft to the lungs and survive a hypothesis backed up in a 2015 paper.

While their current research is focused on idiopathic pulmonary fibrosis, they hope the therapies, if successful, may eventually help people with related diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis. and fibro-cavernous pulmonary tuberculosis.

Asked whether a cure for lung cancer could be on the horizon, Lobo said probably not, due to the different nature of the disease.

But hopefully we will be able to extend into other diseases... any chronic lung disease, he said.

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