Organs grown inside animals for the first time

Lab mouse

Researchers have had success growing organs in controlled lab environments, but repeating that feat inside a complex, messy animal body? That’s more than a little tricky. However, researchers at the University of Edinburgh have managed that daunting feat for the first time. They’ve grown thymus glands inside lab mice by “reprogramming” the genes in tissue-regenerating cells and partnering those with support cells. The team didn’t have to use scaffolds or other “cheats” to trigger the growth; it just injected the cells and waited. There weren’t even any obvious limitations. The organs were full size (unlike the baby-like results from some experiments), and they were just as efficient at producing virus-fighting T-cells as the real deal.

The catch, as you might have guessed, is the scale. Mice aren’t nearly as challenging to work on as humans, and the thymus is one of the simplest organs in any animal. It wouldn’t be nearly as easy to give you a new heart or lung. If the University keeps making progress, though, it could shake up the transplant process. Patients wouldn’t have to wait for donors whose tissues are good matches, and people who’ve lost much of their immune system (such as bone marrow transplant recipients) could rebuild faster. You won’t get on-demand organs any time soon, but the concept isn’t as far-fetched as it once was.

 

Source:  w.engadget.com

Aged brains and muscles in mice made younger


 More progress with GDF 11, anti-aging protein:

Functioning of aged brains and muscles in mice made younger:

Functioning of aged brains and muscles in mice made younger:

Harvard Stem Cell Institute (HSCI) researchers have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice.

 

Professors Amy Wagers and Lee Rubin, of Harvard’s Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice — they could detect smell as younger mice do.

Rubin and Wagers each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years. Postdoctoral fellow Lida Katsimpardi is the lead author on the Rubin group’s paper, and postdocs Manisha Sinha and Young Jang are the lead authors on the paper from the Wagers group.

Both studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, of Brigham and Women’s Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart.

Doug Melton, co-chair of HSCRB and co-director of HSCI, reacted to the two papers by saying that he couldn’t “recall a more exciting finding to come from stem cell science and clever experiments. This should give us all hope for a healthier future. We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer: the higher levels of the protein GDF11 we have when young. There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function,” he said.

Melton, Harvard’s Xander University Professor continued, saying that the ongoing collaboration between Wagers, a stem cell biologist whose focus has been on muscle, Rubin, whose focus is on neurodegenerative diseases and using patient generated stem cells as targets for drug discover, and Lee, a practicing cardiologist and researcher, “is a perfect example of the power of the Harvard Stem Cell Institute as an engine of truly collaborative efforts and discovery, bringing together people with big, unique ideas and expertise in different biological areas.”

As Melton noted, GDF11 is naturally found in much higher concentration in young mice than in older mice, and raising its levels in the older mice has improved the function of every organ system thus far studied.

Wagers first began using the parabiotic system in mice 14 years ago as a post doctoral fellow at Stanford University, when she and colleagues Thomas Rando, of Stanford, Irina Conboy, of UC Berkley, and Irving Weissman, of Stanford, observed that the blood of young mice circulating in old mice seemed to have some rejuvenating effects on muscle repair after injury.

Last year she and Richard Lee published a paper in which they reported that when exposed to the blood of young mice, the enlarged, weakened hearts of older mice returned to a more youthful size, and their function improved. And then working with a Colorado firm, the pair reported that GDF11 was the factor in the blood apparently responsible for the rejuvenating effect. That finding has raised hopes that GDF11 may prove, in some form, to be a possible treatment for diastolic heart failure, a fatal condition in the elderly that now is irreversible, and fatal.

“From the previous work it could have seemed that GD11 was heart specific,” said Wagers, “but this shows that it is active in multiple organs and cell types… Prior studies of skeletal muscle and the parabiotic effect really focused on regenerative biology. Muscle was damaged and assayed on how well it could recover,” Wagers explained.

She continued: “The additional piece is that while prior studies of young blood factors have shown that we achieve restoration of muscle stem cell function and they repair the muscle better, in this study, we also saw repair of DNA damage associated with aging, and we got it in association with recovery of function, and we saw improvements in unmanipulated muscle. Based on other studies, we think that the accumulation DNA damage in muscle stem cells might be reflect an inability of the cells to properly differentiate to make mature muscle cells, which is needed for adequate muscle repair.

Wagers noted that there is still a great deal to be learned about the mechanics of aging in muscle, and its repair. “I don’t think we fully understand how this happening or why. We might say that the damage is modification to the genetic material; the genome does have breaks in it. But whether it’s damaging, or a necessary part of repair, we don’t know yet.”

Rubin, whose primary research focus is on developing treatment for neurodegenerative diseases, particularly in children, said that that when his group began its GDF11 experiments, “we knew that in the old mouse things were bad in the brain, there is a reduced amount of neurogenesis (the development of neurons), and it’s well known that cognition goes down. It wasn’t obvious to me that those things that can be repaired in peripheral tissue could be fixed in the brain.”

Rubin said that post doctoral fellow Lida Katsimpardi, the lead author on his group’s paper, was taught the parabiotic experimental technique by Wagers, but conducted the Rubin group’s experiments independently of the Wagers group, and “she saw an increase in neural stem cells, and saw increased development of blood vessels in the brain.” Rubin said that 3D reconstruction of the brain, and magnetic resonance imaging (MRI) of the mouse brain showed “more new blood vessels and more blood flow,” both of which are normally associated with younger, healthier brain tissue.” Younger mice, Rubin said, “have a keen sense of olfactory discrimination,” they can sense fine differences in odor. “When we tested the young mice, they avoided the smell of mint; the old mice didn’t. But the old mice exposed to the blood of the young mice, and those treated with GDF11 did.

“We think an effect of GDF 11 is the improved vascularity and blood flow, associated with increased neurogenesis,” Rubin said. “This should have other more widespread effect on other areas of the brain. We do think that, at least in principal, there will be a way to reverse some of the decline of aging with a single protein. It could be that a molecule like GDF 11, or GDF 11 itself, could” reverse the damage of aging.

“It isn’t out of question that GDF11,” or a drug developed from it, “might be worthwhile in Alzheimer’s Disease,” Rubin said. “You might be able to separate out the issues of treating the plaque and tangles associated with the disease, and the decline in cognition, and perhaps improve cognition.” Wagers said that the two research groups are in discussions with a venture capital group to obtain funding to “be able to do the additional pre-clinical work” necessary before moving GDF 11 into human trials.

“I would wager that the results of this work, together with the other work, will translate into a clinical trial and a treatment,” said the stem cell biologist. “but of course that’s just a wager.”

“We think an effect of GDF 11 is the improved vascularity and blood flow, which is associated with increased neurogenesis,” Rubin said. “However, the increased blood flow should have more widespread effects on brain function. We do think that, at least in principle, there will be a way to reverse some of the cognitive decline that takes place during aging, perhaps even with a single protein. It could be that a molecule like GDF 11, or GDF 11 itself, could” reverse the damage of aging.

“It isn’t out of question that GDF11,” or a drug developed from it, “might be capable of slowing some of the cognitive defects associated with Alzheimer’s Disease, a disorder whose main risk factor is aging itself,” Rubin said. It is even possible that this could occur without directly changing the “plaque and tangle burden” that are the pathological hallmarks of Alzheimer’s. Thus, a future treatment for this disease might be a combination of a therapeutic that reduces plaques and tangles, such as an antibody directed against the β-amyloid peptide, with a potential cognition enhancer like GDF-11.

 

Source:    sciencedaily.com

Stomach biological clock

Gut clock regulates when we’re hungry:

Gut clock regulates when we're hungry

Gut clock regulates when we’re hungry

Certain nerves in the stomach act as a kind of biological clock, which may help dampen appetite at night and allow heartier eating during the day, researchers have found.

The results, published today in The Journal of Neuroscience, may help shed some light on why shift workers are at high risk of conditions like obesity and diabetes, they say.

Stephen Kentish and colleagues from the University of Adelaide’s Nerve-Gut Research Laboratory studied a particular set of nerves in the muscular layers around the stomachs of laboratory mice.

A major role of these nerves is to help animals know how full they are.

“They send signals back from the stomach to provide feelings of fullness based on the distension of the stomach,” says Kentish.

The researchers wanted to explore how the responses of these nerves varied in the course of a 24-hour period.

To do this, they measured nerve activity when mouse stomach walls were stretched at three-hourly intervals between 6 am and 3 am the following day.

They found that the nerves were least sensitive to the stomach’s stretching at times when the mice were normally awake.

This seems logical, they say, as reduced sensitivity would allow the animals to fill their stomachs at times when they would need more energy.

On the other hand, during times when the mice would normally be sleeping, the nerves in the stomach became much more sensitive. This meant that the brain received a signal of fullness more quickly, shutting down the desire to eat.

“This variation repeats every 24 hours in a circadian manner, with the nerves acting as a clock to coordinate food intake with energy requirements,” Kentish says.

Following on from this work, the researchers also found that these nerve cells expressed a set of “circadian clock” genes that are also expressed in the brain region that regulates the wider circadian rhythm of the body.

In other words, the researchers say, these nerve cells appear to form a kind of neural clock in the stomach, regulating the amount of food needed to elicit fullness during the day and night.

Anti-CD47 eliminates all cancer cells

One Drug to Shrink All Tumors:

 anti-CD47 in addition to chemotherapy

anti-CD47 in addition to chemotherapy

A single drug can shrink or cure human breast, ovary, colon, bladder, brain, liver, and prostate tumors that have been transplanted into mice, researchers have found. The treatment, an antibody that blocks a “do not eat” signal normally displayed on tumor cells, coaxes the immune system to destroy the cancer cells. A decade ago, biologist Irving Weissman of the Stanford University School of Medicine in Palo Alto, California, discovered that leukemia cells produce higher levels of a protein called CD47 than do healthy cells. CD47, he and other scientists found, is also displayed on healthy blood cells; it’s a marker that blocks the immune system from destroying them as they circulate. Cancers take advantage of this flag to trick the immune system into ignoring them. In the past few years, Weissman’s lab showed that blocking CD47 with an antibody cured some cases of lymphomas and leukemias in mice by stimulating the immune system to recognize the cancer cells as invaders. Now, he and colleagues have shown that the CD47-blocking antibody may have a far wider impact than just blood cancers. “What we’ve shown is that CD47 isn’t just important on leukemias and lymphomas,” says Weissman. “It’s on every single human primary tumor that we tested.” Moreover, Weissman’s lab found that cancer cells always had higher levels of CD47 than did healthy cells. How much CD47 a tumor made could predict the survival odds of a patient. To determine whether blocking CD47 was beneficial, the scientists exposed tumor cells to macrophages, a type of immune cell, and anti-CD47 molecules in petri dishes. Without the drug, the macrophages ignored the cancerous cells. But when the CD47 was present, the macrophages engulfed and destroyed cancer cells from all tumor types. Next, the team transplanted human tumors into the feet of mice, where tumors can be easily monitored. When they treated the rodents with anti-CD47, the tumors shrank and did not spread to the rest of the body. In mice given human bladder cancer tumors, for example, 10 of 10 untreated mice had cancer that spread to their lymph nodes. Only one of 10 mice treated with anti-CD47 had a lymph node with signs of cancer. Moreover, the implanted tumor often got smaller after treatment — colon cancers transplanted into the mice shrank to less than one-third of their original size, on average. And in five mice with breast cancer tumors, anti-CD47 eliminated all signs of the cancer cells, and the animals remained cancer-free 4 months after the treatment stopped. “We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis,” says Weissman. Although macrophages also attacked blood cells expressing CD47 when mice were given the antibody, the researchers found that the decrease in blood cells was short-lived; the animals turned up production of new blood cells to replace those they lost from the treatment, the team reports online today in the Proceedings of the National Academy of Sciences. Cancer researcher Tyler Jacks of the Massachusetts Institute of Technology in Cambridge says that although the new study is promising, more research is needed to see whether the results hold true in humans. “The microenvironment of a real tumor is quite a bit more complicated than the microenvironment of a transplanted tumor,” he notes, “and it’s possible that a real tumor has additional immune suppressing effects.” Another important question, Jacks says, is how CD47 antibodies would complement existing treatments. “In what ways might they work together and in what ways might they be antagonistic?” Using anti-CD47 in addition to chemotherapy, for example, could be counterproductive if the stress from chemotherapy causes normal cells to produce more CD47 than usual. Weissman’s team has received a $20 million grant from the California Institute for Regenerative Medicine to move the findings from mouse studies to human safety tests. “We have enough data already,” says Weissman, “that I can say I’m confident that this will move to phase I human trials.”