The anti-inflammatory effect could lead to new therapies.
By Jennifer Chu

Until recently, the promise of stem-cell therapy has centered on stem cells' ability to morph into virtually any kind of cells. But researchers are finding that stem cells may have other healing
effects. In recent studies, scientists have observed stem cells acting as anti-inflammatory agents, reducing swelling and even scarring when administered to injured tissue.

However, while stem cells' anti-inflammatory effects have been observed in a number of disease models, it has been difficult to pinpoint exactly how stem cells have this effect. Now a group at
Tulane University, led by Darwin Prockop, director of the Center for Gene Therapy, has found that injecting human stem cells into the brains of stroke-induced mice triggers immune cells to produce chemicals that protect nerve cells, thereby reducing swelling and scarring. Prockop, now director of the Institute for Regenerative Medicine at Texas A&M Health Science Center, says that understanding the mechanism behind stem cells' anti-inflammatory effect could help researchers develop therapies for stroke and related diseases.

"In diabetes, Alzheimer's, and Parkinson's disease, there is an excessive early inflammatory response, and stem cells can sense that," says Prockop. "If you can turn that inflammation down, everything improves."

In their experiments, described in a paper published today in the Proceedings of the National Academy of Sciences, Prockop and his teaminduced a stroke in mice by blocking blood flow to their brains for 15 minutes. They then injected bone-marrow-derived human stem cells into the oxygen-deprived portion of the brains of some of the mice and observed the interactions between stem cells and the neural environment over a period of about two weeks.

Although the injected stem cells disappeared after just five days, the researchers found that they had a lasting effect on surrounding brain cells. Mice treated with stem cells experienced 60 percent less cell death compared with mice who did not receive the treatment.
Furthermore, when placed in an open environment, the treated mice behaved much like healthy mice, actively exploring the space around them, unlike their more lethargic untreated counterparts.

"It was a hit-and-run effect," says Prockop. "The human stem cells stopped some of the negative processes going on, and stopped the mouse brain from destroying itself."

To investigate further, the team analyzed genetic activity in samples of brain tissue before and after stem-cell injection. They found that 586 genes in the mouse brain were overactive in following brain injury and that 10 percent of these genes were dampened after stem-cell injection. Prockop found that many of these genes produce proteins involved in inflammation and immunity, and he hypothesizes that stem cells actually change the genetic instructions given out by brain cells in response to injury, reducing brain swelling that would otherwise occur.

To confirm the findings, the team also examined mouse brains for cytokines--proteins secreted by immune cells in response to injury. These proteins come in a variety of forms that can induce either inflammatory or anti-inflammatory effects. The researchers found that, following stem-cell injection, the affected brain area was flooded with insulin-like growth factor 1--an anti-inflammatory cytokine secreted by immune cells that protects the brain from blood-deprived injury, such as stroke. Other proteins indicating the presence of immune cells were also found in increased numbers, compared with untreated brain samples.

Identifying the various proteins that reduce inflammation could lead to new drugs that increase the production of such proteins to treat a variety of diseases, Prockop says. However, he believes that stem cells themselves may ultimately be a more effective therapeutic route. "You could find out all the proteins that are made, and give those to patients," says Prockop. "But you may get a better response with stem cells, because they have this marvelous ability to sense and adjust to their environment."

Eva Mezey, a National Institute of Health investigator who studies stem-cell interactions in the brain, agrees that stem cells may have broad applications in treating inflammation but cautions that they may not be the most effective therapy for stroke. "Almost every stroke is a little bit different, and a person may have other diseases, like diabetes," Mezey says. "There are so many other variables that it seems there isn't one drug that's efficacious in humans."

She adds that "stem cells may be a very promising new way in the treatment of a variety of diseases that are somehow related to immunity or inflammation, but they are not a therapy for stroke."

Copyright Technology Review 2008.

The treatment uses umbilical and marrow cells to help develop normal skin. Doctors say it may move his genetic disorder, recessive epidermolysis bullosa, 'off the incurable list' for other patients.

By Thomas H. Maugh II, Los Angeles Times Staff Writer
June 7, 2008

Using stem cells from umbilical cord blood and bone marrow, researchers have apparently cured a fatal genetic disease in a 2-year-old Minneapolis boy, which could open the door for other stem cell treatments.

For the first time in his life, Nate Liao is wearing normal clothes, eating food that has not been pureed, and playing with his siblings.

"Nate's quality of life is forever changed," said Dr. John Wagner of the University of Minnesota Medical School, who performed the treatment. "Maybe we can take one more disorder off the incurable list."

The team later treated Nate's 5-year-old brother, Jacob, and is preparing to treat 9-month-old Sarah Rose Mooreland of Folsom, Calif. Hopes are high for them as well.

Nate suffers from recessive epidermolysis bullosa, which affects 1 in 100,000 children. They lack a critical protein called collagen type VII that anchors the skin and lining of the gastrointestinal system to the body.

Their skin is extraordinarily fragile. Tearing and blistering occur with minimal friction, leading to painful wounds and scarring. Solid food produces erosion of the esophagus. Death usually results from malnutrition, infections or aggressive skin cancer.

The only treatment previously has been to wrap the skin in bandages.

The idea of using circulating stem cells to treat the condition was developed by Dr. Angela M. Christiano of Columbia University Medical Center. This is the first time that cells from bone marrow and cord blood have been used to treat a condition that does not involve blood.

Seven months after treatment, Nate's body is making collagen type VII, Wagner said at a news conference Tuesday. His face has plumped up and he has fewer blisters. "I have watched Nate improve every day," said his mother, Theresa.

The results will be published in a future issue of the New England Journal of Medicine.

04 March 2008

Human embryonic stem cells produce a protein which shows some anti-cancer properties in the lab, according to a new study.

The potential for stem-cell therapies to cause cancer is a major concern, but now researchers at Northwestern University in Chicago, US, say a protein produced by human embryonic stem cells (hESCs) can inhibit the growth and spread of breast cancer and malignant melanoma, the deadliest form of skin cancer.

They suspect that the protein, called Lefty, has similar effects on other tumour types, including those of the prostate.

The similarities between stem cells – primitive cells which can differentiate into the body’s different tissue types – and tumour cells have intrigued researchers. Both are self-renewing and have the capacity to give rise to different cells types.

The team at Northwestern previously showed that hESCs – the most versatile type of stem cell – produce chemicals that caused melanoma cells to revert to normal skin cells.

They also demonstrated that melanoma and breast cancers produce a protein called Nodal that helps tumour cells spread, and that this protein also facilitates embryonic stem cell's ability to turn into different cell types.

Tumours controlled
In the latest study they set out to find the substances produced by hESCs that have anti-cancer properties – perhaps, they believed, by blocking Nodal.

Lefty, the protein they identified, blocks the production of Nodal and therefore controls embryonic cell differentiation and development.

Mary Hendrix, who led the study, showed that unlike hESCs, however, tumour cells do not express Lefty. This allows them to produce Nodal in an unregulated manner – and to keep growing and spreading.

But when the researchers exposed aggressive tumour cells to the chemical environment of hESCs, which contained Lefty, levels of Nodal production fell sharply, and the tumour cells became less invasive and even started to die.

Hendrix told New Scientist she was optimistic that anti-cancer treatments based on stem cell proteins such as Lefty would emerge. "We now hope to interest pharmaceutical or biotech companies into developing partnerships to develop new treatments. We really believe that we are onto something important."

She adds that other stem cells proteins with anti-cancer effects probably remained to be discovered.

Embryonic source
Significantly, Hendrix notes that Lefty is secreted only by hESCs, and not by any other stem-cell type tested – including stem cells isolated from amniotic fluid, cord blood or adult bone marrow – or placental cells.

"After all the controversy about using embryonic stem cells, this shows how potentially important such research is," she says.

Lyle Armstrong at Newcastle University in the UK says the latest study is "convincing" in showing the prominent role the Nodal protein plays in aggressive cancers. He says more research is needed to see if other types of cancer respond equally well when the pathway is switched off.

"The paper clearly shows that factors which probably promote human embryonic stem cell proliferation are important in controlling tumour cell behaviour," notes Stephen Minger, director of the stem cell biology laboratory at Kings College London. "This provides a novel target for developing tumour cell therapies."

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073__pnas.0800467105)

Cancer - Learn more about one of the world’s biggest killers in our comprehensive special report.

Stem Cells - Learn more about the promise and the controversy in our cutting edge special report .

Published: Feb. 12, 2008 at 12:56 PM

DALLAS, Feb. 12 (UPI) -- Balloons and signs greeted 2-year-old Caden Ledbetter's return from the hospital following a rare stem cell cancer treatment, a Dallas newspaper said.

Doctors with the Medical City Dallas Hospital released Caden Monday following a two-month treatment for neuroblastoma, a cancer of the nervous system.

Doctors used chemotherapy to treat the cancer and then used stem cells from Caden's umbilical cord to rebuild his immune system, The Dallas Morning News said Tuesday. The treatment is so rare doctors are unsure whether the cancer will stay in remission or develop again from the umbilical cells.

"We're not talking about his being cured of his neuroblastoma right now," said Dr. Joel Weinthal who treated the boy. "It's certainly a very positive thing that he gets to go home from the hospital but he has a long road ahead of him."

The Ledbetters put air purifiers and a new circulation system in their house to help protect Caden's new immune system and he will undergo more radiation treatments for cancer.

His mother told the Morning News that Caden didn't talk to anyone at the hospital "and everything was 'No, don't touch me,'" but she added that, "Now we're almost back to the Caden that we know."

Monday, 28 Jan 2008 12:56

Stroke victims could see their condition improve after receiving stem cell transplants, two separate studies have concluded today.

Both studies saw transplanted stem cells successfully migrate and one noted significant reductions in cell death.

They are published today in the journal Cell Transplantation.

The first, carried out by Korean researchers, transplanted a type of stem cells into animals with stroke and then tracked their progression through magnetic resonance imaging (MRI) at intervals up to ten weeks after transplant.

Dr Jihwan Song said cells showed indications of migration "as early as one or two weeks following transplantation" and at ten weeks the majority of the cells were detected in the core of the area deprived of blood supply.

He argued that the findings "will provide an important tool for developing novel stroke therapies".

In the second study, Canadian and Chinese researchers injected connective tissue cells into animals 24 hours after blood flow was blocked to parts of their brains.

Using laser canning to track markers attached to the cells, the scientists found that within seven days of the injection the cells had migrated into the scar area.

"The animals exhibited significant reductions in scar size and cell death and improvements in neurological function when compared to controls that received no BMSCs [tissue cells]," said lead author Dr Ren-Ke Li.

The researchers concluded that the intravenous delivery of bone marrow-derived cells may enhance tissue repair and the functional recovery after a stroke.

Commenting on the findings, Cell Transplantation associated editor De Cesar Borlongan said: "Both studies lend important support to a growing body of laboratory evidence that bone marrow is a remarkable adult stem cell source for transplant therapy following stroke.

"The non-invasive MRI visualisation of pre-labeled [tissue cells] could become a routine clinical marker for transplanted cells as well as for safety and efficacy."

About 150,000 people are estimated to have a stroke each year in the UK, causing 67,000 deaths.

ScienceDaily (Nov. 24, 2007) — Researchers at the Stanford University
School of Medicine have taken a small but significant step, in mouse studies, toward the goal of transplanting adult stem cells to create a new immune system for people with autoimmune or genetic blood diseases.

The researchers found a way to transplant new blood-forming stem cells into the bone marrow of mice, effectively replacing their immune systems. Many aspects of the technique would need to be adapted before it can be tested in humans, said Irving Weissman, MD, a co-senior author of the study and director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. The work was done on a particular group of mice that are a poor mimic for the human immune system. Still, Weissman suggested the remaining hurdles could eventually be overcome.

When those barriers are surmounted, the benefits are potentially big.

A person with an autoimmune disease such as multiple sclerosis has a defective immune system in which immune cells attack the person's own body. An immune system transplant, much like a liver or heart transplant, would give the person a new system that might not attack the body.

The way to get a new immune system is to transplant new blood-forming stem cells into the bone marrow, where they generate all the cells of the blood. But before transplanting new stem cells, the old ones first must be removed, which is currently done by intensive chemotherapy or radiation. Those processes eliminate the cells of the bone marrow, but also damage other tissue and can cause lasting effects including infertility, brain damage and an increased risk of cancer. A treatment for M.S. at the expense of brain function is hardly an ideal therapy.

Weissman and co-first author Deepta Bhattacharya, PhD, a postdoctoral scholar in Weissman's lab, thought one way around this problem would be
to eliminate only the blood-forming stem cells without affecting bone marrow cells or other tissues. They worked with Agnieszka Czechowicz, first author and medical student, to accomplish that feat by injecting the mice with molecules that latch on to specific proteins on the surface of the blood-forming stem cells, effectively destroying the cells. That technique eliminated the blood-forming stem cells without otherwise harming the mice.

"It is essentially a surgical strike against the blood-forming stem cells," said Weissman, the Virginia & D.K. Ludwig Professor for
Clinical Investigation in Cancer Research. When they transplanted new blood-forming stem cells into the mice, those cells took up residence in the bone marrow and established a new blood and immune system.

In a person with autoimmune disease, that new immune system would likely no longer attack tissues of the body. Likewise, in people with a genetic disorder such as sickle cell anemia, the new blood system would not have the sickle-cell mutation, eliminating the cause of disease. However, the barriers are still significant.

First, the researchers don't know whether the same molecule on human blood-forming stem cells would be the right one to target with a therapy. Also, the mice they used in the study lack a functioning immune system. They'll need to get the therapy working in mice with a normal immune system before they can begin testing the technique in humans.

Although these steps will take time to overcome, Weissman said he considered this work to be the beginning of research that could lead to human studies.

Source: Forbes

WEDNESDAY, Oct. 31 (HealthDay News) -- A new U.S. study involving mice suggests the brain's own stem cells may have the ability to restore memory after an injury.

These neural stem cells work by protecting existing cells and promoting neuronal connections.

In their experiments, a team at the University of California, Irvine, were able to bring the rodents' memory back to healthy levels up to three months after treatment.

The finding could open new doors for treatment of brain injury, stroke and dementia, experts say.

"This is one of the first reports that you can take a stem cell transplantation approach and restore memory," said lead researcher Mathew Blurton-Jones, a postdoctorate fellow at the university. "There is a lot of awareness that stem cells might be useful in treating diseases that cause loss of motor function, but this study shows that they might benefit memory in stroke or traumatic brain injury, and potentially Alzheimer's disease."

In the study, published in the Oct. 31 issue of the Journal of Neuroscience, Blurton-Jones and his colleagues used genetically engineered mice that naturally develop brain lesions. The researchers destroyed cells in a brain area called the hippocampus. These cells are known to be vital to memory formation and it is in this region that neurons often die after injury, the researchers explained.

To test the mice's memory, Blurton-Jones's group conducted place and object recognition tests with both healthy mice and brain-injured mice.

Healthy mice remembered their surroundings about 70 percent of the time, while brain-injured mice remembered it only 40 percent of the time. For objects, healthy mice recalled objects about 80 percent of the time, but injured mice remembered them only 65 percent of the time.

The researchers then injected each mouse with about 200,000 neural stem cells.

They found that mice with brain injuries that received the stem cells now remembered their surroundings about 70 percent of the time -- the same as healthy mice. However, mice that didn't receive stem cells still had memory deficits.

The researchers also found that in healthy mice injected with stem cells, the stem cells traveled throughout the brain. In contrast, stem cells given to injured mice lingered in the hippocampus. Only about 4 percent of those stem cells became neurons, indicating that the stem cells were repairing existing cells to improve memory, rather than replacing the dead brain cells, Blurton-Jones's team noted.

The researchers are presently doing another study with mice stricken with Alzheimer's. "The initial results are promising," Blurton-Jones said. "This has a huge potential, but we have to be cautious about not rushing into the clinic too early."

One expert is optimistic about the findings.

"Putting in these stem cells could eventually help in age-related memory decline," said Dr. Paul R. Sanberg, director of the Center of Excellence for Aging and Brain Repair at the University of South Florida College of Medicine. "There is clearly a therapeutic potential to this."

Sanberg noted that for the process to work with Alzheimer's it has to work with older brains. "There is clearly therapeutic potential in humans, but there are a lot of hurdles to overcome," he said. "This is another demonstration of the potential for neural stem cells in brain disorders."

Murdoch researchers may have unlocked the key to treating the early onset of osteoarthritis.

Osteoarthritis results in loss of cartilage which cannot repair itself after injury and for which there is no effective therapy. Current treatments attempt to alleviate painful symptoms but are unable to preserve the cartilage lining the joint.

Working with Australia's adult stem cell company, Mesoblast Limited (ASX:MSB), the University’s pre-clinical trials of Mesoblast’s patented adult stem cells had shown the therapy to significantly protect cartilage against damage in knee osteoarthritis.

The project’s principal investigator, Professor Rick Read from Murdoch’s School of Veterinary and Biomedical Sciences, said the studies have so far shown promising results.

"We are delighted with the significant cartilage protective effects of Mesoblast's allogeneic (donor unrelated) cells in our large animal model of knee osteoarthritis, without any adverse events of the cells at all," Professor Read said.

The results of the trials signalled Mesoblast's expansion of its clinical applications to inflammatory and degenerative diseases of joint cartilage, such as osteoarthritis, which affect millions of people world-wide.

Mesoblast's cartilage trials evaluated the effectiveness and safety of the company's allogeneic adult stem cells to treat osteoarthritis of the knee in 48 arthritic sheep joints.

The results showed that osteoarthritic sheep knee joints receiving Mesoblast's stem cells had significantly greater thickness of joint cartilage, reduced cartilage breakdown, and greater biomechanical strength three months later than did control joints receiving hyaluronic acid.

Mesoblast's Vice President of the Cartilage Regenerative Programs, Professor Peter Ghosh, a world-renowned expert in diseases of cartilage, said the results obtained at three months were very encouraging.

"Professor Read’s team at Murdoch University has been involved for almost 20 years in the development and refinement of this model for investigating new treatments for osteoarthritis,” Professor Ghosh said.

“We are very excited by the results of these studies using adult stem cells."

Professor Read said the project was another example of a productive collaboration between the University’s research experts and the industry.

27-Mar-2007

OAK BROOK, Ill. For the first time, researchers have used adult bone marrow stem cells to regenerate healthy human liver tissue, according to a study published in the April issue of the journal Radiology.

When large, fast-growing cancers invade the liver, some patients are unable to undergo surgery, because removing the cancerous tissue would leave too little liver to support the body.

Researchers at Heinrich-Heine-University in D sseldorf, Germany, used adult bone marrow stem cells to help quickly regenerate healthy liver tissue, enabling patients to eventually undergo a surgical resection.

Our study suggests that liver stem cells harvested from the patient s own bone marrow can further augment and accelerate the liver s natural capacity to regenerate itself, said G nther F rst, M.D., co-author and professor of radiology.

In the study, researchers compared the results of portal vein embolization (PVE), a technique currently used to help regenerate liver tissue, to a combination of PVE and an injection of bone marrow stem cells into the liver.

PVE blocks blood flow to the diseased portion of the liver and diverts blood to the organ s healthy tissue, promoting liver growth. Bone marrow stem cells extracted from the patient s hip bone and injected into the liver also help the liver regenerate.

The study included 13 patients with large central liver malignancies who were unable to undergo surgery because resection would leave less than 25 percent of their total liver volume.

Six of the patients underwent both PVE and injection of bone marrow stem cells. Seven patients underwent only PVE. Computed tomography (CT) scans were performed before and up to five weeks after PVE to determine the degree of liver growth.

Patients who received the combination of PVE and stem cell injection had double the liver growth rate and gain in liver volume, compared with those who underwent PVE alone. As a result, the patients who received the combined treatment were able to undergo surgery an average of 18 days sooner than patients who received PVE only.

Our research demonstrates that stem cells are a powerful adjunct to PVE for patients undergoing surgical resection, said Jan Schulte am Esch, M.D., co-author and surgery staff member. Based on our results, we also believe that adult stem cell administration may be a promising therapy for regenerating livers damaged by other chronic and acute diseases.

2007/3/13
By Maggie Fox, Health and Science Editor WASHINGTON, Reuters

Human stem cells taken from both embryos and fetuses delayed a fatal brain and nerve disease in mice, moving throughout the brain to take on the jobs of damaged neurons, scientists reported on Sunday.
They said their study, published in the journal Nature Medicine, represents the first time a human embryonic stem cell has successfully treated a disease in an animal.

Dr. Evan Snyder of the Burnham Institute for Medical Research in La Jolla, California, who led the study, says his team hopes to move quickly to test their method in children with a fatal and incurable brain disease called Sandhoff disease.

Writing in the journal Nature Medicine, they also said their approach could lead to ways to treat a range of neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease.

For their study, Snyder and colleagues used mice bred with the equivalent of Sandhoff disease.

"Children with the disease have severe mental retardation and motor dysfunction, and death typically occurs in infancy," the researchers, who included a team at Oxford University in Britain, Yonsei University in Seoul, Korea and elsewhere, wrote in their report.

It is marked by inflammation that kills brain cells.

Snyder's team used both human embryonic stem cells, taken from days-old human embryos left over at fertility clinics, and human fetal stem cells.

They transplanted these into the brains of the mice and noted no problems. No tumors formed, the mice did not "reject" the foreign cells, and the treatment seemed to reduce inflammation.

"They just don't seem to get rejected," Snyder said.

The treated mice lived 70 percent longer than untreated mice. The disease eventually came back, but Snyder believes they could keep it at bay by giving booster injections of the stem cells to take over the functions of the mutated natural brain cells.

Stem cells are valued because they can give birth to a range of tissue and cell types. But Snyder said scientists are beginning to learn they do even more than this.

"This shows that stem cells engage in cross-talk," he said in a telephone interview.

"They collaborate ... to try to restore a system to balance. They secrete factors that are healthy. They try to restore the health of other cells and detoxify the system."

The transplanted human cells replaced damaged nerve cells and carried nerve signals. They also boosted the brain's supply of the enzyme hex, which is lacking in Sandhoff disease.

Sandhoff is caused by a mutation in the gene for an enzyme called hexosaminidase or hex, which brain cells need to get rid of excess fatty material called lipids.

When the lipids build up, brain cells die. It is similar to Tay-Sachs disease, and there is no treatment for either Tay-Sachs or Sandhoff.

The use of human embryonic stem cells is controversial because some people believe it is wrong to destroy human embryos in experiments.

Snyder said his team used batches of stem cells approved for funding by the U.S. government. He said when his team asks the U.S. Food and Drug Administration for permission to test the treatment on children, they will probably not seek to use the embryonic stem cells at first, but merely the fetal stem cells.

"I think they are a little bit squeamish," he said.