Scientists turn skin cells into beating heart muscle

 Scientists have for the first time succeeded in taking skin cells from patients with heart failure and transforming them into healthy, beating heart tissue that could one day be used to treat the condition.

The researchers, based in Haifa, Israel, said there were still many years of testing and refining ahead. But the results meant they might eventually be able to reprogram patients’ cells to repair their own damaged hearts.

“We have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young – the equivalent to the stage of his heart cells when he was just born,” said Lior Gepstein from the Technion-Israel Institute of Technology, who led the work.

The researchers, whose study was published in the European Heart Journal on Wednesday, said clinical trials of the technique could begin within 10 years.

Heart failure is a debilitating condition in which the heart is unable to pump enough blood around the body. It has become more prevalent in recent decades as advances medical science mean many more people survive heart attacks.

At the moment, people with severe heart failure have to rely on mechanical devices or hope for a transplant.

Researchers have been studying stem cells from various sources for more than a decade, hoping to capitalise on their ability to transform into a wide variety of other kinds of cell to treat a range of health conditions.

There are two main forms of stem cells – embryonic stem cells, which are harvested from embryos, and reprogrammed “human induced pluripotent stem cells” (hiPSCs), often originally from skin or blood.

Gepstein’s team took skin cells from two men with heart failure – aged 51 and 61 – and transformed them by adding three genes and then a small molecule called valproic acid to the cell nucleus.

They found that the resulting hiPSCs were able to differentiate to become heart muscle cells, or cardiomyocytes, just as effectively as hiPSCs that had been developed from healthy, young volunteers who acted as controls for the study.

The team was then able to make the cardiomyocytes develop into heart muscle tissue, which they grew in a laboratory dish together with existing cardiac tissue. 

Within 24 to 48 hours the two types of tissue were beating together, they said.

In a final step of the study, the new tissue was transplanted into healthy rat hearts and the researchers found it began to establish connections with cells in the host tissue.

“We hope that hiPSCs derived cardiomyocytes will not be rejected following transplantation into the same patients from which they were derived,” Gepstein said. “Whether this will be the case or not is the focus of active investigation.”

Experts in stem cell and cardiac medicine who were not involved in Gepstein’s work praised it but also said there was a lot to do before it had a chance of becoming an effective treatment.

“This is an interesting paper, but very early and it’s really important for patients that the promise of such a technique is not over-sold,” said John Martin a professor of cardiovascular medicine at University College London.

“The chances of translation are slim and if it does work it would take around 15 years to come to clinic.”

Nicholas Mills, a consultant cardiologist at Edinburgh University said the technology needs to be refined before it could be used for patients with heart failure, but added: “These findings are encouraging and take us a step closer to … identifying an effective means of repairing the heart.”

 

Source: Kate Kelland, Reuters

Entest BioMedical Excited With Progress on Ten Dog Pilot Study of “Universal Donor” Stem Cell Treatment for Canine Osteoarthritis

 Entest BioMedical and RenovoCyte LLC announced they have treated eight canine patients of a ten dog pilot study utilizing Canine Endometrial Regenerative Cells (CERC)  in the treatment of canine osteoarthritis.

Previously, Entest announced the treatment of the first canine patient on November 18, 2011. Since that time Entest’s McDonald Animal Hospital has treated eight dogs in its ten Dog Pilot Study with RenovoCyte. To date, all of the dogs participating in this study have shown dramatic improvement in their mobility and apparent reduction of pain.

Dr. Greg McDonald, Chief Veterinarian at McDonald Animal Hospital, said, “50 million CERC stem cells have been injected intravenously into eight dogs. Each dog selected for this study showed signs of arthritis. Follow-up blood tests, urinalysis and physical exams are now being scheduled for the patients that have already been treated. So far, all these canine patients have shown improvement.”

Entest BioMedical Chairman David Koos stated, “Osteoarthritis is considered one of the most common causes of lameness in dogs, occurring in up to 30% of all dogs. It is caused by a deterioration of joint cartilage, followed by pain and loss of range of motion of the joint. We expect this treatment to relieve these animals from the pain associated with arthritis. This has extraordinary possibilities for dogs and may lead the way for human treatment of arthritic pain.” 

The CERC is a “universal donor” stem cell product that does not require matching with the recipient allowing for the generation of standardized products that can be delivered to the office of the veterinarian ready for injection. This is in stark contrast to current stem cell therapies utilized in veterinary applications which require the extraction, manipulation, and subsequent implantation of tissue from the animal being treated.

“We are extremely pleased with our research relationship with Entest BioMedical. This study of canine pets suffering from naturally occurring osteoarthritis is a better test model than laboratory induced disease because it will give us the opportunity for long term follow up of these patients. RenovoCyte sees this study as part of the supporting documentation that will be needed to obtain FDA approval for widespread usage of this therapy,” said Shelly Zacharias, DVM, Director of Veterinary Operations, RenovoCyte, LLC.

A spokesperson for Entest noted the Company is also currently conducting a ten dog safety study on its immune-therapeutic cancer vaccine for dogs, having treated three dogs so far.

Growth Factor in Stem Cells May Spur Recovery from Multiple Sclerosis

 A substance in human mesenchymal stem cells that promotes growth appears to spur restoration of nerves and their function in rodent models of multiple sclerosis (MS), researchers at Case Western Reserve University School of Medicine have found.

In animals injected with hepatocyte growth factor, inflammation declined and neural cells grew. Perhaps most important, the myelin sheath, which protects nerves and their ability to gather and send information, regrew, covering lesions caused by the disease.

“The importance of this work is we think we’ve identified the driver of the recovery,” said Robert H. Miller, professor of neurosciences at the School of Medicine and vice president for research at Case Western Reserve University.

Miller, neurosciences instructor Lianhua Bai and biology professor Arnold I. Caplan, designed the study. They worked with Project Manager Anne DeChant, and research assistants Jordan Hecker, Janet Kranso and Anita Zaremba, from the School of Medicine; and Donald P. Lennon, a research assistant from the university’s Skeletal Research Center.

In MS, the immune system attacks myelin, risking injury to exposed nerves’ intricate wiring. When damaged, nerve signals can be interrupted, causing loss of balance and coordination, cognitive ability and other functions. Over time, intermittent losses may become permanent.

Miller and Caplan reported in 2009 that when they injected human mesenchymal stem cells into rodent models of MS, the animals recovered from the damage wrought by the disease. Based on their work, a clinical trial is underway in which MS patients are injected with their own stem cells.

In this study, the researchers first wanted to test whether the presence of stem cells or something cells produce promotes recovery. They injected mice with the medium in which mesenchymal stem cells, culled from bone marrow, grew.

All 11 animals, which have a version of MS, showed a rapid reduction in functional deficits.

Analysis showed that the disease remained on course unless the molecules injected were of a certain size; that is, the molecular weight ranged between 50 and 100 kiloDaltons. Research by others and results of their own work indicated hepatocyte growth factor, which is secreted by mesenchymal stem cells, was a likely instigator.

The scientists injected animals with 50 or 100 nanograms of the growth factor every other day for five days. The level of signaling molecules that promote inflammation decreased while the level of signaling molecules that counter inflammation increased. Neural cells grew and nerves laid bare by MS were rewrapped with myelin. The 100-nanogram injections appeared to provide slightly better recovery.

To test the system further, researchers tied up cell-surface receptors, in this case cMet receptors that are known to work with the growth factor.

When they jammed the receptors with a function-blocking cMet antibody, neither the mesenchymal stem cell medium nor the hepatocyte growth factor injections had any effect on the disease. In another test, injections of an anti-hepatocyte growth factor also blocked recovery.

The researchers will continue their studies, to determine if they can screen mesenchymal stem cells for those that produce the higher amounts of hepatocyte growth factor needed for effective treatment. That could lead to a more precise cell therapy.

“Could we now take away the mesenchymal stem cells and treat only with hepatocyte growth factor?” Miller asked. “We’ve shown we can do that in an animal but it’s not clear if we can do that in a patient.”

They also plan to test whether other factors may be used to stimulate the cMet receptors and induce recovery.

 

Source: Science Daily, Case Western Reserve University

Stem cell shield ‘could protect cancer patients’

 Chemotherapy drugs try to kill rapidly dividing cancer cells, but they can also affect other healthy tissues such as bone marrow.

A study, in Science Translational Medicine, used genetically modified stem cells to protect the bone marrow.

Cancer Research UK said it was a “completely new approach”.

The body constantly churns out new blood cells in the hollow spaces inside bone. However, bone marrow is incredibly susceptible to chemotherapy.

The treatment results in fewer white blood cells being produced, which increases the risk of infection, and fewer red blood cells, which leads to shortness of breath and tiredness.

Researchers at the Fred Hutchinson Cancer Research Center, in Seattle, said these effects were “a major barrier” to using chemotherapy and often meant the treatment had to be stopped, delayed or reduced.

‘Protective shields’

They have tried to protect the bone marrow in three patients with a type of brain cancer, glioblastoma.

One of the researchers, Dr Jennifer Adair, said: “This therapy is analogous to firing at both tumour cells and bone marrow cells, but giving the bone marrow cells protective shields while the tumour cells are unshielded.”

Bone marrow was taken from the patients and stem cells, which produce blood, were isolated. A virus was then used to infect the cells with a gene which protected the cells against a chemotherapy drug. The cells were then put back into the patient.

The lead author of the report, Prof Hans-Peter Kiem, said: “We found that patients were able to tolerate the chemotherapy better, and without negative side effects, after transplantation of the gene-modified stem cells than patients in previous studies who received the same type of chemotherapy without a transplant of gene-modified stem cells.”

The researchers said the three patients had all lived longer than the average survival time of 12 months for the cancer. They said one patient was still alive 34 months after treatment.

Cancer Research UK scientist Prof Susan Short said: “This is a very interesting study and a completely new approach to protecting normal cells during cancer treatment.

“It needs to be tested in more patients but it may mean that we can use temozolomide [a chemotherapy drug] for more brain tumour patients than we previously thought.

“This approach could also be a model for other situations where the bone marrow is affected by cancer treatment.”

Source: James Gallagher, BBC News

Surprise cord-blood find is ‘godsend’ for ailing boy

After half a year of blood transfusions to treat life-threatening anemia, 9-year-old Ricky Martinez was running out of time.

The Murrieta boy needed a bone marrow transplant to save his life. Although his parents had held numerous drives seeking a match for their son, the perfect donor eluded them. 

Then another option appeared —- doctors found Ricky’s own blood from his umbilical cord, banked at birth, and stored in a medical facility.

“I had donated it at birth, when I delivered,” said Ricky’s mother, Cynthia Martinez. “I had no idea that I’d be using it for him nine years later.”

The cord blood discovery represents a “godsend” for the family, Martinez said, because Ricky’s body began rejecting the transfusions that keep him alive.

Cord blood contains stem cells —- undifferentiated cells that can spur production of healthy tissue to help treat various diseases. Doctors believe it could jump-start Ricky’s bone marrow, allowing his body to resume normal blood production.

But it’s not a guarantee.

Ricky’s condition, aplastic anemia, is an extremely rare disease, and cord blood transplantation is an experimental procedure for the condition, said David Buchbinder, a hematologist and transplant physician who is treating Ricky at Children’s Hospital Orange County, in the city of Orange.

Although the procedure offers few risks of complications, it also pushes the boundaries of medical practice, placing Ricky in a realm of mixed medical opinions and uncertain results, Buchbinder said.

His parents say they’re willing to go there to save their son’s life.

“His match is the best chance of survival,” said Ricky’s father, Oscar Martinez. “The doctors have told us it’s not a cure —- it doesn’t mean he’s going to defeat it. But it’s our only hope, and it’s his best chance.”

Sudden illness

The first signs of trouble appeared last summer, when Ricky developed large bruises on his legs, skin eruptions on his chest and nightly nosebleeds, Cynthia Martinez said.

After a particularly severe nosebleed that lasted hours, she took Ricky to the hospital, where tests showed her son had low counts of platelets —- blood cells involved in clotting.

He was diagnosed with aplastic anemia, a condition in which the bone marrow ceases to make blood cells as the body’s immune system turns against itself.

“There’s some sort of insult, whether it’s a virus, that trips your immune system, so that it attacks your own body and empties your bone marrow,” Buchbinder said.

The bright-eyed boy, who loves his guitar and the Los Angeles Lakers, became a regular at the hospital, receiving weekly transfusions to replace the blood his body couldn’t produce.

His mother said Ricky has braved his illness cheerfully.

“The whole entire time, he’s been such a strong, amazing boy throughout this whole ordeal,” Cynthia Martinez said. “He’s had his spirits up and is always smiling.”

Awaiting a donor

While shuttling their son to doctor visits, his parents began preparing for the next step. Aplastic anemia sometimes resolves with treatment, but Ricky’s condition showed no sign of stabilizing. And the transfusions were a temporary fix.

For long-term remission or a cure, he would need a marrow transplant, in which doctors extract marrow from a donor’s blood or bone, then transplant it to the patient in order to restore healthy marrow.

For months, the family had conducted more than 20 bone marrow drives at parks, schools, shopping centers and churches in Southwest Riverside County, and in Escondido, where they originally lived.

Students at Cal State San Marcos chipped in, as well, launching a campuswide marrow drive in lieu of a final exam for instructor Scott Landau’s fall entrepreneurship class.

Together, the Martinez family and students registered 1,509 qualified donors in honor of Ricky, according to Be The Match, the national marrow donor registry.

Unexpected gift

Meanwhile, hospital workers were scanning donor rolls, and they located one potential donor for Ricky who matched most, but not all, of his biochemical markers. They were also surprised to find a cord blood sample that was a perfect match.

As hospital workers researched it, they discovered it was Ricky’s own cord blood, banked at the time of his birth, Buchbinder said.

“The whole thing is wonderful but strange,” Buchbinder said. “This is truly an amazing gift that we have this cord.”

Cord blood banking is an infrequent procedure, limited to parents who can afford the fee to store their child’s cord blood, or to those, such as Cynthia Martinez, who donate it for research. And aplastic anemia itself is an uncommon disease.

Because of that, Buchbinder said, there’s little medical literature on the procedure they plan for Ricky.

“We don’t typically use cord blood as a stem cell source —- it’s used for other diseases, like leukemia,” he said. “Not that many people bank their own cords. The fact that this was donated, and the fact that it’s still there, and Ricky happens to need it, is pretty amazing.”

Experts divided

Because there are few cases on record, experts are divided on whether using cord blood is a viable treatment for aplastic anemia.

The disease can result from a shock to the system or from a hereditary condition, Buchbinder said. In the latter case, transplanting the patient’s own cord blood would simply reintroduce the problem cells.

After extensive testing, however, Buchbinder said Ricky’s doctors have found nothing to suggest he was born with the disease, leaving the cord blood option open.

“This was truly what we would call an acquired aplastic anemia,” he said. “Somehow, Ricky got something that triggered his immune system” to attack his marrow.

Despite the uncertainties, using a patient’s cord blood confers some advantages over donated marrow. There’s no risk that Ricky’s body will reject his own cord blood cells, or that he will develop “graft-versus-host” disease, in which transplanted cells attack the recipient, Buchbinder said.

“Those cells are Ricky’s, so they will be happy inside of Ricky,” Buchbinder said. “There is no risk to using it, other than the fact that we are going to give him immunosuppressive drugs beforehand.”

Preparing for transplant

On Monday, Ricky will be admitted to Children’s Hospital Orange County, where doctors will begin prepping him for the procedure, delivering strong chemotherapeutic agents to wipe out his immune system and make way for his cord blood cells.

If that goes as planned, they will perform the transplant about a week later.

“They want his stem cells to take over in his own body and have a party and say ‘Yay, we’re home!'” Cynthia Martinez said.

Buchbinder said doctors will know about a month later how well the cord blood transplant worked. Martinez said the family is preparing for a three-month hospital stay while Ricky recuperates.

Last week, Ricky met actress Zendaya Coleman, from the Disney Channel show “Shake It Up!” at Disney’s studio in Burbank, through the Make-A-Wish Foundation.

The two shared Xbox games and a pair of friendship bracelets, his mother said, and Coleman tweeted about the meeting, helping Ricky gain an instant following on Twitter.

Before he enters the hospital, his family will take him on a long-awaited outing to ride go-karts this weekend, Martinez said.

Although he has stayed upbeat throughout his illness, Martinez said that he awoke from a recent procedure and confided his fear and fatigue, as well as his resolve.

“He said, ‘I’m going to fight this disease, and I’m going to beat it, Mommy,'” she said.

Ricky’s parents say they will continue to recruit bone marrow donors regardless of the results, knowing that the cord blood transplant may not be a permanent cure.

“It’s just a waiting game for this transplant, to see if the cells can grow on their own,” Cynthia Martinez said. “He can be in remission, but we don’t know for how long. I don’t think we’ll ever know. We’ll just have to leave it in God’s hands, and be grateful for every day we do have with Ricky.”

Source: Deborah Sullivan Brennan, nctimes.com

Researchers at UPMC, Stanford test stem cells to enhance stroke recovery.

Doctors have known for years that when people suffer a stroke, their brains furiously try to repair themselves, but the improvement often plateaus after several weeks or months.

Now, researchers at UPMC and Stanford University hope they can enhance recovery by infusing millions of stem cells directly into patients’ brains. The procedure was carried out on six patients so far and plan to enroll another 12 in a two-year safety trial of the new therapy. 

The cells were culled from adult bone marrow and given a booster containing a gene known as Notch, which is involved in the development of infant brains.

No adverse reactions have occurred in the first half-dozen patients, each of whom got 2.5 million stem cells. During the procedure, doctors sedate the patient, numb the person’s skull, bore a hole through the skull and insert a metal tube into the brain near the area of the stroke damage, said Douglas Kondziolka, a neurosurgeon who heads the UPMC branch of the trial. The stem cells are then infused into the brain through the tube.

Doctors won’t know the outcome for several months, but tests in laboratory rats by Cesario Borlongan at the University of South Florida have shown that the stem cells improved motor function in animals that had suffered a stroke, and the cells secreted several growth and anti-inflammatory factors in the lab.

Mr. Borlongan, a neuroscientist at South Florida, said that when people suffer a stroke from a clot blocking blood flow to the brain, there is a central area of damage and then a surrounding, partially damaged area known as the penumbra.

In the animals, the stem cells seem to work primarily by repairing the penumbra area. Not only do they secrete factors that help new neurons and blood vessels grow, but they also promote the growth of cellular scaffolding to support the brain repair, he said.

Interestingly, he said, the stem cells themselves disappear a few weeks after they are put in, but their beneficial effects seem to persist.

“We think what our cells are doing is providing an environment for improvement,” SanBio’s Mr. Yankee said.

This is not the first time UPMC has been involved in stem cell therapy for stroke.

About a decade ago, Dr. Kondziolka led a trial of a different stem cell line in older stroke patients, and it showed promise, but money to support the experiments ran out when the New York Stock Exchange’s tech investment bubble burst in 2000.

Because the current stem cells are a different type, researchers had to start all over again with animal and safety tests. “Every time a new cell line gets developed, you have to go back to the drawing board,” he said.

The current trial is still enrolling patients. They must be adults and must have experienced their strokes between six months and three years ago. They also must have persistent motor difficulties that have plateaued, he said.

The UPMC-Stanford trial is the only one in the U.S. putting these stem cells directly into patients’ brains. In the United Kingdom, a British company called ReNeuron Ltd. is using a similar procedure on stroke patients with stem cells developed from fetal brain tissue.

Mr. Borlongan said the potential of this therapy comes from the fact that whole cells are secreting a “cocktail” of growth and anti-inflammatory factors into people’s brains. Still, he noted that 178 drugs and biologic agents already have helped repair brain damage in animals but have never successfully worked in humans.

“As a result,” he said, “we in the field of stem cells are very cautious that we don’t fall into giving this too much hype.”

Source: Mark Roth / Pittsburgh Post-Gazette