Monthly Archives: November 2011

Study: Stem cells reverse heart damage

On a June day in 2009, a 39-year-old man named Ken Milles lay on an exam table at Cedars-Sinai Medical Center in Los Angeles. A month earlier, he’d suffered a massive heart attack that destroyed nearly a third of his heart.

“The most difficult part was the uncertainty,” he recalls. “Your heart is 30% damaged, and they tell you this could affect you the rest of your life.” He was about to receive an infusion of stem cells, grown from cells taken from his own heart a few weeks earlier. No one had ever tried this before.

About three weeks later, in Kentucky, a patient named Mike Jones underwent a similar procedure at the University of Louisville’s Jewish Hospital. Jones suffered from advanced heart failure, the result of a heart attack years earlier. Like Milles, he received an infusion of stem cells, grown from his own heart tissue.

“Once you reach this stage of heart disease, you don’t get better,” says Dr. Robert Bolli, who oversaw Jones’ procedure, explaining what doctors have always believed and taught. “You can go down slowly, or go down quickly, but you’re going to go down.”

Conventional wisdom took a hit Monday, as Bolli’s group and a team from Cedars-Sinai each reported that stem cell therapies were able to reverse heart damage, without dangerous side effects, at least in a small group of patients.

In Bolli’s study, published in The Lancet, 16 patients with severe heart failure received a purified batch of cardiac stem cells. Within a year, their heart function markedly improved. The heart’s pumping ability can be quantified through the “Left Ventricle Ejection Fraction,” a measure of how much blood the heart pumps with each contraction. A patient with an LVEF of less than 40% is considered to suffer severe heart failure. When the study began, Bolli’s patients had an average LVEF of 30.3%. Four months after receiving stem cells, it was 38.5%. Among seven patients who were followed for a full year, it improved to an astounding 42.5%. A control group of seven patients, given nothing but standard maintenance medications, showed no improvement at all.

“We were surprised by the magnitude of improvement,” says Bolli, who says traditional therapies, such as placing a stent to physically widen the patient’s artery, typically make a smaller difference. Prior to treatment, Mike Jones couldn’t walk to the restroom without stopping for breath, says Bolli. “Now he can drive a tractor on his farm, even play basketball with his grandchildren. His life was transformed.”

At Cedars-Sinai, 17 patients, including Milles, were given stem cells approximately six weeks after suffering a moderate to major heart attack. All had lost enough tissue to put them “at big risk” of future heart failure, according to Dr. Eduardo Marban, the director of the Cedars-Sinai Heart Institute, who developed the stem cell procedure used there.

The results were striking. Not only did scar tissue retreat — shrinking 40% in Ken Milles, and between 30% and 47% in other test subjects — but the patients actually generated new heart tissue. On average, the stem cell recipients grew the equivalent of 600 million new heart cells, according to Marban, who used MRI imaging to measure changes. By way of perspective, a major heart attack might kill off a billion cells.

“This is unprecedented, the first time anyone has grown living heart muscle,” says Marban. “No one else has demonstrated that. It’s very gratifying, especially when the conventional teaching has been that the damage is irreversible.”

Perhaps even more important, no treated patient in either study suffered a significant health setback.

The twin findings are a boost to the notion that the heart contains the seeds of its own rebirth. For years, doctors believed that heart cells, once destroyed, were gone forever. But in a series of experiments, researchers including Bolli’s collaborator, Dr. Piero Anversa, found that the heart contains a type of stem cell that can develop into either heart muscle or blood vessel components — in essence, whatever the heart requires at a particular point in time. The problem for patients like Mike Jones or Ken Milles is that there simply aren’t enough of these repair cells waiting around. The experimental treatments involve removing stem cells through a biopsy, and making millions of copies in a laboratory.

The Bolli/Anversa group and Marban’s team both used cardiac stem cells, but Bolli and Anversa “purified” the CSCs, so that more than 90% of the infusion was actual stem cells. Marban, on the other hand, used a mixture of stem cells and other types of cells extracted from the patient’s heart. “We’ve found that the mixture is more potent than any subtype we’ve been able to isolate,” he says. He says the additional cells may help by providing a supportive environment for the stem cells to multiply.

Other scientists, including Dr. Douglas Losordo, have produced improvements in cardiac patients using stem cells derived from bone marrow. “The body contains cells that seem to be pre-programmed for repair,” explains Losordo. “The consistent thing about all these approaches is that they’re leveraging what seems to be the body’s own repair mechanism.”

Losordo praised the Lancet paper, and recalls the skepticism that met Anversa’s initial claims, a decade ago, that there were stem cells in the adult heart. “Some scientists are always resistant to that type of novelty. You know the saying: First they ignore you, then they attack you and finally they imitate you.”

Denis Buxton, who oversees stem cell research at the National Heart, Lung and Blood Institute at the National Institutes of Health, calls the new studies “a paradigm shift, harnessing the heart’s own regenerative processes.” But he says he would like to see more head-to-head comparisons to determine which type of cells are most beneficial.

Questions also remain about timing. Patients who suffer large heart attacks are prone to future damage, in part because the weakened heart tries to compensate by dilating — swelling — and by changing shape. In a vicious circle, the changes make the heart a less efficient pump, which leads to more overcompensation, and so on, until the end result is heart failure. Marban’s study aimed to treat patients before they could develop heart failure in the first place.

In a third study released Monday, researchers treated patients with severe heart failure with stem cells derived from bone marrow. In a group of 60 patients, those receiving the treatment had fewer heart problems over the course of a year, as well as improved heart function.

A fourth study also used cells derived from bone marrow, but injected them into patients two to three weeks after a heart attack. Previous studies, with the cells given just days afterward, found a modest improvement in heart function. But Monday, the lead researcher, Dr. Dan Simon of UH Case Medical Center, reported that with the three-week delay, patients did not see the same benefit.

With other methods, there may be a larger window of opportunity. At least in initial studies, Losordo’s bone marrow treatments helped some patients with long-standing heart problems. Bolli’s Lancet paper suggests that CSCs, too, might help patients with advanced disease. “These patients had had heart failure for several years. They were a wreck!” says Bolli. “But we found their stem cells were still very competent.” By that, he means the cells were still capable of multiplying and of turning into useful muscle and blood vessel walls.

Marban has an open mind on the timing issue. In fact, one patient from his control group e-mailed after the study was complete, saying he felt terrible and pleading for an infusion of stem cells. At Marban’s request, the FDA granted special approval to treat him. “He had a very nice response. That was 14 months after his heart attack. Of course that’s just one person, and we need bigger studies,” says Marban.

For Ken Milles, the procedure itself wasn’t painful, but it was unsettling. The biopsy to harvest the stem cells felt “weird,” he recalls, as he felt the doctor poking around inside his heart. The infusion, a few weeks later, was harder. The procedure — basically the same as an angioplasty — involved stopping blood flow through the damaged artery for three minutes, while the stem cells were infused. “It felt exacfly like I was having a heart attack again,” Milles remembers.

Milles had spent the first weeks after his heart attack just lying in bed re-watching his “Sopranos” DVDs, but within a week of the stem cell infusion, he says, “I was reinvigorated.” Today he’s back at work full time, as an accounting manager at a construction company. He’s cut out fast food and shed 50 pounds. His wife and two teenage sons are thrilled.

Denis Buxton says the new papers could prove a milestone. “We don’t have anything else to actually regenerate the heart. These stem cell therapies have the possibility of actually reversing damage.”

Bolli says he’ll have to temper his enthusiasm until he can duplicate the results in larger studies, definitive enough to get stem cell therapy approved as a standard treatment. “If a phase 3 study confirmed this, it would be the biggest advance in cardiology in my lifetime. We would possibly be curing heart failure. It would be a revolution.”

 

Source: Caleb Hellerman, CNN http://bit.ly/uqzitU

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The biological clock controls activation of skin stem cells

 Researchers from the Epithelial Homeostasis and Cancer group at the Centre for Genomic Regulation (CRG) have carried out a study which is to be published in the journal Nature, describing how circadian rhythm, the internal biological clock which controls our behaviour during the day and night, regulates the function of the cells which are responsible for the daily regeneration of the skin (the skin stem cells).

Stem cells regulate cell replacement in tissues. In the case of the skin, they are responsible for constantly producing new cells to replace those that deteriorate through daily use. Correct function of the stem cells is essential for maintaining healthy tissue throughout the life of an organism. The skin is exposed to various harmful agents through the day, such as ultraviolet light during daylight hours, and pathogens such as bacteria and viruses. The main function of the skin is to protect an organism from these potential dangers, whilst being an impermeable barrier separating our body from the outside world.

The researchers involved in the study have found that the behaviour of skin stem cells is regulated by an internal biological clock, and that the correct function of this clock is necessary in order to maintain the tissue. This clock regulates the behavior of stem cells in such a way that, for example, during the peak hours of light exposure, the cells are able to protect themselves from harmful radiation (the main cause of skin cancer), whilst in the evening and at night they can divide and regenerate the tissue replacing damaged cells with healthy ones. In this way, the biological clock allows stem cells to divide at times when the skin is no longer exposed to possible damage, when it would be more vulnerable to the accumulation of mutations in DNA and which would cause a loss of regenerative capacity, or a higher predisposition to tumor development.

“Therefore, the biological clock enables the precise adjustment of the temporal behaviour of stem cells, in such a way that the system adapts to the needs of the tissue according to the time of day and there is constant replacement of the cells of the tissue with minimal risk of accumulating DNA mutations. If this control is lost, stem cells may accumulate DNA damage, and the likelihood of cell aging and generation of tumors increases significantly.” says Salvador Aznar Benitah, coordinator of the study.

The genes Bmal1 and Period1/2 are responsible for controlling this clock and regulating cell regenerative activity or rest. Through genetic manipulation of both genes, researchers showed that disruption of the biological clock in skin stem cells prevented the cells from knowing when to exercise which function, and this can cause long-term problems in cellular aging and tissue generation. Moreover, arrhythmia in the clock also significantly increased the propensity to develop a type of skin cancer which is one of the most commonly diagnosed cancers in industrialised societies.

The biological clock (commonly known as the “circadian rhythm”) arranges all of our biological functions according to the natural cycles of light and darkness to which we are exposed on a daily basis. The results of the group from the Centre for Genomic Regulation show that skin regeneration, essential to prevent from aging and tumor development, is also subject to these rhythms. As we age, the accuracy of this biological clock tends to fade gradually with changes in our daily routine, specially with those who are exposed to constant changes like jet lag in frecuent flyers. Researchers believe this may eventually cause failure in the regenerative capacity of our tissues and consequent ageing, and, in addition, a greater propensity to tumour development. More research will be needed in the future to understand why the biological clock fades as we age, and whether ways to restore a “young” clock can be developed to slow down the tissue degeneration process and reduce the risk of developing tumours.

The study was carried out using mouse skin cells, with the support of the American Institute for Cancer Research (AICR), the Spanish Ministry of Health and the Agency for Management of University and Research Grants (AGAUR). The study involved researchers from the IRB in Barcelona, Ohio State University in the USA and the University of Fribourg in Switzerland.

Reference work: Janich, P., et al. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature (2011). Advance online publication: 09 Nov 2011, 18:00 GMT (19:00 Spanish time). DOI: 10.1038/nature10649

Note for journalists: The study will be published online on Wednesday November 9, 2011 and will be available in print in the edition of the journal issued on December 8, 2011.

For further information: Juan Sarasua, Press Office, Public Relations and Communications Dept., Centre for Genomic regulation (CRG). Tel. +34 93 316 02 37 –  Email: juan.sarasua@crg.eu


Pituitary glands grown from mouse embryonic stem cells

Scientists have grown working pituitary glands in the lab that could potentially transform the treatment of people with a range of debilitating hormone disorders.

The team of Japanese researchers grew the tiny hormone-secreting organs using stem cells taken from a mouse embryo. When the tissue was transplanted into mice with pituitary gland defects, it raised levels of the missing hormones in their bodies.

Dr Yoshiki Sasai, who led the study at the RIKEN Centre for Developmental Biology in Kobe, Japan, said: “It is difficult to guess how long it will take, but we hope that we can produce human pituitary tissue in the next three years.” It would take longer to develop techniques to transplant the cells, he added.

The creation of spare body parts for transplant is one of the goals of stem cell science. Stem cells are the body’s “master cells” and can turn into a range of different types of tissue, such as brain, muscle or pancreatic cells.

Any tissue or organs grown from patients’ own stem cells would not be rejected by the body, doing away with the need for immunosuppressant drugs.

Pituitary glands – the oval, pea-sized organs at the base of the brain – are a particular challenge for stem cell researchers because they are so complex. They have two distinct parts and secrete at least eight hormones regulating growth, fertility, breast milk production, blood pressure, contractions during childbirth, temperature and water balance.

Using mouse stem cells arranged in a three dimensional culture, Dr Sasai’s team mimicked the way pituitary glands develop in the embryo. The resulting tissue contained all five types of cell found in a normal gland and took around three weeks to grow, the scientists report in the journal Nature.

“We have made hundreds of pituitary glands from embryonic stem cells,” said Dr Sasai. When the tissue was transplanted into mice with pituitary defects, levels of missing hormones in their bodies rose to normal.

Although the researchers used embryonic stem cells in their experiment, they believe the technique could work with stem cells derived from adult tissue – so-called induced pluripotent stem cells. That would avoid the ethical concerns some people have about using human embryos in research and therapies.

Even if the scientists can grow a human pituitary, they still face major obstacles in creating a safe and efficient way to transplant it, Dr Sasai said. However, he believes lab-grown glands could lead to treatments for growth hormone deficiencies and damage to the pituitary glands caused by surgery and Sheehan’s syndrome.

Women with Sheehan’s syndrome, which results from blood loss during childbirth, have problems breastfeeding, suffer tiredness, weight gain, constipation, low blood pressure and slowed thinking.

Prof Robin Lovell-Badge, one of Britain’s leading stem cell experts at the Medical Research Council’s National Institute for Medical Research in London, said: “It is unlikely that these in vitro-derived pituitaries are fully developed and make hormones in precisely the same way as normal.

“However, the fact that they got as far as they did is impressive. It suggests that there is a fair amount of self-organisation, which means that it might be easier than we thought to build not just pituitaries, but also other organs from embryonic stem cells and induced pluripotent stem cells – as long as they are not too complex.

“It also opens up new possible ways for treating patients with defective or missing pituitary glands.”

 

Source: The Guardian, David Derbyshire, http://bit.ly/tS6hhr


Stem cells transformed into brain cells to treat Parkinson’s disease

Brain cells that die off in Parkinson’s disease have been grown from stem cells and grafted into monkeys’ brains in a major step towards new treatments for the condition. 

US researchers say they have overcome previous difficulties in coaxing human embryonic stem cells to become the neurons killed by the disease. Tests showed the cells survive and function normally in animals and reverse movement problems caused by Parkinson’s in monkeys.

The breakthrough raises the prospect of transplanting freshly grown dopamine-producing cells into human patients to treat the disease.

“Previously we did not fully understand the particular signals needed to tell stem cells how to differentiate into the right type of cells,” said Dr Lorenz Studer at the Memorial Sloan-Kettering Cancer Centre in New York.

“The cells we produced in the past would produce some dopamine but in fact were not quite the right type of cell, so there were limited improvements in the animals. Now we know how to do it right, which is promising for future clinical use.”

Parkinson’s disease takes hold as cells that produce dopamine die off in part of the brain called the substantia nigra. This causes tremors, rigidity and slowness of movement, though patients may also experience tiredness, pain, depression and constipation, which worsen as the disease progresses.

The main treatments for Parkinson’s are drugs that aim to control the symptoms by increasing the levels of dopamine that reach the brain and stimulating the parts of the brain where dopamine works. Some patients have wires surgically implanted into their brains that deliver electrical pulses to alleviate movement problems.

For around a decade, scientists have been trying to regrow nerve cells lost in neurodegenerative diseases such as Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis (ALS) from stem cells. However experiments in which dopamine neurons were created from mouse stem cells have not been successfully reproduced in humans. There have also been safety concerns, with signs that dopamine neurons developed from human stem cells can trigger the growth of tumours. As a result, clinical trials in humans have yet to start.

Dr Studer and his colleagues, whose work is published in the journal Nature, found the specific chemical signals required to nudge stem cells into the right kind of dopamine-producing brain cells.

In a series of experiments, the team gave animals six injections of more than a million cells each, to parts of the brain affected by Parkinson’s. The neurons survived, formed new connections and restored lost movement in mouse, rat and monkey models of the disease, with no sign of tumour development. The improvement in monkeys was crucial, as the rodent brains required fewer working neurons to overcome their symptoms

On the prospect of future human trials, Dr Studer said: “We now have the right cells, but to put them into humans requires them to be produced in a specialised facility rather than a laboratory, for safety reasons. We have removed the main biological bottleneck and now it’s an engineering problem.”

In the 1990s, doctors transplanted foetal brain tissue into Parkinson’s patients to see whether it improved their symptoms. The results varied substantially, with some patients getting better and others experiencing runaway involuntary movements. Further work revealed that there was a window of opportunity to treat the disease: those who received transplants too early suffered side-effects, while tissue transplanted too late had no beneficial effect.

Parkinson’s disease mostly affects the over 50s, but of the 120,000 people in Britain who have the condition, one in 20 is under 40 years old.

Kieran Breen, director of research at Parkinson’s UK, said: “Stem cells carry a real hope for the treatment and potential cure of some people with Parkinson’s. However, we need to be sure that the cells that are transplanted to replace the brain cells that have died will work correctly.”

He added: “Researchers had already generated the right type of nerve cells from human stem cells to produce the chemical dopamine that is depleted in Parkinson’s, but there were problems when the cells were transplanted into models of Parkinson’s animals. The cells continued to grow and some transformed into tumours.

“In this study, the researchers used a different procedure to differentiate the stem cells into nerve cells. This time they remained as correctly working nerve cells, did not form tumours, and overcame some of the symptoms of Parkinson’s in the monkeys.

Stem cell therapy may still be some way off. However, this study has shown for the first time that it is possible to transplant nerve cells that work from human stem cells.”

 

Source: The Guardian http://bit.ly/tqyqYI


Gene Therapy Shows Promise as Hemophilia Treatment in Animal Studies

For the first time, researchers have combined gene therapy and stem cell transplantation to successfully reverse the severe, crippling bleeding disorder hemophilia A in large animals, opening the door to the development of new therapies for human patients.

Researchers at Wake Forest Baptist Medical Center’s Institute for Regenerative Medicine, collaborating with other institutions, report in Experimental Hematology that a single injection of genetically-modified adult stem cells in two sheep converted the severe disorder to a milder form. The journal is a publication of the Society for Hematology and Stem Cells.

“A new approach to treating severe hemophilia is desperately needed,” said lead author Christopher D. Porada, Ph.D., associate professor of regenerative medicine at Wake Forest Baptist. “About 75 percent of the world doesn’t have access to the current treatment – therapy to replace missing clotting factors. This puts patients in most of the world at risk of severe and permanent disabilities.”

Porada cautioned that challenges will need to be overcome before the treatment can be applied to humans, including that the sheep developed an immune response to the therapy that could decrease its effectiveness and duration.

There is currently no cure for the rare bleeding disorder hemophilia. People with this genetic disorder lack a protein, known as a clotting factor, needed for normal blood clotting. As a result, they may bleed for a longer time than others after an injury, as well as bleed internally, especially in joints such as the knees, ankles, and elbows. This bleeding can damage the organs and tissues and be life threatening. Even when life-threatening bleeds are prevented with replacement therapy, it doesn’t prevent smaller bleeds within the joints that can cause pain and decreased mobility.

People with hemophilia A, the most common type, are missing clotting factor VIII. For the study, the researchers used a combined stem cell/gene therapy approach to increase levels of factor VIII produced by the animals.

The scientists first inserted a gene for factor VIII into engineered mesenchymal stem cells, a type of adult stem cell. The cells – acting as a carrier for the gene – were then injected into the abdominal cavity of the sheep. The scientists selected mesenchymal stem cells to carry the gene because they have the ability to migrate to sites of injury or inflammation.

In the treated animals, the cells migrated to the joints and stopped ongoing bleeding. In addition, all spontaneous bleeding events ceased, and the existing joint damage was completely reversed, restoring normal posture and gait to these crippled animals, and enabling them to resume a normal activity level.

However, a paradox of the treatment was that while the symptoms were eliminated, the sheep developed an immune response to factor VIII, suggesting that the treatment’s effects would be reduced or shorter in duration. The scientists are currently working to learn why the immune response occurred and to develop strategies to prevent it.

“While preliminary, these findings could pave the way for a new therapy for hemophilia patients who experience debilitating bleeding in their joints,” Porada said.

The research was supported by the National Institutes of Health.

Co-authors were Graça Almeida-Porada (senior author) and Chung-Jung Kuo , both with Wake Forest Baptist; Chad Sanada, Evan Colletti, Esmail D. Zanjani, Walter Mandeville and John Hasenau, all with the University of Nevada at Reno; Robert Moot, Aflac Cancer Center and Blood Disorders Service; Christopher Doering, Emory Children’s Center Pediatrics; and H. Trent Spencer, Emory University School of Medicine.

Source: Wake Forest Baptist Medical Center