How a tiny patch of skin helped researchers save the life of a young boy battling a deadly disease

 

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After receiving his new skin, the boy plays on the grounds of the hospital in Bochum, Germany. Credit: RUB

By any standards epidermolysis bullosa (EB) is a nasty disease. It’s a genetic condition that causes the skin to blister, break and tear off. At best, it’s painful and disfiguring. At worst, it can be fatal. Now researchers in Italy have come up with an approach that could offer hope for people battling the condition.

EB is caused by genetic mutations that leave the top layer of skin unable to anchor to inner layers. People born with EB are often called “Butterfly Children” because, as the analogy goes, their skin is as fragile as the wings of a butterfly. There are no cures and the only treatment involves constantly dressing the skin, sometimes several times a day. With each change of dressing, layers of skin can be peeled away, causing pain.

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Hands of a person with EB

Life and death for one boy

For Hassan, a seven-year old boy admitted to the Burn Unit of the Children’s Hospital in Bochum, Germany, the condition was particularly severe. Since birth Hassan had repeatedly developed blisters all over his body, but several weeks before being admitted to the hospital his condition took an even more serious turn. He had lost skin on around 80 percent of his body and he was battling severe infections. His life hung in the balance.

Hassan’s form of EB was caused by a mutation in a single gene, called LAMB3. Fortunately, a team of researchers at the University of Modena and Reggio Emilia in Italy had been doing work in this area and had a potential treatment.

To repair the damage the researchers took a leaf out of the way severe burns are treated, using layers of skin to replace the damaged surface. In this case the team took a tiny piece of skin, about half an inch square, from Hassan and, in the laboratory, used a retrovirus to deliver a corrected version of the defective gene into the skin cells.

 

They then used the stem cells in the skin to grow sizable sheets of new skin, ranging in size from about 20 to 60 square inches, and used that to replace the damaged skin.

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In the study, published in the journal Nature, the researchers say the technique worked quickly:

“Upon removal of the non-adhering gauze (ten days after grafting) epidermal engraftment was evident. One month after grafting, epidermal regeneration was stable and complete. Thus approximately 80% of the patient’s TBSA (total body surface area) was restored by the transgenic epidermis.”

The engrafted skin not only covered all the damaged areas, it also proved remarkably durable. In the two years since the surgery the skin has remained, in the words of the researchers, “stable and robust, and does not blister, itch, or require ointment or medications.”

In an interview in Science, Jakub Tolar, an expert on EB at the University of Minnesota, talked about the significance of this study:

“It is very unusual that we would see a publication with a single case study anymore, but this one is a little different. This is one of these [studies] that can determine where the future of the field is going to go.”

Because the treatment focused on one particular genetic mutation it won’t be a cure for all EB patients, but it could provide vital information to help many people with the disease. The researchers identified a particular category of cells that seemed to play a key role in helping repair the skin. These cells, called holoclones, could be an important target for future research.

The researchers also said that if a child is diagnosed with EB at birth then skin cells can be taken and turned into a ready-made supply of the sheets that can be used to treat skin lesions when they develop. This would enable doctors to treat problems before they become serious, rather than have to try and repair the damage later.

As for Hassan, he is now back in school, leading a normal life and is even able to play soccer.

 

 

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CIRM weekly stem cell roundup: stomach bacteria & cancer; vitamin C may block leukemia; stem cells bring down a 6’2″ 246lb football player

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This is what your stomach glands looks like from the inside:  Credit: MPI for Infection Biology”

Stomach bacteria crank up stem cell renewal, may be link to gastric cancer (Todd Dubnicoff)

The Centers for Disease Control and Prevention estimate that two-thirds of the world’s population is infected with H. pylori, a type of bacteria that thrives in the harsh acidic conditions of the stomach. Data accumulated over the past few decades shows strong evidence that H. pylori infection increases the risk of stomach cancers. The underlying mechanisms of this link have remained unclear. But research published this week in Nature suggests that the bacteria cause stem cells located in the stomach lining to divide more frequently leading to an increased potential for cancerous growth.

Tumors need to make an initial foothold in a tissue in order to grow and spread. But the cells of our stomach lining are replaced every four days. So, how would H. pylori bacterial infection have time to induce a cancer? The research team – a collaboration between scientists at the Max Planck Institute in Berlin and Stanford University – asked that question and found that the bacteria are also able to penetrate down into the stomach glands and infect stem cells whose job it is to continually replenish the stomach lining.

Further analysis in mice revealed that two groups of stem cells exist in the stomach glands – one slowly dividing and one rapidly dividing population. Both stem cell populations respond similarly to an important signaling protein, called Wnt, that sustains stem cell renewal. But the team also discovered a second key stem cell signaling protein called R-spondin that is released by connective tissue underneath the stomach glands. H. pylori infection of these cells causes an increase in R-spondin which shuts down the slowly dividing stem cell population but cranks up the cell division of the rapidly dividing stem cells. First author, Dr. Michal Sigal, summed up in a press release how these results may point to stem cells as the link between bacterial infection and increased risk of stomach cancer:

“Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed.”

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Vitamin C may have anti-blood cancer properties

Vitamin C is known to have a number of health benefits, from preventing scurvy to limiting the buildup of fatty plaque in your arteries. Now a new study says we might soon be able to add another benefit: it may be able to block the progression of leukemia and other blood cancers.

Researchers at the NYU School of Medicine focused their work on an enzyme called TET2. This is found in hematopoietic stem cells (HSCs), the kind of stem cell typically found in bone marrow. The absence of TET2 is known to keep these HSCs in a pre-leukemic state; in effect priming the body to develop leukemia. The researchers showed that high doses of vitamin C can prevent, or even reverse that, by increasing the activity level of TET2.

In the study, in the journal Cell, they showed how they developed mice that could have their levels of TET2 increased or decreased. They then transplanted bone marrow with low levels of TET2 from those mice into healthy, normal mice. The healthy mice started to develop leukemia-like symptoms. However, when the researchers used high doses of vitamin C to restore the activity levels of TET2, they were able to halt the progression of the leukemia.

Now this doesn’t mean you should run out and get as much vitamin C as you can to help protect you against leukemia. In an article in The Scientist, Benjamin Neel, senior author of the study, says while vitamin C does have health benefits,  consuming large doses won’t do you much good:

“They’re unlikely to be a general anti-cancer therapy, and they really should be understood based on the molecular understanding of the many actions vitamin C has in cells.”

However, Neel says these findings do give scientists a new tool to help them target cells before they become leukemic.

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Bad toe forces Jordan Reed to take a knee: Photo courtesy FanRag Sports

Toeing the line: how unapproved stem cell treatment made matters worse for an NFL player  

American football players are tough. They have to be to withstand pounding tackles by 300lb men wearing pads and a helmet. But it wasn’t a crunching hit that took Washington Redskins player Jordan Reed out of the game; all it took to put the 6’2” 246 lb player on the PUP (Physically Unable to Perform) list was a little stem cell injection.

Reed has had a lingering injury problem with the big toe on his left foot. So, during the off-season, he thought he would take care of the issue, and got a stem cell injection in the toe. It didn’t quite work the way he hoped.

In an interview with the Richmond Times Dispatch he said:

“That kind of flared it up a bit on me. Now I’m just letting it calm down before I get out there. I’ve just gotta take my time, let it heal and strengthen up, then get back out there.”

It’s not clear what kind of stem cells Reed got, if they were his own or from a donor. What is clear is that he is just the latest in a long line of athletes who have turned to stem cells to help repair or speed up recovery from an injury. These are treatments that have not been approved by the Food and Drug Administration (FDA) and that have not been tested in a clinical trial to make sure they are both safe and effective.

In Reed’s case the problem seems to be a relatively minor one; his toe is expected to heal and he should be back in action before too long.

Stem cell researcher and avid blogger Dr. Paul Knoepfler wrote he is lucky, others who take a similar approach may not be:

“Fortunately, it sounds like Reed will be fine, but some people have much worse reactions to unproven stem cells than a sore toe, including blindness and tumors. Be careful out there!”

Keeping intestinal stem cells in their prime

Gut stem cells (green) in the small intestine of a mouse.

The average length of the human gut is 25 feet long. That’s equivalent to four really tall people or five really short people lined up head to toe. Intestinal stem cells have the fun job of regenerating and replacing ALL the cells that line the gut. Therefore, it’s important for these stem cells to be able to self-renew, a process that replenishes the stem cell population. If this important biological process is disrupted, the intestine is at risk for diseases like inflammatory bowel disease and cancer.

This week, Stanford Medicine researchers published new findings about the biological processes responsible for regulating the regenerative capacity of intestinal stem cells. Their work, which was partially funded by CIRM, was published in the journal Nature.

Priming gut stem cells to self-renew

Scientists know that the self-renewal of intestinal stem cells is very important for a happy, functioning gut, but the nuances of what molecules and signaling pathways regulate this process have yet to be figured out. The Stanford team, led by senior author and Stanford Professor Dr. Calvin Kuo, studied two signaling pathways, Wnt and R-Spondin, that are involved in the self-renewal of intestinal stem cells in mice.

Dr. Calvin Kuo, Stanford Medicine.

“The cascade of events comprising the Wnt signaling pathway is crucial to stem cell self-renewal,” Dr. Kuo explained in an email exchange. “The Wnt pathway can be induced by either hormones classified as “Wnts” or “R-spondins”.  However, it is not known if Wnts or R-spondins cooperate to induce Wnt signaling, and if these Wnts and R-spondins have distinct functions or if they can mutually substitute for each other.   We explored how Wnts and R-spondins might cooperate to regulate intestinal stem cells – which are extremely active and regenerate the 25-foot lining of the human intestine every week.”

The team used different reagents to activate or block Wnt or R-spondin signaling and monitored the effects on intestinal stem cells. They found that both were important for the self-renewal of intestinal stem cells, but that they played different roles.

“Our work revealed that Wnts and R-spondins are not equivalent and that they have very distinct functions even though they both trigger the Wnt signaling cascade,” said Dr. Kuo. “Both Wnts and R-spondins are required to maintain intestinal stem cells.  However, Wnts perform more of a subservient “priming” function, where they prepare intestinal stem cells for the action of R-spondin, which is the active catalyst for inducing intestinal stem cells to divide.”

The authors believe that this multi-step regulation, involving priming and self-renewal factors could apply to stem cell systems in other organs and tissues in the body. Some of the researchers on this study including Dr. Kuo are pursuing this idea through a new company called Surrozen, which produces artificial bioengineered Wnt molecules that don’t require activation like natural Wnt molecules. These Wnt molecules were used in the current study and are explained in more detail in a separate Nature article published at the same time.

The company believes that artificial Wnts will be useful for understanding stem cell biology and potentially for therapeutic applications. Dr. Kuo explained,

“The new surrogate Wnts are easily produced and can circulate in the bloodstream, unlike natural Wnts.  There may be medical applications of these bioengineered Wnt surrogates in stimulating various stem cell compartments of the body, given the wide range of stem cells that are governed by natural Wnts.”

Pregnant women’s stem cells could help battle brittle bone diseases like osteoporosis

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Sometimes I wonder how a scientist ever came up with an idea for a potential treatment. Case in point is a study in the journal Scientific Reports, where researchers use stem cells from the amniotic fluid of a pregnant woman to cure osteoporosis in mice! What researcher, seeing a pregnant woman, thought to her or himself “I wonder if…..”

Regardless of how they came up with the idea, we might be glad they did because this study showed that those stem cells could reduce the number of fractures in mice with brittle bone disease by 78 percent. And that’s raising hopes they might one day be able to do the same for people.

Researchers at University College London took mesenchymal stem cells (MSCs) that had been shed by babies into the amniotic fluid of their mother, and injected them into mice with brittle bone disease. Previous studies had suggested that MSCs, taken at such an early age, might be more potent than similar cells taken from adults. That certainly seems to have been the case here where the treated mice had far fewer fractures than untreated mice.

Pascale Guillot, the lead researcher of the study, told the Guardian newspaper:

“The stem cells we’ve used are excellent at protecting bones. The bones become much stronger and the way the bone is organised internally is of much higher quality.”

 

What was also interesting was not just what they did but how they did it. You might think that the injected stem cells helped reduce fractures by forming new bones. You might think that, but you’d be wrong. Instead, the stem cells seem to have worked by releasing growth factors that stimulated the mouse’s own bone cells to kick into a higher gear, and help build stronger bones.

In the study the researchers say using MSCs from amniotic fluid has a number of distinct advantages over using MSCs from adults:

  • They are easier to expand into large numbers needed for therapies
  • They don’t create tumors
  • The body’s immune system won’t attack them
  • They are smaller and so can move around with greater ease
  • They are easier to reprogram into different kinds of cells

Next Guillot and his team want to explore if this approach could be used to treat children and adults with brittle bone disease, and to help adults with osteoporosis, a problem that affects around 44 million people in the US.

 “The discovery could have a profound effect on the lives of patients who have fragile bones and could stop a large number of their painful fractures.”

Failed stem cells may cause deadly lung disease

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Breathing is something we take for granted. It’s automatic. We don’t need to think about it. But for people with pulmonary fibrosis, breathing is something that is always on their minds.

Pulmonary fibrosis (PF) is a disease where the tissue in your lungs becomes thick and stiff, even scarred, making it difficult to breathe. It can be a frightening experience; and it doesn’t just affect your lungs.

Because your lungs don’t work properly they aren’t able to move as much oxygen as you need into your bloodstream, and that can have an impact on all your other organs, such as your brain and heart. There are some treatments but no cures, in large part because we didn’t know the cause of the disease. Many patients with PF live only 3-5 years after diagnosis.

Now a new CIRM-funded study from researchers at Cedars-Sinai has uncovered clues as to the cause of the disease, and that in turn could pave the way to new treatments.

The study, published in the journal Nature, found that a class of stem cells in the lung, called AEC2s, are responsible for helping repair damage caused by things such as pollution or infection. People who have PF have far fewer of these AEC2 cells, and those cells also had a much lower concentration of a chemical substance called hyaluronan, which is essential for repair damaged tissue.

They tested this theory with laboratory mice and found that by removing hyaluronan the mice developed thick scarring in their lungs.

In a news release from Cedars-Sinai Carol Liang, the study’s first author, said knowing the cause of the problem may help identify potential solutions:

“These findings are the first published evidence that idiopathic pulmonary fibrosis is primarily a disease of AEC2 stem cell failure. In further studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches.”

Knowing that a problem with AEC2 cells causes PF means the researchers can now start testing different medications to see which ones might help boost production of replacement AEC2 cells, or help protect those still functioning.

Using skin cells to repair damaged hearts

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Heart muscle  cells derived from skin cells

When someone has a heart attack, getting treatment quickly can mean the difference between life and death. Every minute delay in getting help means more heart cells die, and that can have profound consequences. One study found that heart attack patients who underwent surgery to re-open blocked arteries within 60 minutes of arriving in the emergency room had a six times greater survival rate than people who had to wait more than 90 minutes for the same treatment.

Clearly a quick intervention can be life-saving, which means an approach that uses a patient’s own stem cells to treat a heart attack won’t work. It simply takes too long to harvest the healthy heart cells, grow them in the lab, and re-inject them into the patient. By then the damage is done.

Now a new study shows that an off-the-shelf approach, using donor stem cells, might be the most effective way to go. Scientists at Shinshu University in Japan, used heart muscle stem cells from one monkey, to repair the damaged hearts of five other monkeys.

In the study, published in the journal Nature, the researchers took skin cells from a macaque monkey, turned those cells into induced pluripotent stem cells (iPSCs), and then turned those cells into cardiomyocytes or heart muscle cells. They then transplanted those cardiomyocytes into five other monkeys who had experienced an induced heart attack.

After 3 months the transplanted monkeys showed no signs of rejection and their hearts showed improved ability to contract, meaning they were pumping blood around the body more powerfully and efficiently than before they got the cardiomyocytes.

It’s an encouraging sign but it comes with a few caveats. One is that the monkeys used were all chosen to be as close a genetic match to the donor monkey as possible. This reduced the risk that the animals would reject the transplanted cells. But when it comes to treating people, it may not be feasible to have a wide selection of heart stem cell therapies on hand at every emergency room to make sure they are a good genetic match to the patient.

The second caveat is that all the transplanted monkeys experienced an increase in arrhythmias or irregular heartbeats. However, Yuji Shiba, one of the researchers, told the website ResearchGate that he didn’t think this was a serious issue:

“Ventricular arrhythmia was induced by the transplantation, typically within the first four weeks. However, this post-transplant arrhythmia seems to be transient and non-lethal. All five recipients of [the stem cells] survived without any abnormal behaviour for 12 weeks, even during the arrhythmia. So I think we can manage this side effect in clinic.”

Even with the caveats, this study demonstrates the potential for a donor-based stem cell therapy to treat heart attacks. This supports an approach already being tested by Capricor in a CIRM-funded clinical trial. In this trial the company is using donor cells, derived from heart stem cells, to treat patients who developed heart failure after a heart attack. In early studies the cells appear to reduce scar tissue on the heart, promote blood vessel growth and improve heart function.

The study from Japan shows the possibilities of using a ready-made stem cell approach to helping repair damage caused by a heart attacks. We’re hoping Capricor will take it from a possibility, and turn it into a reality.

If you would like to read some recent blog posts about Capricor go here and here.