Deep dive into muscle repair yields new strategies to combat Duchenne muscular dystrophy

Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) reported new findings this week that may lead to novel therapeutic strategies for people suffering from Duchenne muscular dystrophy (DMD). DMD, a muscle-wasting disease that affects 1 in 7250 males aged 5 to 24 years in the United States, is caused by a genetic mutation leading to the lack of a protein called dystrophin. Without dystrophin, muscle cells become fragile and are easily damaged. Instead of self-repair, the muscles are replaced by scar tissue, a process called fibrosis that leads to muscle degeneration and wasting.

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Dystrophin, a protein that maintains the structural integrity of muscle fibers, is missing in people with DMD. Image credit: Khan Academy

Boys with DMD first show signs of muscle weakness between ages 3-5 and often stop walking by the time they’re teenagers. Eventually the muscles critical for breathing and heart function stop working. Average life expectancy is 26 and there is no cure.

The SBP scientists are aiming to treat DMD by boosting muscle repair in affected individuals. But to do that, they sought to better understand how muscle regeneration works in the first place. In the current study, they focused their efforts on so-called fibro/adipogenic precursor (FAP) cells which, in response to acute injury, appear to play a role in stimulating muscle stem cells to divide and replace damaged muscle in healthy individuals. But FAPs are also implicated in the muscle wasting and scarring that’s seen in DMD.

By examining the gene activity of single FAP cells from mouse models of acute injury and DMD, the researchers identified a sub-population of FAP cells (sub-FAPs). Further study of these sub-FAPs showed that during early stages of muscle regeneration, these cells promote muscle stem cell activation but then at later stages, sub-FAPs – identified by a cell surface protein called Vcam1 – stimulate fibrosis. It turns out that during healthy acute muscle injury, the sub-FAPs with cell-surface Vcam1 protein are readily eaten up and removed by immune cells thereby avoiding muscle fibrosis. But in the DMD mouse model, removal of these sub-FAPs is impaired and instead collagen deposits and muscle fibrosis occur which are hallmarks of the progressive degeneration seen in DMD.

Barbora Malecova, Ph.D., a first author of the study, explained the implications of these results in a press release:

“This study elucidates the cellular and molecular pathogenesis of muscular dystrophy. These results indicate that removing or modulating the activity of Vcam1-positive sub-FAPs, which promote fibrosis, could be an effective treatment for DMD.”

The lab, led by Pier Lorenzo Puri, M.D., next will explore the possibility of finding drugs that target the Vcam1 sub-FAPs which in turn could help prevent fibrosis in DMD.

The study, funded in part by CIRM, appears in Nature Communications. CIRM is also funding a Phase 2 clinical trial testing a stem cell-based therapy that aims to improve the life-threatening heart muscle degeneration that occurs in DMD patients.

A scalable, clinic-friendly recipe for converting skin cells to muscle cells

Way back in 1987, about two decades before Shinya Yamanaka would go on to identify four proteins that can reprogram skin cells into induced pluripotent stem cells (iPSCs), Harold Weintraub’s lab identified the first “master control” protein, MyoD, which can directly convert a skin cell into a muscle cell. Though MyoD opened up new approaches for teasing out the molecular mechanisms of a cell’s identity, it did not produce therapeutic paths for replacing muscle damaged by disease and injury.

That’s because MyoD-generated muscle cells are not amenable to a clinical setting. For a cell therapy to be viable, you need to manufacture large amounts of your product to treat many people. But these MyoD cells do not grow well enough to be effective to serve as a cell replacement therapy. Generating iPSC-derived muscle cells provides the potential of overcoming this limitation but the capacity of the embryonic stem cell-like iPSC for unlimited growth carries a risk of forming tumors after the transplanting iPSC-derived cell therapies into the muscle.

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This image shows iMPCs stained for markers of muscle stem, progenitor and differentiated cells. iMPCs recapitulate muscle differentiation in a dish. Credit: Ori Bar-Nur and Mattia Gerli

A recent study in Stem Cell Reports, by Konrad Hochedlinger’s lab at Massachusetts General Hospital and the Harvard Stem Cell Institute, may provide a work around. The team came up with a recipe that calls for the temporary activation of MyoD in mouse skin cells, along with the addition of three molecules that boost cell reprogramming. The result? Cells they dubbed induced myogenic progenitor cells, or iMPCs, that can make self-sustaining copies of themselves and can be scaled up for manufacturing purposes. On top of that, they show that these iMPCs carry the hallmarks of muscle stem cells and generate muscle fibers when transplanted into mice with leg injuries without signs of tumor formation.

A lot of work still remains to be done, like confirming that these iMPCs truly have the same characteristics as muscle stem cells. But if everything pans out, the potential applications for people suffering from various muscle disorders and injuries is very exciting, as co-first author Mattia FM Gerli, PhD points out in a press release:

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Mattia FM Gerli, PhD

“Patient-specific iMPCs could be used for personalized medicine by treating patients with their own genetically matched cells. If disease-causing mutations are known, as is the case in many muscular dystrophies, one could in principle repair the mutation in iMPCs prior to transplantation of the corrected cells back into the patient.”

Stem Cell Roundup: Improving muscle function in muscular dystrophy; Building a better brain; Boosting efficiency in making iPSC’s

Here are the stem cell stories that caught our eye this week.

Photos of the week

TGIF! We’re so excited that the weekend is here that we are sharing not one but TWO amazing stem cell photos of the week.

RMI IntestinalChip

Image caption: Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. (Photo credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute)

Photo #1 is borrowed from a blog we wrote earlier this week about a new stem cell-based path to personalized medicine. Scientists at Cedars-Sinai are collaborating with a company called Emulate to create intestines-on-a-chip using human stem cells. Their goal is to create 3D-organoids that represent the human gut, grow them on chips, and use these gut-chips to screen for precision medicines that could help patients with intestinal diseases. You can read more about this gut-tastic research here.

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Image caption: UCLA scientists used four different fluorescent-colored proteins to determine the origin of cardiomyocytes in mice. (Image credit: UCLA Broad Stem Cell Research Center/Nature Communications)

Photo #2 is another beautiful fluorescent image, this time of a cross-section of a mouse heart. CIRM-funded scientists from UCLA Broad Stem Cell Research Center are tracking the fate of stem cells in the developing mouse heart in hopes of finding new insights that could lead to stem cell-based therapies for heart attack victims. Their research was published this week in the journal Nature Communications and you can read more about it in a UCLA news release.

Stem cell injection improves muscle function in muscular dystrophy mice

Another study by CIRM-funded Cedars-Sinai scientists came out this week in Stem Cell Reports. They discovered that they could improve muscle function in mice with muscular dystrophy by injecting cardiac progenitor cells into their hearts. The injected cells not only improved heart function in these mice, but also improved muscle function throughout their bodies. The effects were due to the release of microscopic vesicles called exosomes by the injected cells. These cells are currently being used in a CIRM-funded clinical trial by Capricor therapeutics for patients with Duchenne muscular dystrophy.

How to build a better brain (blob)

For years stem cell researchers have been looking for ways to create “mini brains”, to better understand how our own brains work and develop new ways to repair damage. So far, the best they have done is to create blobs, clusters of cells that resemble some parts of the brain. But now researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have come up with a new method they think can advance the field.

Their approach is explained in a fascinating article in the journal Science News, where lead researcher Bennet Novitch says finding the right method is like being a chef:

“It’s like making a cake: You have many different ways in which you can do it. There are all sorts of little tricks that people have come up with to overcome some of the common challenges.”

Brain cake. Yum.

A more efficient way to make iPS cells

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Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

In 2006 Shinya Yamanaka discovered a way to take ordinary adult cells and reprogram them into embryonic-like stem cells that have the ability to turn into any other cell in the body. He called these cells induced pluripotent stem cells or iPSC’s. Since then researchers have been using these iPSC’s to try and develop new treatments for deadly diseases.

There’s been a big problem, however. Making these cells is really tricky and current methods are really inefficient. Out of a batch of, say, 1,000 cells sometimes only one or two are turned into iPSCs. Obviously, this slows down the pace of research.

Now researchers in Colorado have found a way they say dramatically improves on that. The team says it has to do with controlling the precise levels of reprogramming factors and microRNA and…. Well, you can read how they did it in a news release on Eurekalert.

 

 

 

Stem Cell Stories that Caught Our Eye: GPS for Skin & Different Therapies for Aging vs. Injured Muscles?

Skin stem cells specialize into new skin by sensing neighborhood crowding
When embarking on a road trip, the GPS technology inside our smartphones helps us know where we are and how to get where we’re going. The stem cells buried in the deepest layers of our skin don’t have a GPS and yet, they do just fine determining their location, finding their correct destination and becoming the appropriate type of skin cell. And as a single organ, all the skin covering your body maintains the right density and just the right balance of skin stem cells versus mature skin cells as we grow from a newborn into adult.

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Skin cells growing in a petri dish (green: cytoskeleton, red: cell-cell junction protein).
Credit: MPI for Biology of Aging

This easily overlooked but amazing feat is accomplished as skin cells are continually born and die about every 30 days over your lifetime. How does this happen? It’s an important question to answer considering the skin is our first line of defense against germs, toxins and other harmful substances.

This week, researchers at the Max Planck Institute for Biology of Aging in Cologne, Germany reported a new insight into this poorly understood topic. The team showed that it all comes down to the skin cells sensing the level of crowding in their local environment. As skin stem cells divide, it puts the squeeze on neighboring stem cells. This physical change in tension on these cells “next door” triggers signals that cause them to move upward toward the skin surface and to begin maturing into skin cells.

Lead author Yekaterina Miroshnikova explained in a press release the beauty of this mechanism:

“The fact that cells sense what their neighbors are doing and do the exact opposite provides a very efficient and simple way to maintain tissue size, architecture and function.”

The research was picked up by Phys.Org on Tuesday and was published in Nature Cell Biology.

Stem cells respond differently to aging vs. injured muscle
From aging skin, we now move on to our aging and injured muscles, two topics I know oh too well as a late-to-the-game runner. Researchers at the Sanford Burnham Prebys Medical Discovery Institute (SBP) in La Jolla report a surprising discovery that muscle stem cells respond differently to aging versus injury. This important new insight could help guide future therapeutic strategies for repairing muscle injuries or disorders.

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Muscle stem cell (pink with green outline) sits along a muscle fiber.
Image: Michael Rudnicki/OIRM

Muscle stem cells, also called satellite cells, make a small, dormant population of cells in muscle tissue that springs to life when muscle is in need of repair. It turns out that these stem cells are not identical clones of each other but instead are a diverse pool of cells.  To understand how the assortment of muscle stem cells might respond differently to the normal wear and tear of aging, versus damage due to injury or disease, the research team used a technology that tracks the fate of individual muscle stem cells within living mice.

The analysis showed a clear but unexpected result. In aging muscle, the muscle stem cells maintained their diversity but their ability to divide and grow declined. However, the opposite result was observed in injured muscle: the muscle stem cell diversity became limited but the capacity to divide was not affected. In a press release, team leader Alessandra Sacco explains the implications of these findings for therapy development:

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Alessandra Sacco, PhD

“This study has shown clear-cut differences in the dynamics of muscle stem cell pools during the aging process compared to a sudden injury. This means that there probably isn’t a ‘one size fits all’ approach to prevent the decline of muscle stem cells. Therapeutic strategies to maintain muscle mass and strength in seniors will most likely need to differ from those for patients with degenerative diseases.”

This report was picked up yesterday by Eureka Alert and published in Cell Stem Cell.

Stem Cell Stories That Caught our Eye: Stem Cell Therapies for Stroke and Duchenne Muscular Dystrophy Patients

With the Thanksgiving holiday behind us, we’re back to the grind at CIRM. Here are two exciting CIRM-funded stem cell stories that happened while you were away.

Stanford Scientists Are Treating Stroke Patients with Stem Cells

Smithsonian Magazine featured the work of a CIRM-funded scientist in their December Magazine issue. The article, “A Neurosurgeon’s Remarkable Plan to Treat Stroke Victims with Stem Cells”, features Dr. Gary Steinberg, who is the Chair of Neurosurgery at Stanford Medical Center and the founder of the Stanford Stroke Center.

Gary Steinberg (Photo by Jonathan Sprague)

The brain and its 100 billion cells need blood, which carries oxygen and nutrients, to function. When that blood supply is cut off, brain cells start to die and patients experience a stroke. Stroke can happen in one of two ways: either by blood clots that block the arteries and blood vessels that send blood to the brain or by blood vessels that burst within the brain itself. Symptoms experienced by stroke victims vary based on the severity of the stroke, but often patients report experiencing numbness or paralysis in their limbs or face, difficulty walking, talking and understanding.

Steinberg and his team at Stanford are developing a stem cell treatment to help stroke patients. Steinberg believes that not all brain cells die during a stroke, but rather some brain cells become “dormant” and stop functioning instead. By transplanting stem cells derived from donated bone marrow into the brains of stroke patients, Steinberg thinks he can wake up these dormant cells much like how the prince wakens Sleeping Beauty from her century of enchanted sleep.

Basically, the transplanted cells act like a defibrillator for the dormant cells in the stroke-damaged area of the brain. Steinberg thinks that the transplanted cells secrete proteins that signal dormant brain cells to wake up and start functioning normally again, and that they also trigger a “helpful immune response” that prompts the brain to repair itself.

Sonia has seen first hand how a stroke can rob you of even your most basic abilities.

Steinberg tested this stem cell treatment in a small clinical trial back in 2013. 18 patients were treated and many of them showed improvements in their symptoms. The Smithsonian piece mentions a particular patient who had a remarkable response to the treatment. Sonia Olea Coontz, at age 32, suffered a stroke that robbed her of most of her speech and her ability to use her right arm and leg. After receiving Steinberg’s stem cell treatment, Sonia rapidly improved and was able to raise her arm above her head and gained most of her speech back. You can read more about her experience in our Stories of Hope.

In collaboration with a company called SanBio, Steinberg’s team is now testing this stem cell therapy in 156 stroke patients in a CIRM-funded phase 2 clinical trial. The trial will help answer the question of whether this treatment is safe and also effective in a larger group of patients.

The Smithsonian article, which I highly recommend reading, shared Steinberg’s future aspirations to pursue stem cell therapies for traumatic brain and spinal cord injuries as well as neurodegenerative diseases like Alzheimer’s, Parkinson’s and ALS.

 

Capricor Approved to Launch New Clinical Trial for Duchenne Muscular Dystrophy

On Wednesday, Capricor Therapeutics achieved an exciting milestone for its leading candidate CAP-1002 – a stem cell-based therapy developed to treat boys and young men with a muscle-wasting disease called Duchenne muscular dystrophy (DMD).

The Los Angeles-based company announced that it received approval from the US Food and Drug Administration (FDA) for their investigational new drug (IND) application to launch a new clinical trial called HOPE II that’s testing repeated doses of CAP-1002 cells in DMD patients. The cells are derived from donated heart tissue and are believed to release regenerative factors that strengthen heart and other muscle function in DMD patients.

Capricor is currently conducting a Phase 2 trial, called HOPE-1, that’s testing a single dose of CAP-1002 cells in 24 DMD patients. CIRM is funding this trial and you can learn more about it on our clinical dashboard website and watch a video interview we did with a young man who participated in the trial.

Earlier this year, the company shared encouraging, positive results from the HOPE-1 trial suggesting that the therapy was improving some heart function and upper limb movement six months after treatment and was well-tolerated in patients. The goal of the new trial will be to determine whether giving patients repeated doses of the cell therapy over time will extend the benefits in upper limb movement in DMD patients.

In a news release, Capricor President and CEO Dr. Linda Marbán shared her company’s excitement for the launch of their new trial and what this treatment could mean for DMD patients,

Linda Marban, CEO of Capricor Therapeutics

“The FDA’s clearance of this IND upon its initial submission is a significant step forward in our development of CAP-1002. While there are many clinical initiatives in Duchenne muscular dystrophy, this is one of the very few to focus on non-ambulant patients. These boys and young men are looking to maintain what function they have in their arms and hands and, based on our previous study, we think CAP-1002 may be able to do exactly that.”

Raising awareness about Rare Disease Day

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One of the goals we set ourselves at CIRM in our 2016 Strategic Plan was to fund 50 new clinical trials over the next five years, including ten rare or orphan diseases. Since then we have funded 13 new clinical trials including four targeting rare diseases (retinitis pigmentosa, severe combined immunodeficiency, ALS or Lou Gehrig’s disease, and Duchenne’s Muscular Dystrophy). It’s a good start but clearly, with almost 7,000 rare diseases, this is just the tip of the iceberg. There is still so much work to do.

And all around the world people are doing that work. Today we have asked Emily Walsh, the Community Outreach Director at the Mesothelioma Cancer Alliance,  to write about the efforts underway to raise awareness about rare diseases, and to raise funds for research to develop new treatments for them.

“February 28th marks the annual worldwide event for Rare Disease Day. This is a day dedicated to raising awareness for rare diseases that affect people all over the world. The campaign works to target the general public as well as policy makers in hopes of bringing attention to diseases that receive little attention and funding. For the year 2017 it was decided that the focus would fall on “research,” with the slogan, “With research, possibilities are limitless.”

Getting involved for Rare Disease Day means taking this message and spreading it far and wide. Awareness for rare diseases is extremely important, especially among researchers, universities, students, companies, policy makers, and clinicians. It has long been known that the best advocates for rare diseases are the patients themselves. They use their specific perspectives to raise their voice, share their story, and shed light on the areas where additional funding and research are most necessary.

To see how you can help support the Rare Disease Day efforts this year, click here.

Groups like the Mesothelioma Cancer Alliance and the Mesothelioma Group are adding their voices to the cause to raise awareness about mesothelioma cancer, a rare form of cancer caused by exposure and inhalation of airborne asbestos fibers

Rare diseases affect 300 million people worldwide, but only 5% of them have an FDA approved treatment or cure. Malignant mesothelioma is among the 95 percent that doesn’t have a treatment or cure.

Asbestos has been used throughout history in building materials because of its fire retardant properties. Having a home with asbestos insulation, ceiling tiles, and roof shingles meant that the house was safer. However, it was found that once asbestos crumbled and became powder-like, the tiny fibers could become airborne and be inhaled and lodge themselves in lung tissue causing mesothelioma. The late stage discovery of mesothelioma is often what causes it to have such a high mortality rate. Symptoms can have a very sudden onset, even though the person may have been exposed decades prior.

Right now, treatment for mesothelioma includes the usual combination of chemotherapy, radiation, and surgery, but researchers are looking at other approaches to see if they can be more effective or can help in conjunction with the standard methods. For example one drug, Defactinib, has shown some promise in inhibiting the growth and spread of cancer stem cells – these are stem cells that can evade chemotherapy and cause patients to relapse.”

Some people might ask why spend limited resources on something that affects so few people. But the lessons we learn in developing treatments for a rare disease can often lead us to treatments for diseases that affect many millions of people.

But numbers aside, there is no hierarchy of need, no scale to say the suffering of people with Huntington’s disease is any greater or less than that of people with Alzheimer’s. We are not in the business of making value judgements about who has the greatest need. We are in the business of accelerating treatments to patients with unmet medical needs. And those suffering from rare disease are very clearly  people in need.

 


Related Links:

Cured by Stem Cells

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To get anywhere you need a good map, and you need to check it constantly to make sure you are still on the right path and haven’t strayed off course. A year ago the CIRM Board gave us a map, a Strategic Plan, that laid out our course for the next five years. Our Annual Report for 2016, now online, is our way of checking that we are still on the right path.

I think, without wishing to boast, that it’s safe to say not only are we on target, but we might even be a little bit ahead of schedule.

The Annual Report is chock full of facts and figures but at the heart of it are the stories of the people who are the focus of all that we do, the patients. We profile six patients and one patient advocate, each of whom has an extraordinary story to tell, and each of whom exemplifies the importance of the work we support.

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Brenden Whittaker: Cured

Two stand out for one simple reason, they were both cured of life-threatening conditions. Now, cured is not a word we use lightly. The stem cell field has been rife with hyperbole over the years so we are always very cautious in the way we talk about the impact of treatments. But in these two cases there is no need to hold back: Evangelina Padilla Vaccaro and Brenden Whittaker have been cured.

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Evangelina: Cured

 

In the coming weeks we’ll feature our conversations with all those profiled in the Annual Report, giving you a better idea of the impact the stem cell treatments have had on their lives and the lives of their family. But today we just wanted to give a broad overview of the Annual Report.

The Strategic Plan was very specific in the goals it laid out for us. As an agency we had six big goals, but each Team within the agency, and each individual within those teams had their own goals. They were our own mini-maps if you like, to help us keep track of where we were individually, knowing that every time an individual met a goal they helped the Team get closer to meeting its goals.

As you read through the report you’ll see we did a pretty good job of meeting our targets. In fact, we missed only one and we’re hoping to make up for that early in 2017.

But good as 2016 was, we know that to truly fulfill our mission of accelerating treatments to patients with unmet medical needs we are going to have do equally well, if not even better, in 2017.

That work starts today.

 

Stem cells have a neat trick to prevent tissue scarring

A CIRM-funded study from the Stanford University School of Medicine has discovered that stem cells in muscle tissue “police themselves” to reduce fibrosis or the buildup of scar tissue. The ability to prevent scarring could promote anti-aging properties by keeping muscles healthy and functional and could also benefit patients with muscle wasting diseases like muscular dystrophy. The study appeared in the journal Nature earlier this week.

The Stanford team, led by Professor Thomas Rando, was interested in understanding how healthy muscle tissue regenerates under normal conditions and in response to injury. They focused on cells called fibro-adipogenic progenitors (FAPs), which live in the muscle and produce a framework of connective tissue that promotes muscle regeneration.

By studying FAPs in mice, the scientists found that these cells produced a protein called platelet-derived growth factor receptor alpha (PDGFRa), which regulates their ability to proliferate, or make more copies of themselves. FAPs produce different versions of PDGFRa as a way to police themselves and deal with injury and disease.

The normal version of PDGFRa tells FAPs to divide and proliferate. Typically, this response is a good thing if FAPs are trying to repair tissue damage, but too much cell proliferation can lead to fibrosis and scarring. To counteract this, FAPs can produce a truncated version of PDGFRa, which tells FAPs to stop dividing and prevents tissue scarring.

Senior author on the study, Professor Thomas Rando, explained in a Stanford Medicine news release why it’s important to prevent scarring in muscle tissue:

Dr. Thomas Rando, Stanford

Dr. Thomas Rando, Stanford

“Fibrosis occurs in many degenerative diseases and also in normal aging. It negatively impacts muscle regeneration by altering the stem cell niche and inhibiting the stem cell function. In addition, as more scarring occurs, muscles become stiff and can’t contract and relax smoothly.”

 

Knowing that the truncated version of PDGFRa can stop FAPs from proliferating too much and cause scarring, the team found a way to force FAPs to generate this shortened version of PDGFRa in mice. When they tried this approach in mice, they observed that both young and old mice produced less scarring after healing from muscle injury. On the other hand, if these mice produced less of the truncated PDGFRa, the mice had more scarring than they normally would.

Nature.

Muscle tissue in old mice shows signs of scarring (left) while old mice treated with the truncated PDGFRa have reduced scarring in their muscle (right). (Nature)

Rando’s team believes that they can harness the properties of self-policing stem cells like FAPs to develop new potential therapies that can treat fibrotic diseases. In future studies, Rando hopes to apply their approach to treating muscular dystrophy – a muscle wasting disease that also is associated with increased fibrosis.

“We’d like to test this approach in a mouse model of muscular dystrophy next. Perhaps we could also use this approach to reduce fibrosis in this disease.”

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.

Scientists find new stem cell target for regenerating aging muscles

Young Arnold (wiki)

Young Arnold (wiki)

Today I’m going to use our former governor Arnold Schwarzenegger as an example of what happens to our muscles when we age.

One of Arnold’s many talents when he was younger was being a professional bodybuilder. As you can see in this photo, Arnold worked hard to generate an impressive amount of muscle that landed him lead roles in movies Conan the Barbarian and The Terminator.

Older Arnold

Older Arnold

If you look at pictures of Arnold now (who is now 68), while still being an impressively large human being, it’s obvious that much of his muscular bulk has diminished. That’s because as humans age, so do their muscles.

Muscles shrink with age

As muscles age, they slowly lose mass and shrink (a condition called sarcopenia) because of a number of reasons – one of them being their inability to regenerate new muscle tissue efficiently. The adult stem cells responsible for muscle regeneration are called satellite cells. When muscles are injured, satellite cells are activated to divide and generate new muscle fibers that can repair injury and also improve muscle function.

However, satellite cells become less efficient at doing their job over time because of environmental and internal reasons, and scientists are looking for new targets that can restore and promote the regenerative abilities of muscle stem cells for human therapeutic applications.

A study published earlier this week in Nature Medicine, identified a potential new target that could boost muscle stem cell regeneration and improved muscle function in a mouse model of Duchenne muscular dystrophy.

β1-integrin is important for muscle regeneration

Scientists from the Carnegie Institute of Washington found that β1-integrin is important for maintaining the homeostasis (or balance) of the muscle stem cell environment. If β1-integrin is doing its job properly, muscle stem cells are able to go about their regular routine of being dormant, activating in response to injury, dividing to create new muscle tissue, and then going back to sleep.

When the scientists studied the function of β1-integrin in the muscles of aged mice, they found that the integrin wasn’t functioning properly. Without β1-integrin, mouse satellite cells spontaneously turned into muscle tissue and were unable to maintain their regenerative capacity following muscle injury.

Upon further inspection, they found that β1-integrin interacts with a growth factor called fibroblast growth factor 2 (Fgf2) and this relationship was essential for promoting muscle regeneration following injury. When β1-integrin function deteriorates as in the muscles of aged mice, the mice lose sensitivity to the regenerative capacity of Fgf2.

Restoring muscle function in mice with muscular dystrophy

By using an antibody to artificially activate β1-integrin function in the muscles of aged mice, they were able to restore Fgf2 responsiveness and boosted muscle regeneration after injury. When a similar technique was used in mice with Duchenne muscular dystrophy, they observed muscle regeneration and improved muscle function.

Muscle loss seen in muscular dystrophy mice (left). Treatment with beta1 intern boosts muscle regeneration in the same mice (right). (Nature Medicine)

Muscle loss seen in muscular dystrophy mice (left). Treatment with B1-integrin boosts muscle regeneration in the same mice (right). (Nature Medicine)

The authors believe that β1-integrin acts as a sensor of the muscle stem cell environment that it maintains a balance between a dormant and a regenerative stem cell state. They conclude in their publication:

“β1-integrin senses the SC [satellite cell] niche to maintain responsiveness to Fgf2, and this integrin represents a potential therapeutic target for pathological conditions of the muscle in which the stem cell niche is compromised.”

Co-author on the study Dr. Chen-Ming Fan also spoke to the clinical relevance of their findings in a piece by GenBio:

“Inefficient muscular healing in the elderly is a significant clinical problem and therapeutic approaches are much needed, especially given the aging population. Finding a way to target muscle stem cells could greatly improve muscle renewal in older individuals.”

Does this mean anyone can be a body builder?

So does this study mean that one day we can prevent muscle loss in the elderly and all be body builders like Arnold? I highly doubt that. It’s important to remember these are preclinical studies done in mouse models and much work needs to be done to test whether β1-integrin is an appropriate therapeutic target in humans.

However, I do think this study sheds new light on the inner workings of the muscle stem cell environment. Finding out more clues about how to promote the health and regenerative function of this environment will bring the field closer to generating new treatments for patients suffering from muscle wasting diseases like muscular dystrophy.