Of Mice and Men, and Women Too; Stem cell stories you might have missed

Mice brains can teach us a lot

Last week’s news headlines were dominated by one big story, the use of a stem cell transplant to effectively cure a person of HIV. But there were other stories that, while not quite as striking, did also highlight how the field is advancing.

A new way to boost brain cells (in mice!)

It’s hard to fix something if you don’t really know what’s wrong in the first place. It would be like trying to determine why a car is not working just by looking at the hood and not looking inside at the engine. The human brain is far more complex than a car so trying to determine what’s going wrong is infinitely more challenging. But a new study could help give us a new option.

Researchers in Luxembourg and Germany have developed a new computer model for what’s happening inside the brain, identifying what cells are not operating properly, and fixing them.

Antonio del Sol, one of the lead authors of the study – published in the journal Cell – says their new model allows them to identify which stem cells are active and ready to divide, or dormant. 

“Our results constitute an important step towards the implementation of stem cell-based therapies, for instance for neurodegenerative diseases. We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.”

The work, done in mice, identified a protein that helped keep brain stem cells inactive in older animals. By blocking this protein they were able to help “wake up” those stem cells so they could divide and proliferate and help regenerate the aging brain.

And if it works in mice it must work in people right? Well, that’s what they hope to see next.

Deeper understanding of fetal development

According to the Mayo Clinic between 10 and 20 percent of known pregnancies end in miscarriage (though they admit the real number may be even higher) and our lack of understanding of fetal development makes it hard to understand why. A new study reveals a previously unknown step in this development that could help provide some answers and, hopefully, lead to ways to prevent miscarriages.

Researchers at the Karolinska Institute in Sweden used genetic sequencing to follow the development stages of mice embryos. By sorting those different sequences into a kind of blueprint for what’s happening at every stage of development they were able to identify a previously unknown phase. It’s the time between when the embryo attaches to the uterus and when it begins to turn these embryonic stem cells into identifiable parts of the body.

Qiaolin Deng, Karolinska Institute

Lead researcher Qiaolin Deng says this finding provides vital new evidence.

“Being able to follow the differentiation process of every cell is the Holy Grail of developmental biology. Knowledge of the events and factors that govern the development of the early embryo is indispensable for understanding miscarriages and congenital disease. Around three in every 100 babies are born with fetal malformation caused by faulty cellular differentiation.”

The study is published in the journal Cell Reports.

Could a new drug discovery reduce damage from a heart attack?

Every 40 seconds someone in the US has a heart attack. For many it is fatal but even for those who survive it can lead to long-term damage to the heart that ultimately leads to heart failure. Now British researchers think they may have found a way to reduce that likelihood.

Using stem cells to create human heart muscle tissue in the lab, they identified a protein that is activated after a heart attack or when exposed to stress chemicals. They then identified a drug that can block that protein and, when tested in mice that had experienced a heart attack, they found it could reduce damage to the heart muscle by around 60 percent.

Prof Michael Schneider, the lead researcher on the study, published in Cell Stem Cell, said this could be a game changer.

“There are no existing therapies that directly address the problem of muscle cell death and this would be a revolution in the treatment of heart attacks. One reason why many heart drugs have failed in clinical trials may be that they have not been tested in human cells before the clinic. Using both human cells and animals allows us to be more confident about the molecules we take forward.”

Creating a platform to help transplanted stem cells survive after a heart attack

heart

Developing new tools to repair damaged hearts

Repairing, even reversing, the damage caused by a heart attack is the Holy Grail of stem cell researchers. For years the Grail seemed out of reach because the cells that researchers transplanted into heart attack patients didn’t stick around long enough to do much good. Now researchers at Stanford may have found a way around that problem.

In a heart attack, a blockage cuts off the oxygen supply to muscle cells. Like any part of our body starved off oxygen the muscle cells start to die, and as they do the body responds by creating a layer of scars, effectively walling off the dead tissue from the surviving healthy tissue.  But that scar tissue makes it harder for the heart to effectively and efficiently pump blood around the body. That reduced blood flow has a big impact on a person’s ability to return to a normal life.

In the past, efforts to transplant stem cells into the heart had limited success. Researchers tried pairing the cells with factors called peptides to help boost their odds of surviving. That worked a little better but most of the peptides were also short-lived and weren’t able to make a big difference in the ability of transplanted cells to stick around long enough to help the heart heal.

Slow and steady approach

Now, in a CIRM-funded study published in the journal Nature Biomedical Engineering, a team at Stanford – led by Dr. Joseph Wu – believe they have managed to create a new way of delivering these cells, one that combines them with a slow-release delivery mechanism to increase their chances of success.

The team began by working with a subset of bone marrow cells that had been shown in previous studies to have what are called “pro-survival factors.” Then, working in mice, they identified three peptides that lived longer than other peptides. That was step one.

Step two involved creating a matrix, a kind of supporting scaffold, that would enable the researchers to link the three peptides and combine them with a delivery system they hoped would produce a slow release of pro-survival factors.

Step three was seeing if it worked. Using fluorescent markers, they were able to show, in laboratory tests, that unlinked peptides were rapidly released over two or three days. However, the linked peptides had a much slower release, lasting more than 15 days.

Out of the lab and into animals

While these petri dish experiments looked promising the big question was could this approach work in an animal model and, ultimately, in people. So, the team focused on cardiac progenitor cells (CPCs) which have shown potential to help repair damaged hearts, but which also have a low survival rate when transplanted into hearts that have experienced a heart attack.

The team delivered CPCs to the hearts of mice and found the cells without the pro-survival matrix didn’t last long – 80 percent of the cells were gone four days after they were injected, 90 percent were gone by day ten. In contrast the cells on the peptide-infused matrix were found in large numbers up to eight weeks after injection. And the cells didn’t just survive, they also engrafted and activated the heart’s own survival pathways.

Impact on heart

The team then tested to see if the treatment was helping improve heart function. They did echocardiograms and magnetic resonance imaging up to 8 weeks after the transplant surgery and found that the mice treated with the matrix combination had a statistically improved left ventricular function compared to the other mice.

Jayakumar Rajadas, one of the authors on the paper told CIRM that, because the matrix was partly made out of collagen, a substance the FDA has already approved for use in people, this could help in applying for approval to test it in people in the future:

“This paper is the first comprehensive report to demonstrate an FDA-compliant biomaterial to improve stem cell engraftment in the ischemic heart. Importantly, the biomaterial is collagen-based and can be readily tested in humans once regulatory approval is obtained.”

 

How mice and zebrafish are unlocking clues to repairing damaged hearts

Bee-Gees

The Bee Gees, pioneers in trying to find ways to mend a broken heart. Photograph: Michael Ochs Archives

This may be the first time that the Australian pop group the Bee Gees have ever been featured in a blog about stem cell research, but in this case I think it’s appropriate. One of the Bee Gees biggest hits was “How can you mend a broken heart” and while it was a fine song, Barry and Robin Gibb (who wrote the song) never really came up with a viable answer.

Happily some researchers at the University of Southern California may succeed where Barry and Robin failed. In a study, published in the journal Nature Genetics, the USC team identify a gene that may help regenerate damaged heart tissue after a heart attack.

When babies are born they have a lot of a heart muscle cell called a mononuclear diploid cardiomyocyte or MNDCM for short. This cell type has powerful regenerative properties and so is able to rebuild heart muscle. However, as we get older we have less and less MNDCMs. By the time most of us are at an age where we are most likely to have a heart attack we are also most likely to have very few of these cells, and so have a limited ability to repair the damage.

Michaela Patterson, and her colleagues at USC, set out to find ways to change that. They found that in some adult mice less than 2 percent of their heart cells were MNDCMs, while other mice had a much higher percentage, around 10 percent. Not surprisingly the mice with the higher percentage of MNDCMs were better able to regenerate heart muscle after a heart attack or other injury.

So the USC team – with a little help from CIRM funding – dug a little deeper and did a genome-wide association study of these mice, that’s where they look at all the genetic variants in different individuals to see if they can spot common traits. They found one gene, Tnni3k, that seems to play a key role in generating MNDCMs.

Turning Tnni3K off in mice resulted in higher numbers of MNDCMs, increasing their ability to regenerate heart muscle. But when they activated Tnni3k in zebrafish it reduced the number of MNDCMs and impaired the fish’s ability to repair heart damage.

While it’s a long way from identifying something interesting in mice and zebrafish to seeing if it can be used to help people, Henry Sucov, the senior author on the study, says these findings represent an important first step in that direction:

“The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure.”

 

 

 

Using skin cells to repair damaged hearts

heart-muscle

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.

Regenerating damaged muscle after a heart attack

Cardio cells image

Images of clusters of heart muscle cells (in red and green) derived from human embryonic stem cells 40 days after transplantation. Courtesy UCLA

Every year more than 735,000 Americans have a heart attack. Many of those who survive often have lasting damage to their heart muscle and are at increased risk for future attacks and heart failure. Now CIRM-funded researchers at UCLA have identified a way that could help regenerate heart muscle after a heart attack, potentially not only saving lives but also increasing the quality of life.

The researchers used human embryonic stem cells to create a kind of cell, called a cardiac mesoderm cell, which has the ability to turn into cardiomyocytes, fibroblasts, smooth muscle, and endothelial cells. All these types of cells play an important role in helping repair a damaged heart.

As those embryonic cells were in the process of changing into cardiac mesoderms, the team was able to identify two key markers on the cell surface. The markers, called CD13 and ROR2 – which makes them sound like extras in the latest Star Wars movie – pinpointed the cells that were likely to be the most efficient at changing into the kind of cells needed to repair damaged heart tissue.

The researchers then transplanted those cells into an animal model and found that not only did many of the cells survive but they also produced the cells needed to regenerate heart muscle and vessels.

Big step forward

The research was published in the journal Stem Cell Reports. Dr. Reza Ardehali, the senior author of the CIRM-funded study, says this is a big step forward in the use of embryonic stem cells to help treat heart attacks:

“In a major heart attack, a person loses an estimated 1 billion heart cells, which results in permanent scar tissue in the heart muscle. Our findings seek to unlock some of the mysteries of heart regeneration in order to move the possibility of cardiovascular cell therapies forward. We have now found a way to identify the right type of stem cells that create heart cells that successfully engraft when transplanted and generate muscle tissue in the heart, which means we’re one step closer to developing cell-based therapies for people living with heart disease.”

More good news

But wait, as they say in cheesy TV infomercials, there’s more. Ardehali and his team not only found the markers to help them identify the right kinds of cell to use in regenerating damaged heart muscle, they also found a way to track the transplanted cells so they could make sure they were going where they wanted them to, and doing what they needed them to.

In a study published in Stem Cells Translational Medicine,  Ardehali and his team used special particles that can be tracked using MRI. They used those particles to label the cardiac mesoderm cells. Once transplanted into the animal model the team was able to follow the cells for up to 40 days.

Ardehali says knowing how to identify the best cells to repair a damaged heart, and then being able to track them over a long period, gives us valuable tools to use as we work to develop better, more effective treatments for people who have had a heart attack.

CIRM is already funding a Phase 2 clinical trial, run by a company called Capricor, using stem cells to treat heart attack patients.

 

UCLA Study Suggests New Way to Mend a Broken Heart

When you suffer a heart attack, your heart-muscle cells become deprived of oxygen. Without oxygen, the cells soon whither and die—and are entombed within scar tissue. And once these cells die, they can’t be brought back to life.

But maybe—just maybe—there is another way to build new heart muscle. And if there is, scientists like Dr. Arjun Deb at the University of California, Los Angeles (UCLA), are hot on the trail to find it.

Scar forming cells (in red) in a region of the injured heart expressing blood vessel cell marker in green and thus appearing yellow (see arrows). This study observed that approximately a third of the scar-forming cells in the injured region of the heart adopted "blood vessel" cell-like characteristics. [Credit: Dr. Arjun Deb/Nature]

Scar forming cells (in red) in a region of the injured heart expressing blood vessel cell marker in green and thus appearing yellow (see arrows). This study observed that approximately a third of the scar-forming cells in the injured region of the heart adopted “blood vessel” cell-like characteristics. [Credit: Dr. Arjun Deb/Nature]

Published yesterday in the journal Nature, Deb and his team at UCLA’s Eli & Edythe Broad Center for Regenerative Medicine and Stem Cell Research have found some scar-forming cells in the heart have the ability to become blood vessel-forming cells—if given the proper chemical ‘boost.’

“It is well known that increasing the number of blood vessels in the injured heart following a heart attack improves its ability to heal,” said Deb. “We know that scar tissue in the heart is associated with poor prognosis. Reversing or preventing scar tissue from forming has been one of the major challenges in cardiovascular medicine.”

Tackling the ever-growing problem in heart disease can seem an almost insurmountable task. While heart disease claims more lives worldwide than any other disease, advances in modern medicine in recent decades mean that more and more people are surviving heart attacks, and living with what’s called ‘heart failure,’ for their hearts can no longer beat at full capacity, and they have trouble taking long walks or even going up a flight of stairs.

Transforming this scar tissue into functioning heart muscle has therefore been the focus of many research teams, including CIRM grantees such as Drs. Deepak Srivastava and Eduardo Marbán, who have each tackled the problem from different angles. Late last year, treatment first designed by Marbán and developed by Capricor Therapeutics got the green light for a Phase 2 Clinical Trial.

In this study, Deb and his team focused on scar-forming cells, called fibroblasts, and blood-vessel forming cells, called endothelial cells. Previously, experiments in mice revealed that many fibroblasts literally transformed into endothelial cells—and helped contribute to blood vessel formation in the injured area of the heart. The team noted this phenomenon has been called the mesenchymal-endothelial transition, or MEndoT.

In this study, the researchers identified the molecular mechanism behind MEndoT—and further identified a small molecule that can enhance this transition, thus boosting the formation of blood vessels in the injured heart. This study bolsters the idea of focusing on the creation of blood vessels as a way to help reverse damage caused by a heart attack. Said Deb:

“Our findings suggest the possibility of coaxing scar-forming cells in the heart to change their identity into blood vessel-forming cells, which could potentially be a useful approach to better heart repair.”

Protein Drip Spurs Stem Cells to Save Heart Tissue

When you suffer a heart attack, beating heart muscle cells become deprived of oxygen and die—and become encased in scar tissue. Once these cells die, they can’t be brought back to life. But new research presented this week has found that injecting a protein into the heart immediately following an attack can spur stem cells to repair the damaged heart tissue.

Researchers have identified a protein that can mitigate the damage to cells caused by a heart attack

Researchers have identified a protein that can mitigate the damage to cells caused by a heart attack

Presenting at this week’s Society of Nuclear Medicine and Molecular Imaging’s Annual Meeting in St. Louis, MO, researchers from the Gunma Prefectural Cardiovascular Center in Maebashi, Japan, have found that a protein called G-CSF—when injected into the hearts of patients who recently suffered an attack—can actually spur a type of bone marrow stem cells to migrate to the heart and curb the spread of cellular death that normally takes place.

Previous research had revealed that administering G-CSF improves the heart’s ability to pump blood. In this study, the team wanted to understand how G-CSF could do so in a patient who just suffered a heart attack. Dr. Takuji Toyoma, the study’s lead author, explained in a news release:

“This study shows that the first intravenous drip infusion of G-CSF during treatment just after hospitalization was able to rescue our patients. I am confident that with additional data from a forthcoming clinical trial, this protocol can be adopted as a standard of practice.”

In this study, the researchers gathered 40 patients who had recently suffered an acute heart attack. They gave half of them an intravenous G-CSF for a period of five days, while the others received a saline solution. A year’s worth of imaging and stress tests then revealed that the earlier the G-CSF was administered, the greater the improvement in blood flow and overall cardiac function.

As Toyoma explained above, the next steps involve a forthcoming clinical trial where the precise effects of G-CSF, including the timing of when best to administer the protein, can be determined.

The research team’s preliminary efforts hold promise in the fight against heart disease. While heart disease is still the world’s number one killer, recent medical advances have increased the chances of surviving an attack. However, for those that do survive they often must live with heart failure—their hearts unable to beat at full capacity.

Many scientists, including a variety of researchers supported by CIRM, have therefore looked to regenerative medicine to regenerate lost heart muscle. The findings presented by Toyoma and his team point to another avenue by which stem cells could be harnessed to improve the quality of lives for those who have experienced a heart attack, and maybe prevent their slide into heart failure.

Protein Drip Spurs Stem Cells to Save Heart Tissue

When you suffer a heart attack, beating heart muscle cells become deprived of oxygen and die—and become encased in scar tissue. Once these cells die, they can’t be brought back to life. But new research presented this week has found that injecting a protein into the heart immediately following an attack can spur stem cells to repair the damaged heart tissue.

Researchers have identified a protein that can mitigate the damage to cells caused by a heart attack

Researchers have identified a protein that can mitigate the damage to cells caused by a heart attack

Presenting at this week’s Society of Nuclear Medicine and Molecular Imaging’s Annual Meeting in St. Louis, MO, researchers from the Gunma Prefectural Cardiovascular Center in Maebashi, Japan, have found that a protein called G-CSF—when injected into the hearts of patients who recently suffered an attack—can actually spur a type of bone marrow stem cells to migrate to the heart and curb the spread of cellular death that normally takes place.

Previous research had revealed that administering G-CSF improves the heart’s ability to pump blood. In this study, the team wanted to understand how G-CSF could do so in a patient who just suffered a heart attack. Dr. Takuji Toyoma, the study’s lead author, explained in a news release:

“This study shows that the first intravenous drip infusion of G-CSF during treatment just after hospitalization was able to rescue our patients. I am confident that with additional data from a forthcoming clinical trial, this protocol can be adopted as a standard of practice.”

In this study, the researchers gathered 40 patients who had recently suffered an acute heart attack. They gave half of them an intravenous G-CSF for a period of five days, while the others received a saline solution. A year’s worth of imaging and stress tests then revealed that the earlier the G-CSF was administered, the greater the improvement in blood flow and overall cardiac function.

As Toyoma explained above, the next steps involve a forthcoming clinical trial where the precise effects of G-CSF, including the timing of when best to administer the protein, can be determined.

The research team’s preliminary efforts hold promise in the fight against heart disease. While heart disease is still the world’s number one killer, recent medical advances have increased the chances of surviving an attack. However, for those that do survive they often must live with heart failure—their hearts unable to beat at full capacity.

Many scientists, including a variety of researchers supported by CIRM, have therefore looked to regenerative medicine to regenerate lost heart muscle. The findings presented by Toyoma and his team point to another avenue by which stem cells could be harnessed to improve the quality of lives for those who have experienced a heart attack, and maybe prevent their slide into heart failure.