Could revving up stem cells help senior citizens heal as fast as high school seniors?

All physicians, especially surgeons, sport medicine doctors, and military medical corps share a similar wish: to able to speed up the healing process for their patients’ incisions and injuries. Data published this week in Cell Reports may one day fulfill that wish. The study – reported by a Stanford University research team – pinpoints a single protein that revs up stem cells in the body, enabling them to repair tissue at a quicker rate.

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Muscle fibers (dark areas surrounding by green circles) are larger in mice injected with HGFA protein (right panel) compared to untreated mice (left panel), an indication of faster healing after muscle injury.
(Image: Cell Reports 19 (3) p. 479-486, fig 3C)

Most of the time, adult stem cells in the body keep to themselves and rarely divide. This calmness helps preserve this important, small pool of cells and avoids unnecessary mutations that may happen whenever DNA is copied during cell division.

To respond to injury, stem cells must be primed by dividing one time, which is a very slow process and can take several days. Once in this “alert” state, the stem cells are poised to start dividing much faster and help repair damaged tissue. The Stanford team, led by Dr. Thomas Rando, aimed to track down the signals that are responsible for this priming process with the hope of developing drugs that could help jump-start the healing process.

Super healing serum: it’s not just in video games
The team collected blood serum from mice two days after the animals had been subjected to a muscle injury (the mice were placed under anesthesia during the procedure and given pain medication afterwards). When that “injured” blood was injected into a different set of mice, their muscle stem cells became primed much faster than mice injected with “uninjured” blood.

“Clearly, blood from the injured animal contains a factor that alerts the stem cells,” said Rando in a press release. “We wanted to know, what is it in the blood that is doing this?”

 

A deeper examination of the priming process zeroed in on a muscle stem cell signal that is turned on by a protein in the blood called hepatocyte growth factor (HGF). So, it seemed likely that HGF was the protein that they had been looking for. But, to their surprise, there were no differences in the amount of HGF found in blood from injured and uninjured mice.

HGFA: the holy grail of healing?
It turns out, though, that HGF must first be chopped in two by an enzyme called HGFA to become active. When the team went back and examined the injured and uninjured blood, they found that it was HGFA which showed a difference: it was more active in the injured blood.

To show that HGFA was directly involved in stimulating tissue repair, the team injected mice with the enzyme two days before the muscle injury procedure. Twenty days post injury, the mice injected with HGFA had regenerated larger muscle fibers compared to untreated mice. Even more telling, nine days after the HGFA treatment, the mice had better recovery in terms of their wheel running activity compared to untreated mice.

To mimic tissue repair after a surgery incision, the team also looked at the impact of HGFA on skin wound healing. Like the muscle injury results, injecting animals with HGFA two days before creating a skin injury led to better wound healing compared to untreated mice. Even the hair that had been shaved at the surgical site grew back faster. First author Dr. Joseph Rodgers, now at USC, summed up the clinical implications of these results :

“Our research shows that by priming the body before an injury you can speed the process of tissue repair and recovery, similar to how a vaccine prepares the body to fight infection. We believe this could be a therapeutic approach to improve recovery in situations where injuries can be anticipated, such as surgery, combat or sports.”

Could we help senior citizens heal as fast as high school seniors?
Another application for this therapeutic approach may be for the elderly. Lots of things slow down when you get older including your body’s ability to heal itself. This observation sparks an intriguing question for Rando:

“Stem cell activity diminishes with advancing age, and older people heal more slowly and less effectively than younger people. Might it be possible to restore youthful healing by activating this [HGFA] pathway? We’d love to find out.”

I bet a lot of people would love for you to find out, too.

A horse, stem cells and an inspiring comeback story that may revolutionize tendon repair

Everyone loves a good comeback story. Probably because it leaves us feeling inspired and full of hope. But the comeback story about a horse named Dream Alliance may do more than that: his experience promises to help people with Achilles tendon injuries get fully healed and back on their feet more quickly.

Dream Alliance

Dream Alliance was bred and raised in a very poor Welsh town in the United Kingdom. One of the villagers had the dream of owning a thoroughbred racehorse. She convinced a group of her fellow townsfolk to pitch in $15 dollars a week to cover the costs of training the horse. Despite his lowly origins, Dream Alliance won his fourth race ever and his future looked bright. But during a race in 2008, one of his back hoofs cut a tendon in his front leg. The seemingly career-ending injury was so severe that the horse was nearly euthanized.

It works in horses, how about humans?
Instead, he received a novel stem cell procedure which healed the tendon and, incredibly, the thoroughbred went on to win the Welsh Grand National race 15 months later – one of the biggest races in the UK that is almost 4 miles long and involves jumping 22 fences. Researchers at the Royal Veterinary College in Liverpool developed the method and data gathered from the treatment of 1500 horses with this stem cell therapy show a 50% decrease in re-injury of the tendon.

It’s been so successful in horses that researchers at the University College of London and the Royal National Orthopaedic Hospital are currently running a clinical trial to test the procedure in humans.  Over the weekend, the Daily Mail ran a news story about the clinical trial. In it, team lead Andrew Goldberg explained how they got the human trial off the ground:

“Tendon injuries in horses are identical to those in humans, and using this evidence [from the 1500 treated horses] we were able to persuade the regulators to allow us to launch a small safety study in humans.”

Tendon repair: there’s got to be another way

Achilles tendon connects the calf muscle to the heel bone

The Achilles tendon is the largest tendon in the body and connects the calf muscle to the heel bone. It takes on a lot of strain during running and jumping so it’s a well-known injury to professional and recreational athletes but injuries also occur in those with a sedentary lifestyle. Altogether Achilles tendon injury occurs in about 5-10 people per 100,000. And about 25%-45% of those injuries require surgery which involves many months of crutches and it doesn’t always work. That’s why this stem cell approach is sorely needed.

The procedure is pretty straight forward as far as stem cell therapies go. Bone marrow from the patient’s hip is collected and mesenchymal stem cells – making up a small fraction of the marrow – are isolated. The stem cells are transferred to petri dishes and allowed to divide until there are several million cells. Then they are injected directly into the injured tendon.

A reason to be cautiously optimistic
Early results from the clinical trial are encouraging with a couple of the patients experiencing improvements. The Daily Mail article featured the clinical trial’s first patient who went from a very active lifestyle to one of excruciating ankle pain due to a gradually deteriorating Achilles tendon. Though hesitant when she first learned about the trial, the 46-year-old ultimately figured that the benefits outweighed the risk. That turned out to be a good decision:

“I worried, because no one had ever had it before, except a horse. But I was more worried I’d end up in a wheelchair. The difference now is amazing. I can do five miles on the treadmill without pain, and take my dog Honey on long walks again.”

The researchers aren’t exactly sure how the therapy works but mesenchymal stem cells are known to release factors that promote regeneration and reduce inflammation. The first patient’s positive results are just anecdotal at this point. The clinical trial is still recruiting volunteers so definitive results are still on the horizon. And even if that small trial is successful, larger clinical trials will be required to confirm effectiveness and safety. It will take time but without the careful gathering of this data, doctors and patients will remain in the dark about their chances for success with this stem cell treatment.

Hopefully the treatment proves to be successful and ushers in a golden era of comeback stories. Not just for star athletes eager to get back on the field but also for the average person whose career, good health and quality of life depends on their mobility.

Stem cell stories that caught our eye; viral genes in embryos, underuse of transplants and joint pain clinics

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Ancient viral invaders help make us, us. The cells of our ancestors millions of years ago may have found a way to turn viral invasion into a good thing. This genetic lemons-to-lemonade tale comes from a team in Singapore that meticulously looked at 650,000 bits of virus genes that have been left behind in our cells after viral infections.

Retroviruses like HIV can only replicate by integrating their genes into ours and getting our cellular machinery to make new copies of themselves. Biologists have long known that they often leave behind bits of their genes, but had assumed this became part of the “junk DNA” that does not serve any function and that makes up the bulk of the genetic material in our cells. That scenario has started to change over the past few years as teams have reported examples of those retroviral genetic elements playing a role in the regulation—the turning on and off—of our functional genes.
virus
Jonathan Goke, the lead researcher on the project at the Genome Institute of Singapore, wrote that roughly 1,400 of those viral gene elements were involved in the very early stages of embryo development, helping determine how cells decide to mature into different types of tissue. They seem to be needed for determining who we are.

In an article on the website science 2.0 Goke speculated that these viruses may have been able to speed-up evolution by making changes in gene function faster than random mutation.

Blood stem cell transplants under used. Even as the number of blood stem cell transplants ever performed has passed the one million mark, a new report warns that lives are at risk because too many patients that could benefit are not getting these transplants. Blood stem cell transplants, which started as bone marrow transplants, provide the only shot at life-saving therapy for many patients, mostly those with blood cancers.

An international team, led by Dietger Niederwieser of the University Hospital Leipzig in Germany, found a dramatic under use of donor cells for transplants that varied widely around the world. Writing in the Lancet they reported that just 0.4 people per 10 million in the Philippines get such transplants, but in Israel the number shoots up to 506. The report noted both uneven distribution of resources needed to perform the complex procedure and inconsistent support for and participation in donor registries. Niederwieser was quoted in a press release from the journal picked up by ScienceDaily:

“Patients, many of them children, are facing a life and death situation. Ultimately they will die if they cannot get the treatment they need. All countries need to provide adequate infrastructure for patients and donors to make sure that everyone who needs a transplant gets one, rather than the present situation in which access remains restricted to countries and people with sufficient resources.”

What is real with stem cells and joint pain? Bethesda Magazine, the local publication for the county that is home to the National Institutes of Health (NIH), produced a good piece giving the perspective of patients wanting to avoid joint replacement surgery as well as scientists leery of cell-based procedures that have very little evidence to back them up.

The magazine reached out to its neighbor, the NIH to provide some perspective. It quotes Pamela Robey, the co-coordinator of the NIH Bone Marrow Stromal Cell Transplantation Center—those stromal cells are one type of cell often touted by clinics offering to treat joint pain.

“There are a huge number of clinical trials, but there has been next to no published information. The bottom line is there’s no real rigorous data showing it is actually repairing the joint.”

The author also talked to CIRM grantee Larry Goldstein of the University of California, San Diego, in his role as a member of the Ethics and Public Policy Committee of the International Society for Stem Cell Research. He notes that what clinics are offering is unproven and the author directs readers to the ISSCR web site’s “Closer Look” section to get more information on how to evaluate potential therapies they may be considering.

Stem cell stories that caught our eye: new ways to reprogram, shifting attitudes on tissue donation, and hockey legend’s miracle questioned

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Insulin-producing cells produced from skin. Starting with human skin cells a team at the University of Iowa has created iPS-type stem cells through genetic reprogramming and matured those stem cells into insulin-producing cells that successfully brought blood-sugar levels closer to normal when transplanted in mice.

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left). [Credit: University of Iowa]

University of Iowa researchers reprogrammed human skin cells to create iPS cells, which were then differentiated in a stepwise fashion to create insulin-producing cells. When these cells were transplanted into diabetic mice, the cells secreted insulin and reduced the blood sugar levels of the mice to normal or near-normal levels. The image shows the insulin-producing cells (right) and precursor cells (left).
[Credit: University of Iowa]

The cells did not completely restore blood-sugar levels to normal, but did point to the possibility of achieving that goal in the future, something the team leader Nicholas Zavazava noted in an article in the Des Moines Register, calling the work an “encouraging first step” toward a potential cure for diabetes.

The Register discussed the possibility of making personalized cells that match the genetics of the patient and avoiding the need for immune suppression. This has long been a goal with iPS cells, but increasingly the research community has turned to looking for options that would avoid immune rejection with donor cells that could be off-the-shelf and less expensive than making new cells for each patient.

Heart cells from reprogramming work in mice. Like several other teams, a group in Japan created beating heart cells from iPS-type stem cells. But they went the additional step of growing them into sheets of heart muscle that when transplanted into mice integrated into the animals own heart and beat to the same rhythm.

The team published the work in Cell Transplantation and the news agency AlianzaNews ran a story noting that it has previously been unclear if these cells would get in sync with the host heart muscle. The result provides hope this could be a route to repair hearts damaged by heart attack.

Patient attitudes on donating tissue. A University of Michigan study suggests most folks don’t care how you use body tissue they donate for research if you ask them about research generically. But their attitudes change when you ask about specific research, with positive responses increasing for only one type of research: stem cell research.

On the generic question, 69 percent said go for it, but when you mentioned the possibility of abortion research more than half said no and if told the cells might lead to commercial products 45 percent said nix. The team published their work in the Journal of the American Medical Association and HealthCanal picked up the university’s press release that quoted the lead researcher, Tom Tomlinson, on why paying attention to donor preference is so critical:

“Biobanks are becoming more and more important to health research, so it’s important to understand these concerns and how transparent these facilities need to be in the research they support.”

CIRM has begun building a bank of iPS-type stem cells made from tissue donated by people with one of 11 diseases. We went through a very detailed process to develop uniform informed consent forms to make sure the donors for our cell bank knew exactly how their cells could be used. Read more about the consent process here.

Mainstream media start to question hockey legend’s miracle. Finally some healthy skepticism has arrived. Hockey legend Gordie Howe’s recovery from a pair of strokes just before the holidays was treated by the general media as a true Christmas miracle. The scientific press tried to layer the coverage with some questions of what we don’t know about his case but not the mainstream media. The one exception I saw was Brad Fikes in the San Diego Union Tribune who had to rely on a couple of scientists who were openly speaking out at the time. We wrote about their concerns then as well.

Now two major outlets have raised questions in long pieces back-to-back yesterday and this morning. The Star in hockey-crazed Canada wrote the first piece and New York Magazine wrote today’s. Both raise serious questions about whether stem cells could have been the cause of Howe’s recovery and are valuable additions to the coverage.

Scientists Send Rodents to Space; Test New Therapy to Prevent Bone Loss

In just a few months, 40 very special rodents will embark upon the journey of a lifetime.

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Today UCLA scientists are announcing the start of a project that will test a new therapy that has the potential to slow, halt or even reverse bone loss due to disease or injury.

With grant funding from the Center for the Advancement of Science in Space (CASIS), a team of stem cell scientists led by UCLA professor of orthopedic surgery Chia Soo will send 40 rodents to the International Space Station (ISS). Living under microgravity conditions for two months, these rodents will begin to undergo bone loss—thus closely mimicking the conditions of bone loss, known as osteoporosis, seen in humans back on Earth.

At that point, the rodents will be injected with a molecule called NELL-1. Discovered by Soo’s UCLA colleague Kang Ting, this molecule has been shown in early tests to spur bone growth. In this new set of experiments on the ISS, the researchers hope to test the ability of NELL-1 to spur bone growth in the rodents.

The team is optimistic that NELL-1 could really be key to transforming how doctors treat bone loss. Said Ting in a news release:

“NELL-1 holds tremendous hope, not only for preventing bone loss but one day even restoring healthy bone. For patients who are bed-bound and suffering from bone loss, it could be life-changing.”

“Besides testing the limits of NELL-1’s robust bone-producing efforts, this mission will provide new insights about bone biology and could uncover important clues for curing diseases such as osteoporosis,” added Ben Wu, a UCLA bioengineer responsible for initially modifying NELL-1 to make it useful for treating bone loss.

The UCLA team will oversee ground operations while the experiments will be performed by NASA scientists on the ISS and coordinated by CASIS.

These experiments are important not only for developing new therapies to treat gradual bone loss, such as osteoporosis, which normally affects the elderly, but also those who have bone loss due to trauma or injury—including bone loss due to extended microgravity conditions, a persistent problem for astronauts living on the ISS. Said Soo:

“This research has enormous translational application for astronauts in space flight and for patients on Earth who have osteoporosis or other bone-loss problems from disease, illness or trauma.”

A Christmas miracle or untested therapy? Why even feel-good stem cell stories need to be checked for accuracy

We’ve written several pieces over the last couple of years about the trend for professional athletes to turn to untested and/or unproven stem cell therapies to help them bounce back from injuries. This week, however, came news of something a little more worrying. Ice hockey legend Gordie Howe was given stem cells to help him recover from a series of debilitating strokes. As is often the case with these stories it’s not just the nature of the treatment that raises questions, it’s also the way the media has covered it.

Gordie Howe - photo courtesy Sean Hagen from Maple Ridge, Canada

Gordie Howe – photo courtesy Sean Hagen from Maple Ridge, Canada

The facts are pretty straightforward. Howe’s strokes left him “essentially bedridden with little ability to eat or communicate on his own”, according to a statement issued by his family. Two companies – Stemedica and Novastem – then “volunteered” their services, delivering a stem cell therapy to Howe. According to the family “The response was truly miraculous.”

And that was often the extent of the digging that dozens of media outlets that reported the news did. They reported the facts of the stroke, and then just reprinted the statement from the family without questioning what kinds of cells, how they might work, etc etc. They didn’t bother to interview other stem cell scientists about this kind of approach to see if it was something that might benefit other stroke patients. They didn’t even take a closer look at the two companies involved to see what their track record on this kind of research is.

In short, it’s clearly a feel-good story about a sports legend and no one wanted to be the one to say, “hey, wait a minute here, how do we know this is real.”

No one, except Dr. Paul Knoepfler. Paul, as regular readers of this blog know, is a CIRM-funded stem cell researcher at the University of California, Davis and an avid blogger. In a post on his blog he took a much closer look at the story, posed some thoughtful questions and raised some doubts about it. He also reached out to Stemedica who, to their credit, responded promptly to his questions. You can read what they had to say here.

Paul, like the rest of us, would love to be able to say that this kind of approach worked for Gordie Howe and could work for millions of others left disabled by strokes. But Paul, unlike many news outlets that reported the story, isn’t willing to just accept it on face value.

There’s an old adage in journalism: “If your mother tells you she loves you, check to see if it’s true.” It basically means don’t accept anything on face value; dig a little deeper to see if it’s really true. Paul is doing that, and doing it very well. Other journalists might do well to follow his lead.

Stem cells and professional sports: a call for more science and less speculation

In the world of professional sports, teams invest tens of millions of dollars in players. Those players are under intense pressure to show a return on that investment for the team, and that means playing as hard as possible for as long as possible. So it’s no surprise that players facing serious injuries will often turn to any treatment that might get them back in the game.

image courtesy Scientific American

image courtesy Scientific American

A new study published last week in 2014 World Stem Cell Report (we blogged about it here) highlighted how far some players will go to keep playing, saying at least 12 NFL players have undergone unproven stem cell treatments in the last five years. A session at the recent World Stem Cell Summit in San Antonio, Texas showed that football is not unique, that this is a trend in all professional sports.

Dr. Shane Shapiro, an orthopedic surgeon at the Mayo Clinic, says it was an article in the New York Times in 2009 about two of the NFL players named in the World Stem Cell Report that led him to becoming interested in stem cells. The article focused on two members of the Pittsburgh Steelers team who were able to overcome injuries and play in the Super Bowl after undergoing stem cell treatment, although there was no direct evidence the stem cells caused the improvement.

“The next day, the day after the article appeared, I had multiple patients in my office with copies of the New York Times asking if I could perform the same procedure on them.”

Dr. Shapiro had experienced what has since become one of the driving factors behind many people seeking stem cell therapies, even ones that are unproven; the media reports high profile athletes getting a treatment that seems to work leading many non-athletes to want the same.

“This is not just about high profile athletes it’s also about older patients, weekend warriors and all those with degenerative joint disease, which affects around 50 million Americans. Currently for a lot of these degenerative conditions we don’t have many good non- surgical options, basically physical therapy, gentle pain relievers or steroid injections. That’s it. We have to get somewhere where we have options to slow down this trend, to slow down the progression of these injuries and problems.”

Shapiro says one of the most popular stem cell-based approaches in sports medicine today is the use of plasma rich platelets or PRP. The idea behind it makes sense, at least in theory. Blood contains platelets that contain growth factors that have been shown to help tissue heal. So injecting a patient’s platelets into the injury site might speed recovery and, because it’s the patient’s own platelets, the treatment probably won’t cause any immune response or prove to be harmful.

That’s the theory. The problem is few well-designed clinical trials have been done to see if that’s actually the case. Shapiro talked about one relatively small, non-randomized study that used PRP and in a 14-month follow-up found that 83% of patients reported feeling satisfied with their pain relief. However, 84% of this group did not have any visible improved appearance on ultrasound.

He is now in the process of carrying out a clinical trial, approved by the Food and Drug Administration (FDA), using bone marrow aspirate concentrate (BMAC) cells harvested from the patient’s own bone marrow. Because those cells secrete growth factors such as cytokines and chemokines they hope they may have anti-inflammatory and regenerative properties. The cells will be injected into 25 patients, all of whom have arthritic knees. They hope to have results next year.

Dr. Paul Saenz is a sports medicine specialist and the team physician for the San Antonio Spurs, the current National Basketball Association champions. He says that sports teams are frequently criticized for allowing players to undergo unproven stem cell treatments but he says it’s unrealistic to expect teams to do clinical studies to see if these therapies work, that’s not their area of expertise. But he also says team physicians are very careful in what they are willing to try.

“As fervent as we are to help bring an athlete back to form, we are equally fervent in our desire not to harm a $10 million athlete. Sports physicians are very conservative and for them stem cells are never the first thing they try, they are options when other approaches have failed.”

Saenz said while there are not enough double blind, randomized controlled clinical trials he has seen many individual cases, anecdotal evidence, where the use of stem cells has made a big difference. He talked about one basketball player, a 13-year NBA veteran, who was experiencing pain and mobility problems with his knee. He put the player on a biologic regimen and performed a PRP procedure on the knee.

“What we saw over the next few years was decreased pain, and a dramatic decrease in his reliance on non-steroidal anti inflammatory drugs. We saw improved MRI findings, improved athletic performance with more time on court, more baskets and more rebounds.”

But Saenz acknowledges that for the field to advance anecdotal stories like this are not enough, well-designed clinical trials are needed. He says right now there is too much guesswork in treatments, that there is not even any agreement on best practices or standardized treatment protocols.

Dr. Shapiro says for too long the use of stem cells in sports medicine has been the realm of individual physicians or medical groups. That has to change:

“If we are ever to move forward on this it has to be opened up to the scientific community, we have to do the work, do the studies, complete the analysis, open it up to our peers, report it in a reputable journal. If we want to treat the 50 million Americans who need this kind of therapy we need to go through the FDA approval process. We can’t just continue to treat the one patient a month who can afford to pay for all this themselves. “