Translating great stem cell ideas into effective therapies


CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

Finally a possible use for your excess fat; using it to fix your arthritic knee


One of the most common questions we get asked at CIRM, almost every other day to be honest, is “are there any stem cell treatments for people with arthritis in their knees?” It’s not surprising. This is a problem that plagues millions of Americans and is one of the leading causes of disability in the US.

Sadly, we have to tell people that there are no stem cell treatments for osteoarthritis (OA) in the knee that have been approved by the Food and Drug Administration (FDA). There’s also a lack of solid evidence from clinical trials that the various approaches are effective.

But that could be changing. There’s a growing number of clinical trials underway looking at different approaches to treating OA in the knee using various forms of stem cells. Sixteen of those are listed at And one new study suggests that just one injection of stem cells may be able to help reduce pain and inflammation in arthritic knees, at least for six months. The operative word here being may.

The study, published in the journal Stem Cells Translational Medicine,  used adipose-derived stromal cells, a kind of stem cell taken from the patient’s own fat. Previous studies have shown that these cells can have immune boosting and anti-scarring properties.

The cells were removed by liposuction, so not only did the patient’s get a boost for their knees they also got a little fat reduction. A nice bonus if desired.

The study was quite small. It involved 18 patients, between the ages of 50 and 75, all of whom had suffered from osteoarthritis (OA) in the knee for at least a year before the treatment. This condition is caused by the cartilage in the knee breaking down, allowing bones to rub against each other, leading to pain, stiffness and swelling.

One group of patients were given a low dose of the cells (23,000) injected directly into the knee, one a medium dose (103,000) and one a high dose (503,000).

Over the next six months, the patients were closely followed to see if there were any side effects and, of course, any improvement in their condition. In a news release, Christian Jorgensen, of University Hospital of Montpellier, the director of the study, said the results were encouraging:

“Although this phase I study included a limited number of patients without a placebo arm we were able to show that this innovative treatment was well tolerated in patients with knee OA and it provided encouraging preliminary evidence of efficacy. Interestingly, patients treated with low-dose ASCs significantly improved in pain and function compared with the baseline.”

The researchers caution that the treatment doesn’t halt the progression of OA and does not restore the damaged cartilage, instead it seems to help patients by reducing inflammation.

In a news article about the study Tony Atala, director of the Wake Forest Institute for Regenerative Medicine, in Winston-Salem, N.C. and the editor of Stem Cells Translational Medicine said the study offered the patients involved another benefit:

“In fact, most of the patients (in the study group) who had previously scheduled total knee replacement surgery decided to cancel the surgery. It will be interesting to see if these improvements are seen in larger groups of study participants.”

Interesting is an understatement.

But while this is encouraging it’s important to remember it was done in a small group of patients and needs to be replicated in a much larger group before we can draw any solid conclusions. It will also be important to see if the benefits last longer than six months.

We might not have to wait too long for some answers. The researchers are already running a 2-year trial involving 150 people in Europe.

We’ll let you know what they find.


Stem cell stories that caught our eye: reducing radiation damage, making good cartilage, watching muscle repair and bar coding cells

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.

A bomb blastaStem cells key to reducing radiation damage. With the anniversary of Hiroshima and President Obama’s historic visit to the site all over the news this week, it was nice to read about research that could result in many more people surviving a major radiation event—either from a power plant accident or the unthinkable repeat of history.

Much of the life-threatening damage that occurs early after radiation exposure happens in the gut, so a way to reduce that damage could buy time for other medical care. A team at the University of Texas Medical Branch at Galveston has discovered a drug that activates stem cells in the gut, which help maintain a healthy population of crypt cells that can repair gut damage.

A single injection of the small protein drug in mice significantly increased their survival, even if it was given 24 hours after exposure to radiation. The researchers published their work in the journal Laboratory Investigation and in a story written for MedicalNewsToday the lead author, Carla Kantara suggested the role the drug might have:

 “The current results suggest that the peptide may be an effective emergency nuclear countermeasure that could be delivered within 24 hours after exposure to increase survival and delay mortality, giving victims time to reach facilities for advanced medical treatment.”

The small protein, or peptide, named TP508, has already been tested in humans for diabetic foot ulcers so could be tested in humans fairly quickly.


Making good cartilage for your knees. Rarely a week goes by that I don’t tell a desperate osteoarthritis patient with painful knees that I am treating my own rotten knees with physical therapy until we learn how to use stem cells to make the right kind of cartilage needed for lasting knee repair. So, I was thrilled to read this week that the National Institutes of Health awarded Case Western Reserve University in Cleveland $6.7 million to develop a center to create standardized systems for monitoring stem cells as they convert into cartilage and for evaluating the resulting cartilage.

ear_wakeforest There are a couple problems with existing attempts to use stem cells for knee and other cartilage repair. First not all cartilage is equal and too often stem cells form the soft kind like in your earlobe, not the hard kind needed to protect knees. Also, it has been hard to generate enough cells to replace the entire area that tends to be eroded away in osteoarthritis, one of the leading causes of disability.

The new center, which will be available to researchers anywhere in the world, will develop tools for them to measure four things:

  • which genes are turned on or off as stem cells take the many steps toward becoming various forms of cartilage;
  • predict the best makeup of the extracellular matrix, the support structures outside cells that help them organize as they become a specific tissue;
  • evaluate the biochemical environment around the cells that helps direct their growth;
  • measure the mechanical properties of the resulting cartilage—is it more like the ear or the knee.

NewsWise posted the university’s press release


Damaged muscle grabs stem cells.  All our tissues have varying skills in self repair. Muscles generally get pretty high marks in that department, but we don’t really know how they do it. A team at Australia’s Monash University used the transparent Zebra fish and fancy microscopes to actually watch the process.

When they injured mature muscle cells they saw those cells send out projections that actually grabbed nearby muscle stem cells, which regenerated the damaged muscle. They published their findings in Science, the university issued a press release and a news site for Western Australia, WAtoday wrote a story quoting the lead researcher Peter Currie:

 “A significant finding is that the wound site itself plays a pivotal role in coordinating the repair of damaged tissue. If that response could be sped up, we are going to get better, or more timely, regeneration and healing.”

The online publication posted four beautiful florescent images of the cells in action.


muscle stem cells Monash

Muscle stem cells in action

“Bar coding” cells points to better transplants.  A team at the University of Southern California, partially funded by CIRM, developed a way genetically “bar code” stem cells so they can be tracked after transplant. In this case they watched the behavior of blood-forming stem cells and found the dose of cells transplanted had a significant impact on what the cells became as they matured.

The general dogma has blood stem cells producing all the various types of cells in our blood system including all the immune cells needed by cancer patients after certain therapies. But the USC tracking showed that only 20 to 30 percent of the stem cells displayed this do-it-all behavior. The type of immune cells created by the remaining 70 to 80 percent varied depending on whether there was a low dose of cells or a high dose, which can be critical to the effectiveness of the transplant.

 “The dose of transplanted bone marrow has strong and lasting effects on how HSCs specialize and coordinate their behavior,” said Rong Lu, senior author, in a USC press release posted by ScienceDaily. “This suggests that altering transplantation dose could be a tool for improving outcomes for patients — promoting bone marrow engraftment, reducing the risk of infection and ultimately saving lives.”

Stem cell stories that caught our eye: the future of iPS cells, a biopen for arthritis, shistosomiasis and early embryos

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.

Discoverer predicts bright clinical future for iPSCs. Shinya Yamanaka, who won the Nobel Prize in 2012 for figuring out how to reprogram adult cells into embryonic-like stem cells, predicts the resulting induced pluripotent stem cells (iPS cells) will soon make it out of the lab and into clinical practice in increasing numbers. In an interview in the Nikkei Asian Review he said iPS research is “entering a second stage.” The interview occurred during a conference marking the 10th anniversary of his discovery.




Yamanaka told the publication he wanted to establish a method to transplant nerve tissue made from iPS cells into patients, suggesting Kyoto University intends to test such a treatment in Parkinson’s patients in the next year or so. This work has garnered major support from the Japanese science ministry, which is pushing for added clinical trials with blood platelets and cartilage created from iPS cells and eventually with liver and kidney tissue. Yamanka’s institute at the University receives about $35 million a year from the government, but he has big plans that will require added support from industry partners.


 “My dream is that a young person will come upon ideas I haven’t thought of and win the Nobel Prize.”


Biopen to deposit stem cells in sore knees. People like me who write for a living often talk about the power of the pen.  Now the millions of people around the world who have joined me with a diagnosis of arthritis will be rooting for the power of a different type of pen. An Australian team has developed a biopen that can precisely lay down a new layer of cartilage where it is needed.

For now it is still only helping out aching lab animals, but once fully developed the pen holds great promise for people with arthritis and sports injuries. Loaded with stem cells embedded in a gel the biopen lets a surgeon lay down cells in precise rows. More important, like many of the gels used in bioengineering, the one they use becomes rigid when exposed to ultraviolet light and the pen has an ultraviolet light at its tip.

Scientists at the ARC Centre of Excellence for Electromaterials Science in Melbourne created the pen and published their work in Biofabrication. They produced a fun video describing the tool which was posted in an article on Forbes.


Parasite’s stem cells help it evade immune system. A nasty little parasitic flat worm causes Shistosomiasis, one of the most devastating tropical diseases. It kills nearly 300,000 people a year, mostly in Africa, and leaves many more unable to work. It chronically infects its victims, damaging organs while evading the host’s immune system.

A team at the University of Illinois at Urbana-Champaign and the University of Texas Southwestern Medical Center now report that the parasite evades immune attack by constantly replacing its outer skin, the tegument, and that it does this via special stem cells. The lead author of the study published in eLife James Collins from Texas explained the importance of the finding in a press release issued by the journal and picked up by Science Newsline.

 “This tissue has long been considered an evolutionary innovation for parasitic flatworms to evade their host’s immune defenses. Our current findings suggest that stem cells are playing a key role in perpetually renewing it, and we believe this is important for the parasite’s ability to survive for decades inside their human host.”

The team tested their hypothesis by depleting the stem cells in some worms and sure enough, the outer skin failed to be replaced. They are now looking for ways to disrupt those stem cells in the parasites in patients to treat their disease.




A blastocyst

Cells in embryo diverge as early as day two.  In writing about stem cells we often talk about the blastocyst with its ball of cells called the inner cell mass surrounded by fluid and an outer membrane. Those cells inside the blastocysts are what we use to develop embryonic stem cells lines. In the embryo those cells go on to develop all the different parts of the body. The membrane, called the trophoblast goes on to become the placenta. But how do the cells in the early embryo decide which ones become the inner cell mass and which become the outer membrane.


It turns out this decision starts as early as day two after fertilization when the embryo is only four cells. Using the latest technology that shows which genes are turned on in individual cells, a team at the University of Cambridge in the U.K. found some cells had highly active Sox21 genes, which is known to be active in stem cells. Other cells had low Sox21 activity and were destined to become the trophoblast and eventually the placenta.

The university issued a press release that was posted by ScienceDaily And The New Scientist wrote their own fun piece on the work.


Stem cell stories that caught our eye: Kidney stem cells, high fat diets, breast cancer and sore joints

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.

Young source of kidney stem cells. Some of our organs, like our liver and gut have massive armies of stem cells that can replace and repair tissue. Other organs like our kidney have relatively few adult stem cells and are not very good at self repair. Now, a Belgian team has found a new source for plentiful kidney stem cells for research and possibly therapy, the urine of premature infants.

shutterstock_385607698Because our kidneys don’t fully develop until about 34 weeks into pregnancy, premature infants retain bountiful kidney stem cells and shed them in their urine where they can be painlessly collected.  The lead author on the study published in the Journal of the American Society of Nephrology, Fanny Oliveira Arcolino from the Katholieke Universiteit Leuven described the potential of these cells in a university press release posted by Medical News Today:

Preterm neonatal progenitor cells might represent a powerful tool to be used in cell therapy and regeneration of damaged kidneys.”

She also noted that the first patients to benefit may be the pre-term infants themselves.  They often have renal insufficiency and there may be a way to use these cells to boost their kidney function.

Fatty diets, over active stem cells, and cancer.  While the kidney may have too few adult stem cells, sometimes it appears the gut can have too many and result in some beginning to form tumors. The long-seen link between high fat diets and certain cancers may turn out to be the result of that diet ratcheting up the production of gut stem cells.

“Our study for the first time showed the precise mechanisms of how a high-fat diet regulates intestinal stem-cell function and how this regulation contributes to tumor formation,” said Semir Beyaz the lead author from Harvard Medical School in a version of the widely printed story written by MSN.

In mice fed an extremely high fat diet, the researchers saw significant increases in gut stem cells as well as conversion of neighboring cells to ones that behave like stem stem cells, which began to divide and become tumors. There is no readily apparent pathway for scientists to use this knowledge to somehow let you eat a pound of bacon without guilt, but perhaps more impetus for moderation.

Add the breast to list of mini-organs. Over the past year or so researchers have announced a steady parade of miniature “organs” made in the laboratory that mimic the function of everything from the gut to the brain. A team at the Whitehead Institute in Cambridge, Massachusetts has added one that has been difficult to replicate, breast tissue.

Whitehead breast tissue

Fluorescent image of complex breast tissue grown in the Whitehead lab

With animal models of breast cancer routinely producing results that don’t pair well with what happens in humans, there has been a real need for functional three-dimensional breast tissue that can be used to study how different parts of the breast interact and react to potential therapies. Until now it has been difficult to keep breast tissue alive in the lab.

“I wouldn’t have thought it possible that these tissues could grow with such complexity and to such a size,” Piyush Gupta, a member of the team said in a press release used for a story by UPI. “It’s really quite remarkable.”

The researchers’ success came from a strategy similar to ones used by the creators of other mini-organs. They created an environment that more closely matched what the cells would find themselves in when in a person. They used a gel to give them a 3D structure and added some proteins and carbohydrates that would normally surround the cells. The stem cells seeded on to this structure produced all the various types of cells found in the breast, self-organized into ducts and those ducts produced material that is a precursor to milk—a very valuable tool for research.

A link to healthy cartilage. One federally approved therapy, several sanctioned clinical trials, and many unsanctioned clinics are striving to repair damaged joints by using stem cells to produce cartilage. Most of the unsanctioned clinics provide little or no data, and even when patients say the therapy seemed to help they often report that their “benefit” wears off after some months. The data from the sanctioned work has generally shown modest improvement at best.

This lack of dramatic results that many of us with aching knees would like to see comes in large part from our incomplete understanding of how stem cells and their intermediate cells produce healthy articular cartilage, the hard type you want in your knees not the soft kind found in your ear lobes. A team at Japan’s Okayama University and the National Institutes of Health in the US has identified a protein that seems to be a key trigger to get stem cells to form the chondrocytes needed to create articular cartilage. This protein, CCN4 could eventually become a sort of booster added to stem cell therapies for aching joints.

The researchers published their work in the journal Bone and HealthCanal posted a press release from the Japanese university.

Cartilage Repair using Embryonic Stem Cells: A Promising Path to Treating Millions of Osteoarthritis Sufferers

Bone scraping on bone — you can practically feel the excruciating pain just thinking about it. Sadly, that’s what happens to people suffering with osteoarthritis (OA), a degenerative joint disease. Except for joint replacement surgery, no cure exists and the available medicines only work on the symptoms, pain and swelling, and not the underlying cause. On top of that, long-term use of the drugs carries potential serious side effects including gastrointestinal bleeding and increased risk of a heart attack.

The statistics on this disease are just plain dreadful. It’s estimated that 250 million people worldwide have osteoarthritis of the knee. And 43 million globally have a moderate to severe form of OA. Based on a 2011 analysis, OA was the second-most expensive condition treated in U.S. hospitals amounting to nearly $15 billion in costs.

Imagine the increased quality of life for millions of people around world and the enormous health care savings if a cure were developed?

A study published on Tuesday in Stem Cells Translational Medicine may turn the tide toward a lasting treatment for osteoarthritis. A research team at the University of Manchester in England reported that they repaired knee joints in animal studies by implanting cartilage cells derived from human embryonic stem cells (hESC).


As cartilage degrades in the joints of people with osteoarthritis, bone rubs against bone causing severe pain

In a healthy joint, the ends of the bones are capped with cartilage, a hard but slippery substance that allow the bones to slide smoothly against each other. The cartilage also acts as a shock absorber for the joints when the body is in motion.


In X-rays, a healthy cartilage appears as an invisible gap between the bone joints. In the osteoarthritic joint that gap between the bones is mostly gone. (image credit: Mend My Knee)

This protective tissue in the joint gradually degrades in OA. The degradation in some cases is initiated by an injury even a minor one. Because cartilage lacks blood vessels, it doesn’t receive nourishment from the blood and is no good at repairing itself. And so eventually the bones at the joint are exposed and begin to rub against each other leading to severe pain, swelling, and reduced mobility.

In previous studies, the University of Manchester research team led by professor Sue Kimber, devised a method for specializing human embryonic stem cells into so-called chondroprogenitors, or cells with the potential to form cartilage.

The team implanted the cells into the knee joints of rats modeled with OA-like defects to test their ability to repair cartilage. By four weeks after the implant, the treated rats began to show signs of cartilage healing compared to an untreated group. By 12 weeks the treated joints revealed a shiny smooth surface characteristic of healthy cartilage while the untreated group still showed rough misshapen cartilage, a hallmark of OA.  In a press release, Professor Kimber put these results in perspective:

 “This work represents an important step forward in treating cartilage damage by using embryonic stem cells to form new tissue, although it’s still in its early experimental stages.”

Compared to this preliminary hESC work, the use of cartilage-producing cells derived from adult stem cells is already being tested but the source material is limited making that method ultimately very costly and not scalable. hESCs, on the other hand, can be grown in unlimited quantities for large-scale, off the shelf cell therapy for the millions of OA sufferers. If you’re still following along, you might be thinking “but wouldn’t those hESC-derived therapies be recognized as foreign and rejected by the OA patient’s immune system?” That is a serious hurdle, but data from other labs hint at the possibility that cartilage repair may be possible with minimal tissue matching between the donor cells and the patient.

There is also reason to believe the cartilage derived by embryonic stem cells (ESCs) might be superior to that created to-date from adult stem cells. The latter tends to produce a softer form of cartilage than the hard cartilage found in our knees called articular cartilage. Because the ESCs produce cells that are earlier in the development cycle it may be possible to push them to become the sturdier cartilage we want in our knees. CIRM grantee Darryl D’Lima at The Scripps Research Institute has shown that seems to be the case in his preliminary studies.

Finally, a big concern of using hESC derived cell therapies is that some unspecialized cells will remain in the implant with the potential of unlimited growth leading to tumor formation and cancer. But in this study the results were encouraging since no irregular cartilage formation or tumors were seen.

Clearly it’s still early days for a hESC approach to curing OA. But these results are promising enough to draw out this response from Stephen Simpson Director of research at Arthritis Research UK which funded this study:

“Embryonic stem cells offer an alternative source of cartilage cells to adult stem cells, and we’re excited about the immense potential of Professor Kimber’s work and the impact it could have for people with osteoarthritis.”