Stem Cell Stories that Caught our Eye: finding the perfect match, imaging stem cells and understanding gene activity

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

LAPD officer in search of the perfect match.

LAPD Officer Matthew Medina with his wife, Angelee, and their daughters Sadie and Cassiah. (Family photo)

This week, the San Diego Union-Tribune featured a story that tugs at your heart strings about an LAPD officer in desperate need of a bone marrow transplant. Matthew Medina is a 40-year-old man who was diagnosed earlier this year with aplastic anemia, a rare disorder that prevents the bone marrow from producing enough blood cells and platelets. Patients with this disorder are prone to chronic fatigue and are at higher risk for infection and uncontrolled bleeding.

Matthew needs a bone marrow transplant to replace his diseased bone marrow with healthy marrow from a donor, but so far, he has yet to find a match. Part of the reason for this difficulty is the lack of diversity in the national bone marrow registry, which has over 25 million registered donors, the majority of which are white Americans of European decent. As a Filipino, Matthew has a 40% chance of finding a perfect match in the national registry compared to a 75% chance if he were white. An even more unsettling fact is that Filipinos make up less than 1% of donors on the national registry.

Matthew has a sister, but unfortunately, she wasn’t a match. For now, Matthew is being kept alive with blood transfusions at his home in Bellflower while he waits for good news. With the support of his family and friends, the hope is that he won’t have to wait for long. Already 1000 people in his local community have signed up to be bone marrow donors.

On a larger scale, organizations like A3M and Mixed Marrow are hoping to help patients like Matthew by increasing the diversity of the national bone marrow registry. A3M specifically recruits Asian donors while Mixed Match focuses on people with multi-ethnic backgrounds. Ayumi Nagata, a recruitment manager at A3M, said their main challenge is making healthy people realize the importance of being a bone marrow donor.

“They could be the cure for someone’s cancer or other disease and save their life. How often do we have that kind of opportunity?”

An algorithm that makes it easier to see stem cell development.

To understand how certain organs like the brain develop, scientists rely on advanced technologies that can track individual stem cells and monitor their fate as they mature into more specialized cells. Scientists can observe stem cell development with fluorescent proteins that light up when a stem cell expresses specific transcription factors that help decide the cell’s fate. Using a time-lapse microscope, these fluorescent stem cells can easily be identified and tracked throughout their lifetime.

But the pictures don’t always come out crystal clear. Just as a dirty camera lens makes for a dirty picture, images produced by time-lapse microscopy images can be plagued by shadows, artifacts and lighting inconsistencies, making it difficult to observe the orchestrated expression of transcription factors involved in a stem cell’s development.

This week in the journal Nature Communications, a team of scientists from Germany reported a solution that gives a clear view of stem cell development. The team developed a computer algorithm called BaSiC that acts like a filter and removes the background noise from time-lapse images of individual cells. Unlike previous algorithms, BaSiC requires fewer reference images to make its corrections.

The software BaSiC improves microscope images. (Credit: Tingying Peng / TUM/HMGU)

In coverage by Phys.org, author Dr. Tingying Peng explained the advantages of their algorithm,

“Contrary to other programs, BaSiC can correct changes in the background of time-lapse videos. This makes it a valuable tool for stem cell researchers who want to detect the appearance of specific transcription factors early on.”

The team proved that BaSiC is an effective image correcting tool by using it to study the development of hematopoietic or blood stem cells. They took time-lapse videos of blood stem cells over six days and observed that the stem cells chose between two developmental tracks that produced different types of mature blood cells. Using BaSiC, they found that blood stem cells that specialized into white blood cells expressed the transcription factor Pu.1 while the stem cells that specialized into red blood cells did not. Without the algorithm, they didn’t see this difference.

Senior author on the study, Dr. Nassir Navab, concluded by highlighting the importance of their technology and sharing his team’s vision for the future.

“Using BaSiC, we were able to make important decision factors visible that would otherwise have been drowned out by noise. The long-term goal of this research is to facilitate influencing the development of stem cells in a targeted manner, for example to cultivate new heart muscle cells for heat-attack patients. The novel possibilities for observation are bringing us a step closer to this goal.”

Silenced vs active genes: it’s like oil and water (Todd Dubicoff)

The DNA from just one of your cells would be an astounding six feet in length if stretched out end to end. To fit into a nucleus that is a mere 4/10,000th of an inch in diameter, DNA’s double helical structure is organized into intricate twists within twists with the help of proteins called histones.

Together the DNA and histones are called chromatin. And it turns out that chromatin isn’t just for stuffing all that genetic material into a tiny space. The amount of DNA folding also affects the regulation of genes. Areas of chromatin that are less densely packed are more accessible to DNA-binding proteins called transcription factors that activate gene activity. Other regions, called heterochromatin, are compacted which leads to silencing of genes because transcription factors are shut out.

But there’s a wrinkle in this story. More recently, scientists have shown that large proteins are able to wriggle their way into heterochromatin while smaller proteins cannot. So, there must be additional factors at play. This week, a CIRM-funded research project published in Nature provides a possible explanation.

Liquid-like fusion of heterochromatin protein 1a droplets is shown in the embryo of a fruit fly. (Credit: Amy Strom/Berkeley Lab)

Examining the nuclei of fruit fly embryos, a UC Berkeley research team report that various regions of heterochromatin coalesce into liquid droplets which physically separates them from regions where gene activity is high. This phenomenon, called phase-phase separation, is what causes oil droplets to fuse together when added to water. Lead author Dr. Amy Strom explained the novelty of this finding and its implications in a press release:

“We are excited about these findings because they explain a mystery that’s existed in the field for a decade. That is, if compaction [of chromatin] controls access to silenced [DNA] sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners.”

Phase-phase separation can also affect other cell components, and problems with it have been linked to neurological disorders like dementia. In diseases like Alzheimer’s and Huntington’s, proteins aggregate causing them to become more solid than liquid over time. Strom is excited about how phase-phase separation insights could lead to novel therapeutic strategies:

“If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease.”

Cancer-causing mutations in blood stem cells may also link to heart disease

Whether we read about it in the news or hear it from our doctor, when we think about the causes of heart disease it’s usually some combination of inheriting bad genes from our parents and making poor life style choices like smoking or eating a diet high in fat and cholesterol. But in a fascinating research published yesterday in the New England Journal of Medicine, scientists show evidence that in some people, heart disease may develop much in the same way that a blood cancer does; that is, through a gradual, lifetime accumulation of mutations in hematopoietic cells, or blood stem cells.

This surprising discovery began as a project, published in 2014, aimed at early detection of blood cancers in the general population. This earlier study focused on the line of evidence that cells don’t become cancerous overnight but rather progress slowly as we age. So, in the case of a blood cancer, or leukemia, a blood stem cell can acquire a mutation that transforms the cell into a pre-cancerous state. When that stem cell multiplies it creates “clones” of the blood stem cell that had the cancer-initiating mutation. It’s only after additional genetic insults that these stem cells become full blown cancers.

The research team, composed of scientists from Brigham and Women’s Hospital as well as the Broad Institute of Harvard and MIT, examined DNA sequences from blood samples of over 17,000 people who didn’t have blood cancer. They analyzed these samples, specifically looking at 160 genes that are often mutated in blood cancer. The results from the 2014 study showed that mutations in these genes in people 40 years and under were few and far between. Interestingly, the frequency noticeably increased in older folks with those 10% over 70 years of age carrying the mutations.

Most of these so-called “clonal hematopoiesis of indeterminate potential”, or CHIP, mutations occurred in three genes called DNMT3A, TET2, and ASXL1. While these mutations were indeed associated with a 10-fold higher risk of blood cancer, the team also saw an unexpected correlation: people with these mutations had a 40% higher overall risk of dying due to other causes compared to those who did not carry the mutations. They pinpointed heart disease as one primary cause of the increased mortality risk.

The current follow-up study not only sought to confirm this correlation between the mutations and heart disease but also show the mutations cause the increased risk. This time around, the team looked for the mutations in a group of four different populations totaling over 8000 people. Again, they saw a correlation between the mutations and the risk of heart disease or a heart attack later in life. One of the team leads, Dr. Sekar Kathiresan from the Broad Institute, talked about his team’s reaction to these results in a Time Magazine interview:

Sekar Kathiresan, Photo: Broad Institute

“We were fully expecting not to find anything here. But the odds of having an early heart attack are four-fold higher among younger people with CHIP mutations.”

 

To show a causal link, they turned to mouse studies. They collected bone marrow stem cells from mice engineered to lack Tet2, one of the three genes that when mutated had been associated with increased risk of heart disease. The bone marrow cells were then transplanted into mice which are prone to have increased blood cholesterol and symptoms of heart disease. The presence of these cells that lacked Tet2 led to increased hardening of major arteries – a precursor to clogged blood vessels, heart disease and heart attacks – compared to mice that received normal bone marrow cells.

Though more work remains, Kathiresan thinks these current results offer some tantalizing therapeutic possibilities:

“This is a totally different type of risk factor than hypertension or hypercholestserolemia [high blood cholesterol] or smoking. And since it’s a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present.”

Humacyte Receives Prestigious Technology Pioneer Award for Kidney Failure Treatment

This month, a CIRM-funded company called Humacyte was named one of the World Economic Forum’s 30 Technology Pioneers for 2017. This prestigious award “recognizes early-stage companies from around the world that are involved in the design, development and deployment of new technologies and innovations, and are poised to have a significant impact on business and society.”

Humacyte is a North Carolina-based company that’s developing a promising human-tissue based treatment for kidney failure. They’ve developed a technology to manufacture a bioengineered human vein that they hope will improve kidney function in patients with end stage kidney disease and patients on hemodialysis. We’ve blogged about their exciting technology previously on the Stem Cellar (here).

The technology is fascinating. The first step involves stimulating human smooth muscle cells from donor tissue to develop into tubular vessels. After the vessels are made, the cells are removed, leaving a 3D extracellular matrix structure composed of molecules secreted by the cells. This decellularized tube-like structure is called a human acellular vessels or HAV.

Human acellular vessel (HAV) from Humacyte.

The HAV is then implanted under a patient’s skin, where it recruits the patient’s own stem cells to migrate into the HAV and develop into vascular smooth muscle cells that line the insides of actual blood vessels. For patients with kidney failure, HAVs provide vascular access for hemodialysis, the process of collecting and filtering a patient’s blood through an artificial kidney and then returning “clean” blood back to the body. It would provide an alternative to the current procedures that insert a plastic tube called a shunt into the patient’s vein. Shunts can cause infection, blood clots, and can also be rejected by a patient’s immune system.

In July of 2016, CIRM awarded Humacyte almost $10 million to launch a Phase 3 trial in California to test their bioengineered blood vessels in patients with kidney failure. Since launching the trial, Humacyte received Regenerative Medicine Advanced Therapy or RMAT designation from the US Food and Drug Administration in March of this year. This designation is a sign that the FDA sees promise in Humacyte’s stem cell-based therapy and “will help facilitate the efficient development and expedited review of the HAV for vascular access to patients in need of life-sustaining hemodialysis.”

Humacyte’s technology has wide-ranging applications beyond treating kidney disease, including peripheral arterial disease, “repairing or replacing damaged arteries, coronary artery bypass surgery, and vascular trauma.” Other key benefits of this technology are that HAVs can be designed on demand and can be stored for later use without fear of a rapidly degrading shelf-life.

In a recent Humacyte news release, Carrie Cox, Chair and CEO of Humacyte, commented on her company’s purpose and vision to help patients.

“Keeping patient care at its core, Humacyte’s scientific discoveries are designed to create ‘off-the-shelf,’ or ready to use, bioengineered blood vessels. Today these conduits are being investigated clinically for patients undergoing kidney dialysis who require vascular access and for patients with peripheral arterial disease. However, this technology may be extended into a range of vascular applications in the future, with the potential for better clinical outcomes and lower healthcare costs. Our vision is to make a meaningful impact in healthcare by advancing innovation in regenerative medicine to produce life-sustaining improvements for patients with vascular disease.”

The potential impact that Humacyte’s technology could have for patients with unmet medical needs was compelling enough to earn the company a coveted spot in the World Economic Forum’s Technology Pioneer community. This recognition will likely foster new partnerships and collaborations to further advance Humacyte’s technology down the clinical pipeline. Fulvia Montresor, Head of Technology Pioneers at the World Economic Forum, concluded in a news release.

“We welcome Humacyte in this group of extraordinary pioneers. We hope that thanks to this selection, the World Economic Forum can facilitate greater collaboration with business leaders, governments, civil society and other relevant individuals to accelerate the development of technological solutions to the world’s greatest challenges.”

According to coverage by North Carolina Biotechnology Center, Humacyte and the other Technology Pioneers will be honored at the “Summer Davos” World Economic Forum Annual Meeting of the New Champions later this month in China. You can learn more about this meeting here.


Related Links:

4 things to know about stem cell clinical trials [Video]

Every day, we receive phone calls and emails from people who are desperately seeking our help. Sometimes they reach out on their own behalf, though often it’s for a family member or close friend. In every case, someone is suffering or dying from a disorder that has no available cure or effective treatment and they look to stem cell treatments as their only hope.

It’s heartbreaking to hear these personal stories that are unfolding in real time. Though they contact us from a wide range of places about a wide range of disorders, their initial set of questions are often similar and go something like this:

  • “Where can I find stem cell clinical trial for my condition?”
  • “What are my chances of being cured?”
  • “How much does it cost to be in a clinical trial?”
  • “How can I be sure it’s safe?”

We think anyone thinking about taking part in a clinical trial should consider these important questions. So, in addition to providing answers as we receive them through phone calls and emails, we wanted to find a way to reach out to as many people as possible. The result? The four-minute animation video you can watch below:

As mentioned in the video, the answers to these questions are only the tip of the iceberg for finding out if a particular clinical trial is right for you. The website, A Closer Look at Stem Cells, produced by the International Society for Stem Cell Research (ISSCR), is an excellent source for more advice on what things you should know before participating in a stem cell clinical trial or any experimental stem cell treatment.

And visit the Patient Resources section of our website for even more practical information including our growing list of CIRM-funded clinical trials as well as trials supported by our Alpha Stem Cell Clinic Network.

World Sickle Cell Day: A View from the Front Line

June 19th is World Sickle Cell Day. Sickle cell disease is an inherited blood disorder that causes normally round red blood cells to take on an abnormal sickle shape, resulting in clogged arteries, severe pain, increased risk of stroke and reduced life expectancy. To mark the occasion we asked Nancy M. Rene to write a guest blog for us. Nancy is certainly qualified; she is the grandmother of a child with sickle cell disease, and the co-founder of Axis Advocacy, a non-profit advocating for those with sickle cell disease and their families.

Nancy ReneOn this World Sickle Cell Day, 2017, we can look back to the trailblazers in the fight against Sickle Cell Disease.  More than 40 years ago, the Black Panther Party established the People’s Free Medical Clinics in several cities across the country. One of the functions of these free clinics: to screen people for sickle cell disease and sickle cell trait. This life-saving screening began  in 1971.

Around that same time, President Richard Nixon allocated $10 million to begin the National Sickle Cell Anemia Control Act. This included counseling and screening, educational activities, and money for research.

In the early part of the twentieth century, most children with sickle cell died before their fifth birthday. With newborn screening available nationwide, the use of penicillin to prevent common infections, and the finding that hydroxyurea was useful in fighting the disease, life expectancy began to improve.

For much of the twentieth century, people with sickle cell disease felt that they were fighting the fight alone, knowledgeable doctors were scarce and insurance was often denied.

Making progress

As we moved into the twenty-first century, patients and families found they had some powerful allies. The National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) joined the battle.  In 2016 the NIH held its tenth annual international conference on sickle cell disease that featured speakers from all over the world.  Participants were able to learn about best practices in Europe, Africa, India, and South America.

Sickle Cell centers at Howard University, the Foundation for Sickle Cell Disease Research, and other major universities across the country are pointing the way to the best that medicine has to offer.

Last year, the prestigious American Society of Hematology (ASH) launched an initiative to improve understanding and treatment of sickle cell disease.  Their four-point plan includes education, training, advocacy, and expanding its global reach.

Just last month, May 2017, the FDA looked at Endari, developed by Emmaus Medical in Torrance, California.  It is the first drug specifically developed for sickle cell disease to go through the FDA’s approval process. We should have a decision on whether or not the drug goes to market in July.

The progress that had been made up to the beginning of the twenty-first century was basically about alleviating the symptoms of the disease: the sickling, the organ damage and the pervasive anemia. But a cure was still elusive.

But in 2004, California’s Stem Cell Agency, CIRM, was created and it was as if the gates had opened.

Researchers had a new source of funding to enable  them to work on Sickle Cell Disease and many other chronic debilitating diseases at the cellular level. Scientists like Donald Kohn at UCLA, were able to research gene editing and find ways to use autologous bone marrow transplants to actually cure people with sickle cell. While some children with sickle cell have been cured with traditional bone marrow transplants, these transplants must come from a matched donor, and for most patients, a matched donor is simply not available. CIRM has provided the support needed so that researchers are closing in on the cure. They are able to share strategies with doctors and researchers throughout the world

And finally, support from the federal government came with the passage of the Affordable Care Act and adequate funding for the NIH, CDC, the Health Resources and Services Administration (HRSA), and FDA.

Going backwards

And yet, here we are, World Sickle Cell Day, 2017.

Will this be a case of one step forward two steps back?

Are we really going back to the time when people with Sickle Cell Disease could not get health insurance because sickle cell is a pre-existing condition, to the time when there was little money and no interest in research or professional training, to a time when patients and their families were fighting this fight alone?

For all of those with chronic disease, it’s as if we are living a very bad dream.

Time to wake up

For me, I want to wake up from that dream.  I want to look forward to a future where patients and families, where Joseph and Tiffany and Marissa and Ken and Marcus and all the others, will no longer have to worry about getting well-informed, professional treatment for their disease.

Where patients will no longer fear going to the Emergency Room

Where doctors and researchers have the funding they need to support them in their work toward the cure,

Where all children, those here in the United States along with those in Africa, India, and South America, will have access to treatments that can free them from pain and organ damage of sickle cell disease.

And where all people with this disease can be cured.

Stories that caught our eye: An antibody that could make stem cell research safer; scientists prepare for clinical trial for Parkinson’s disease; and the stem cell scientist running for Congress

Antibody to make stem cells safer:

There is an old Chinese proverb that states: ‘What seems like a blessing could be a curse’. In some ways that proverb could apply to stem cells. For example, pluripotent stem cells have the extraordinary ability to turn into many other kinds of cells, giving researchers a tool to repair damaged organs and tissues. But that same ability to turn into other kinds of cells means that a pluripotent stem cell could also turn into a cancerous one, endangering someone’s life.

A*STAR

Researchers at the A*STAR Bioprocessing Technology Institute: Photo courtesy A*STAR

Now researchers at the Agency for Science, Technology and Research (A*STAR) in Singapore may have found a way to stop that happening.

When you change, or differentiate, stem cells into other kinds of cells there will always be some of the original material that didn’t make the transformation. Those cells could turn into tumors called teratomas. Scientists have long sought for a way to identify pluripotent cells that haven’t differentiated, without harming the ones that have.

The team at A*STAR injected mice with embryonic stem cells to generate antibodies. They then tested the ability of the different antibodies to destroy pluripotent stem cells. They found one, they called A1, that did just that; killing pluripotent cells but leaving other cells unharmed.

Further study showed that A1 worked by attaching itself to specific molecules that are only found on the surface of pluripotent cells.

In an article on Phys.Org Andre Choo, the leader of the team, says this gives them a tool to get rid of the undifferentiated cells that could potentially cause problems:

“That was quite exciting because it now gives us a view of the mechanism that is responsible for the cell-killing effect.”

Reviving hope for Parkinson’s patients:

In the 1980’s and 1990’s scientists transplanted fetal tissue into the brains of people with Parkinson’s disease. They hoped the cells in the tissue would replace the dopamine-producing cells destroyed by Parkinson’s, and stop the progression of the disease.

For some patients the transplants worked well. For some they produced unwanted side effects. But for most they had little discernible effect. The disappointing results pretty much brought the field to a halt for more than a decade.

But now researchers are getting ready to try again, and a news story on NPR explained why they think things could turn out differently this time.

tabar-viviane

Viviane Tabar, MD; Photo courtesy Memorial Sloan Kettering Cancer Center

Viviane Tabar, a stem cell researcher at Memorial Sloan Kettering Cancer Center in New York, says in the past the transplanted tissue contained a mixture of cells:

“What you were placing in the patient was just a soup of brain. It did not have only the dopamine neurons, which exist in the tissue, but also several different types of cells.”

This time Tabar and her husband, Lorenz Studer, are using only cells that have been turned into the kind of cell destroyed by the disease. She says that will, hopefully, make all the difference:

“So you are confident that everything you are putting in the patient’s brain will consist of  the right type of cell.”

Tabar and Studer are now ready to apply to the Food and Drug Administration (FDA) for permission to try their approach out in a clinical trial. They hope that could start as early as next year.

Hans runs for Congress:

Keirstead

Hans Keirstead: Photo courtesy Orange County Register

Hans Keirstead is a name familiar to many in the stem cell field. Now it could become familiar to a lot of people in the political arena too, because Keirstead has announced he’s planning to run for Congress.

Keirstead is considered by some to be a pioneer in stem cell research. A CIRM grant helped him develop a treatment for spinal cord injury.  That work is now in a clinical trial being run by Asterias. We reported on encouraging results from that trial earlier this week.

Over the years the companies he has founded – focused on ovarian, skin and brain cancer – have made him millions of dollars.

Now he says it’s time to turn his sights to a different stage, Congress. Keirstead has announced he is going to challenge 18-term Orange County Republican Dana Rohrabacher.

In an article in the Los Angeles Times, Keirstead says his science and business acumen will prove important assets in his bid for the seat:

“I’ve come to realize more acutely than ever before the deficits in Congress and how my profile can actually benefit Congress. I’d like to do what I’m doing but on a larger stage — and I think Congress provides that, provides a forum for doing the greater good.”

 

 

 

 

 

 

 

 

 

School is out which means SPARK is in for the summer!

It’s mid-June, which means that school’s out for the summer! While most students are cheering about their newfound freedom from the classroom, a special group of high school students are cheering about the start of the CIRM SPARK internship program.

SPARK is CIRM’s high school educational program that gives students from underrepresented communities the opportunity to conduct stem cell research at top-notch universities in California. Students will spend the summer working in stem cell labs under the guidance and mentorship of scientists, PhDs, master’s students and postdocs. They will learn basic lab techniques like how to do PCR and how to grow stem cells.

Each student will have their own research project that answers an important question in the stem cell field. Students will also attend scientific lectures at their host university, participate in patient-centered activities and write blogs and social media posts about their experiences in the lab. At the end of the summer, they will show off their hard work through posters and talks at the annual SPARK conference.

SPARK gives students early exposure to research and proves to them that science is not only fun but is also a promising career option within their reach. We’ve offered a high school internship summer program for the past few years, and many students who’ve previously participated have told us that they are excited to pursue an education in science or medicine in college.

Ranya taking care of her stem cells!

I’ve featured some of these exciting success stories previously on our blog. One of these stellar students is Ranya Odeh. She was a student in the UC Davis SPARK program and recently told us that she will attend Stanford University to pursue bioengineering after receiving the prestigious QuestBridge scholarship. Another student we featured recently is Shannon Larsuel who participated in the Stanford SPARK program. Shannon was inspired after she worked at the Stanford bone marrow registry as part of her SPARK experience and now plans to be a pediatric oncologist.

Now that the 2017 SPARK program is in session, we can look forward to another exciting summer of talented and motivated students. Our SPARK students are encouraged to document their summer experiences on social media, so you’ll be able to follow their journeys on Instagram. Make sure to check out @CIRM_stemcells Instagram account and the #CIRMSPARKlab hashtag on both Instagram and Twitter.

If you’re a student or teacher who wants to learn more about the CIRM SPARK program, visit our website for more details. And with that, I’ll leave you with a few of the most recent Instagram posts from our new cohort of SPARK students!

Looking at our infected tissue cells!! 🔬🔬#CIRMSPARKLab

A post shared by monse mendoza (@mawnsay) on

Happy #workwednesday! I'm so excited that the @cirm_stemcells #cirmsparklab high school stem cell program has begun! It's a summer internship program where students from underrepresented communities do research in stem cell labs at universities in California. . These smiling students are part of the @uc_davis_stem_cells SPARK program led by Dr. Gerhard Bauer (left). To get into SPARK, they had to win the UC Davis #teenbiotechchallenge by creating a website about a specific science topic. . These students will spend two months doing stem cell research in a lab at UC Davis with grad student and postdoc mentors. At the end of the summer they will present their work at the CIRM spark conference. . I'm so excited for this year's new batch of students. They are posting pictures of their lab work on Instagram (see #cirmsparklab) and their enthusiasm for communicating their science is contagious. I'll be sharing more pictures from this program this summer! 👍🔬 . PS thanks to Dr. Jan Nolta from UC Davis for this photo and for her dedication to the SPARK program as a mentor and teacher!

A post shared by Dr. Karen Ring (@drkarenring) on

Have scientists discovered a natural way to boost muscle regeneration?

Painkillers like ibuprofen and aspirin are often a part of an athlete’s post-exercise regimen after intense workouts. Sore muscles, aches and stiffness can be more manageable by taking these drugs – collectively called non-steroidal anti-inflammatory drugs, or NSAIDS – to reduce inflammation and pain. But research suggests that the anti-inflammatory effects of these painkillers might cause more harm than good by preventing muscle repair and regeneration after injury or exercise.

A new study out of Stanford Medicine supports these findings and proposes that a component of the inflammatory process is necessary to promote muscle regeneration. Their study was funded in part by a CIRM grant and was published this week in the Proceedings of the National Academy of Sciences.

Muscle stem cells are scattered throughout skeletal muscle tissue and remain inactive until they are stimulated to divide. When muscles are damaged or injured, an inflammatory response involving a cascade of immune cells, molecules and growth factors activates these stem cells, prompting them to regenerate muscle tissue.

Andrew Ho, Helen Blau and Adelaida Palla led a study that found drugs like aspirin and ibuprofen can inhibit the ability of muscle tissue to repair itself in mice. (Image credit: Scott Reiff)

The Stanford team discovered that a molecule called Prostaglandin E2 or PGE2 is released during the inflammatory response and stimulates muscle repair by directly targeting the EP4 receptor on the surface of muscle stem cells. The interaction between PGE2 and EP4 causes muscle stem cells to divide and robustly regenerate muscle tissue.

Senior author on the study, Dr. Helen Blau, explained her team’s interest in PGE2-mediated muscle repair in a news release,

“Traditionally, inflammation has been considered a natural, but sometimes harmful, response to injury. But we wondered whether there might be a component in the pro-inflammatory signaling cascade that also stimulated muscle repair. We found that a single exposure to prostaglandin E2 has a profound effect on the proliferation of muscle stem cells in living animals. We postulated that we could enhance muscle regeneration by simply augmenting this natural physiological process in existing stem cells already located along the muscle fiber.”

Further studies in mice revealed that injury increased PGE2 levels in muscle tissue and increased expression of the EP4 receptor on muscle stem cells. This gave the authors the idea that treating mice with a pulse of PGE2 could stimulate their muscle stem cells to regenerate muscle tissue.

Their hunch turned out to be right. Co-first author Dr. Adelaida Palla explained,

“When we gave mice a single shot of PGE2 directly to the muscle, it robustly affected muscle regeneration and even increased strength. Conversely, if we inhibited the ability of the muscle stem cells to respond to naturally produced PGE2 by blocking the expression of EP4 or by giving them a single dose of a nonsteroidal anti-inflammatory drug to suppress PGE2 production, the acquisition of strength was impeded.”

Their research not only adds more evidence against the using NSAID painkillers like ibuprofen and aspirin to treat sore muscles, but also suggests that PGE2 could be a natural therapeutic strategy to boost muscle regeneration.

This cross-section of regenerated muscle shows muscle stem cells (red) in their niche along the muscle fibers (green). (Photo courtesy of Blau lab)

PGE2 is already approved by the US Food and Drug Administration (FDA) to induce labor in pregnant women, and Dr. Blau hopes that further research in her lab will pave the way for repurposing PGE2 to treat muscle injury and other conditions.

“Our goal has always been to find regulators of human muscle stem cells that can be useful in regenerative medicine. It might be possible to repurpose this already FDA-approved drug for use in muscle. This could be a novel way to target existing stem cells in their native environment to help people with muscle injury or trauma, or even to combat natural aging.”

Nine months in, stem cell-based therapy for spinal cord injury continues to improve paralyzed patients’ lives

If you’ve been following the Stem Cellar blog this year, then you must be as encouraged as we are with Asterias Biotherapeutics’ CIRM-funded clinical trial, which is testing an embryonic stem cell-based therapy for spinal cord injury.

astopc1Over many months, we’ve covered the company’s string of positive announcements that their cell therapy product – called AST-OPC1 – appears safe, is doing what is it’s supposed to after injection into the damaged spinal cord, and shows signs of restoring upper body function at 3 and 6 months after treatment. We’ve also written about first-hand accounts from some of the clinical trial participants who describe their remarkable recoveries.

That streak of good news continues today with Asterias’ early morning press release. The announcement summarizes 9-month results for a group of six patients who received an injection of 10 million AST-OPC1 cells 2 to 4 weeks after their injury (this particular trial is not testing the therapy on those with less recent injuries). In a nut shell, their improvements in arm, hand and finger movement seen at the earlier time points have persisted and even gotten better at 9 months.

Two motors levels = a higher quality of life
These participants sustained severe spinal cord injuries in the neck, leading to a loss of feeling and movement in their body from the neck down. To quantify the results of the cell therapy, researchers refer to “motor levels” of improvement. These levels correspond to an increasing number of motor, or movement, abilities. For a spinal cord injury victim paralyzed from the neck down, recovering two motor levels of function can mean the difference between needing 24-hour a day home care versus dressing, feeding and bathing themselves. The impact of this level of improvement cannot be overstated. As mentioned in the press release, regaining these abilities, “can result in lower healthcare costs, significant improvements in quality of life, increased ability to engage in activities of daily living, and increased independence.”

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9-month follow-up results of Asterias’ spinal cord injury trial. Patients treated with stem cell-based therapy (green line) have greater movement recovery compared to historical data from 62 untreated patients (Blue dotted line). Image: Asterias Biotherapeutics.

With the new 9-month follow-up data, the clinical researchers have confirmed that 3 out of the 6 (50%) patients show two motor levels of improvement. This result is up from 2 of 6 patients at the earlier time points. And all six patients have at least one motor level of improvement up through 9 months post-treatment. Now, make no mistake, spontaneous recovery from spinal cord injuries does occur. But historical data collected from 62 untreated patients show that only 29% reached two motor levels of improvement after 12-months.

As you can imagine, the Asterias team is optimistic about these latest results. Here’s what Chief Medical Officer, Dr. Edward Wirth had to say:

Edward-Wirth

Edward Wirth
Photo: Asterias

“The new efficacy results show that previously reported meaningful improvements in arm, hand and finger function in the 10 million cell cohort treated with AST-OPC1 cells have been maintained and in some patients have been further enhanced even 9 months following dosing. We are increasingly encouraged by these continued positive results, which are remarkable compared with spontaneous recovery rates observed in a closely matched untreated patient population.”

Equally encouraging is the therapy’s steady safety profile with no serious adverse events reported through the 9-month follow up.

Looking ahead
Dr. Jane Lebkowski, Asterias’ President of R&D and Chief Scientific Officer, will be presenting these data today during the International Society for Stem Cell Research (ISSCR) 2017 Annual Meeting held in Boston. Asterias expects to share more results later this fall after all six patients complete their 12-month follow-up visit.

The clinical trial is also treating another group of patients with a maximum dose of 20 million cells. The hope is that this cohort will show even more effectiveness.

For the sake of the more than 17,000 people who are incapacitated by a severe spinal cord injury each year, let’s hope the streak of good news continues.

Baseball’s loss is CIRM’s gain as Stanford’s Linda Boxer is appointed to Stem Cell Agency Board

Boxer

Dr. Linda Boxer: Photo courtesy Stanford University

One of the things that fascinates me is finding out how people end up in the job they have, the job they love. It is rare that the direction they started out on is the one they end on. Usually, people take several different paths, some intended, some unintended, to get to where they want to be.

A case in point is Dr. Linda Boxer, a renowned and respected researcher and physician at the Stanford School of Medicine, and now the newest member of the CIRM Board (you can read all about that in our news release).

In Dr. Boxer’s case, her original career path was a million miles from working with California’s stem cell agency:

“The first career choice that I recall as a young child was professional baseball—growing up in Minnesota, I was a huge Twins fan—I did learn fairly quickly that this was not likely to be a career that was available for a girl, and it wasn’t clear what one did after that career ended at a relatively young age.”

Fortunately for us she became interested in science.

“I have always been curious about how things work—science classes in grade school were fascinating to me. I was given a chemistry kit as a birthday gift, and I was amazed at what happened when different chemicals were mixed together: color changes, precipitates forming, gas bubbles, explosions (small ones, of course).

Then when we studied biology in middle school, I was fascinated by what one could observe with a microscope and became very interested in trying to understand how living organisms work.

It was an easy decision to plan a career in science.  The tougher decision came in college when I had planned to apply to graduate school and earn a PhD, but I was also interested in human health and disease and thought that perhaps going to medical school made more sense.  Fortunately, one of my faculty advisors told me about combined MD/PhD programs, and that choice seemed perfect for me.”

Along the way she says she got a lot of help and support from her colleagues. Now she wants to do the same for others:

“Mentors are incredibly important at every career stage.  I have been fortunate to have been mentored by some dedicated scientists and physicians.  Interestingly, they have all been men.  There were really very few women available as mentors at the time—of course, that has changed for the better now.  It never occurred to me then that gender made a difference, and I just looked for mentors who had successful careers as scientists and physicians and who could provide advice to someone more junior.

One of the aspects of my role now that I enjoy the most is mentoring junior faculty and trainees.  I don’t think one can have too many mentors—different mentors can help with different aspects of one’s life and career.  I think it is very important for established scientists to give back and to help develop the next generation of physicians and scientists.”

Dr. Boxer is already well known to everyone at CIRM, having served as the “alternate” on the Board for Stanford’s Dr. Lloyd Minor. But her appointment by State Controller Betty Yee makes her the “official” Board member for Stanford. She brings a valuable perspective as both a scientist and a physician.

The Minnesota Twins lost out when she decided to pursue a career in science. We’re glad she did.