Starving stem cells of oxygen can help build stronger bones

Leach_Kent_BME.2012

J. Kent Leach: Photo courtesy UC Davis

We usually think that starving something of oxygen is going to make it weaker and maybe even kill it. But a new study by J. Kent Leach at UC Davis shows that instead of weakening bone defects, depriving them of oxygen might help boost their ability to create new bone or repair existing bone.

Leach says in the past the use of stem cells to repair damaged or defective bone had limited success because the stem cells often didn’t engraft in the bone or survive long if they did. That was because the cells were being placed in an environment that lacked oxygen (concentration levels in bone range from 3% to 8%) so the cells found it hard to survive.

However, studies in the lab had shown that if you preconditioned mesenchymal stem cells (MSCs), by exposing them to low oxygen levels before you placed them on the injury site, you helped prolong their viability. That was further enhanced by forming the MSCs into three dimensional clumps called spheroids.

Lightbulb goes off

In the  current study, published in Stem Cells, Leach says the earlier spheroid results  gave him an idea:

“We hypothesized that preconditioning MSCs in hypoxic (low oxygen) culture before spheroid formation would increase cell viability, proangiogenic potential (ability to create new blood vessels), and resultant bone repair compared with that of individual MSCs.”

So, the researchers placed one group of human MSCs, taken from bone marrow, in a dish with just 1% oxygen, and another identical group of MSCs in a dish with normal oxygen levels. After three days both groups were formed into spheroids and placed in an alginate hydrogel, a biopolymer derived from brown seaweed that is often used to build cellular cultures.

Seaweed

Brown seaweed

The team found that the oxygen-starved cells lasted longer than the ones left in normal oxygen, and the longer those cells were deprived of oxygen the better they did.

Theory is great, how does it work in practice?

Next was to see how those two groups did in actually repairing bones in rats. Leach says the results were encouraging:

“Once again, the oxygen-deprived, spheroid-containing gels induced significantly more bone healing than did gels containing either preconditioned individual MSCs or acellular gels.”

The team say this shows the use of these oxygen-starved cells could be an effective approach to repairing hard-to-heal bone injuries in people.

“Short‐term exposure to low oxygen primes MSCs for survival and initiates angiogenesis (the development of new blood vessels). Furthermore, these pathways are sustained through cell‐cell signaling following spheroid formation. Hypoxic (low oxygen) preconditioning of MSCs, in synergy with transplantation of cells as spheroids, should be considered for cell‐based therapies to promote cell survival, angiogenesis, and bone formation.”

CIRM & Dr. Leach

While CIRM did not fund this study we have invested more than $1.8 million in another study Dr. Leach is doing to develop a new kind of imaging technology that will help us see more clearly what is happening in bone and cartilage-targeted therapies.

In addition, back in March of 2012, Dr. Leach spoke to the CIRM Board about his work developing new approaches to growing bone.

 

Stories that caught our eye: How dying cells could help save lives; could modified blood stem cells reverse diabetes?; and FDA has good news for patients, bad news for rogue clinics

Gunsmoke

Growing up I loved watching old cowboy movies. Invariably the hero, even though mortally wounded, would manage to save the day and rescue the heroine and/or the town.

Now it seems some stem cells perform the same function, dying in order to save the lives of others.

Researchers at Kings College in London were trying to better understand Graft vs Host Disease (GvHD), a potentially fatal complication that can occur when a patient receives a blood stem cell transplant. In cases of GvHD, the transplanted donor cells turn on the patient and attack their healthy cells and tissues.

Some previous research had found that using bone marrow cells called mesenchymal stem cells (MSCs) had some success in combating GvHD. But it was unpredictable who it helped and why.

Working with mice, the Kings College team found that the MSCs were only effective if they died after being transplanted. It appears that it is only as they are dying that the MSCs engage with the individual’s immune system, telling it to stop attacking healthy tissues. The team also found that if they kill the MSCs just before transplanting them into mice, they were just as effective.

In a news article on HealthCanal, lead researcher Professor Francesco Dazzi, said the next step is to see if this will apply to, and help, people:

“The side effects of a stem cell transplant can be fatal and this factor is a serious consideration in deciding whether some people are suitable to undergo one. If we can be more confident that we can control these lethal complications in all patients, more people will be able to receive this life saving procedure. The next step will be to introduce clinical trials for patients with GvHD, either using the procedure only in patients with immune systems capable of killing mesenchymal stem cells, or killing these cells before they are infused into the patient, to see if this does indeed improve the success of treatment.”

The study is published in Science Translational Medicine.

Genetically modified blood stem cells reverse diabetes in mice (Todd Dubnicoff)

When functioning properly, the T cells of our immune system keep us healthy by detecting and killing off infected, damaged or cancerous cells in our body. But in the case of type 1 diabetes, a person’s own T cells turn against the body by mistakenly targeting and destroying perfectly normal islet cells in the pancreas, which are responsible for producing insulin. As a result, the insulin-dependent delivery of blood sugar to the energy-hungry organs is disrupted leading to many serious complications. Blood stem cell transplants have been performed to treat the disease by attempting to restart the immune system. The results have failed to provide a cure.

Now a new study, published in Science Translational Medicine, appears to explain why those previous attempts failed and how some genetic rejiggering could lead to a successful treatment for type 1 diabetes.

An analysis of the gene activity inside the blood stem cells of diabetic mice and humans reveals that these cells lack a protein called PD-L1. This protein is known to play an important role in putting the brakes on T cell activity. Because T cells are potent cell killers, it’s important for proteins like PD-L1 to keep the activated T cells in check.

Cell based image for t 1 diabetes

Credit: Andrea Panigada/Nancy Fliesler

Researchers from Boston Children’s Hospital hypothesized that adding back PD-L1 may prevent T cells from the indiscriminate killing of the body’s own insulin-producing cells. To test this idea, the research team genetically engineered mouse blood stem cells to produce the PD-L1 protein. Experiments with the cells in a petri dish showed that the addition of PD-L1 did indeed block the attack-on-self activity. And when these blood stem cells were transplanted into a diabetic mouse strain, the disease was reversed in most of the animals over the short term while a third of the mice had long-lasting benefits.

The researchers hope this targeting of PD-L1 production – which the researchers could also stimulate with pharmacological drugs – will contribute to a cure for type 1 diabetes.

FDA’s new guidelines for stem cell treatments

Gottlieb

FDA Commissioner Scott Gottlieb

Yesterday Scott Gottlieb, the Commissioner at the US Food and Drug Administration (FDA), laid out some new guidelines for the way the agency regulates stem cells and regenerative medicine. The news was good for patients, not so good for clinics offering unproven treatments.

First the good. Gottlieb announced new guidelines encouraging innovation in the development of stem cell therapies, and faster pathways for therapies, that show they are both safe and effective, to reach the patient.

At the same time, he detailed new rules that provide greater clarity about what clinics can do with stem cells without incurring the wrath of the FDA. Those guidelines detail the limits on the kinds of procedures clinics can offer and what ways they can “manipulate” those cells. Clinics that go beyond those limits could be in trouble.

In making the announcement Gottlieb said:

“To be clear, we remain committed to ensuring that patients have access to safe and effective regenerative medicine products as efficiently as possible. We are also committed to making sure we take action against products being unlawfully marketed that pose a potential significant risk to their safety. The framework we’re announcing today gives us the solid platform we need to continue to take enforcement action against a small number of clearly unscrupulous actors.”

Many of the details in the announcement match what CIRM has been pushing for some years. Randy Mills, our previous President and CEO, called for many of these changes in an Op Ed he co-wrote with former US Senator Bill Frist.

Our hope now is that the FDA continues to follow this promising path and turns these draft proposals into hard policy.

 

CIRM Board invests in three new stem cell clinical trials targeting arthritis, cancer and deadly infections

knee

Arthritis of the knee

Every day at CIRM we get calls from people looking for a stem cell therapy to help them fight a life-threatening or life-altering disease or condition. One of the most common calls is about osteoarthritis, a painful condition where the cartilage that helps cushion our joints is worn away, leaving bone to rub on bone. People call asking if we have something, anything, that might be able to help them. Now we do.

At yesterday’s CIRM Board meeting the Independent Citizens’ Oversight Committee or ICOC (the formal title of the Board) awarded almost $8.5 million to the California Institute for Biomedical Research (CALIBR) to test a drug that appears to help the body regenerate cartilage. In preclinical tests the drug, KA34, stimulated mesenchymal stem cells to turn into chondrocytes, the kind of cell found in healthy cartilage. It’s hoped these new cells will replace those killed off by osteoarthritis and repair the damage.

This is a Phase 1 clinical trial where the goal is primarily to make sure this approach is safe in patients. If the treatment also shows hints it’s working – and of course we hope it will – that’s a bonus which will need to be confirmed in later stage, and larger, clinical trials.

From a purely selfish perspective, it will be nice for us to be able to tell callers that we do have a clinical trial underway and are hopeful it could lead to an effective treatment. Right now the only alternatives for many patients are powerful opioids and pain killers, surgery, or turning to clinics that offer unproven stem cell therapies.

Targeting immune system cancer

The CIRM Board also awarded Poseida Therapeutics $19.8 million to target multiple myeloma, using the patient’s own genetically re-engineered stem cells. Multiple myeloma is caused when plasma cells, which are a type of white blood cell found in the bone marrow and are a key part of our immune system, turn cancerous and grow out of control.

As Dr. Maria Millan, CIRM’s President & CEO, said in a news release:

“Multiple myeloma disproportionately affects people over the age of 65 and African Americans, and it leads to progressive bone destruction, severe anemia, infectious complications and kidney and heart damage from abnormal proteins produced by the malignant plasma cells.  Less than half of patients with multiple myeloma live beyond 5 years. Poseida’s technology is seeking to destroy these cancerous myeloma cells with an immunotherapy approach that uses the patient’s own engineered immune system T cells to seek and destroy the myeloma cells.”

In a news release from Poseida, CEO Dr. Eric Ostertag, said the therapy – called P-BCMA-101 – holds a lot of promise:

“P-BCMA-101 is elegantly designed with several key characteristics, including an exceptionally high concentration of stem cell memory T cells which has the potential to significantly improve durability of response to treatment.”

Deadly infections

The third clinical trial funded by the Board yesterday also uses T cells. Researchers at Children’s Hospital of Los Angeles were awarded $4.8 million for a Phase 1 clinical trial targeting potentially deadly infections in people who have a weakened immune system.

Viruses such as cytomegalovirus, Epstein-Barr, and adenovirus are commonly found in all of us, but our bodies are usually able to easily fight them off. However, patients with weakened immune systems resulting from chemotherapy, bone marrow or cord blood transplant often lack that ability to combat these viruses and it can prove fatal.

The researchers are taking T cells from healthy donors that have been genetically matched to the patient’s immune system and engineered to fight these viruses. The cells are then transplanted into the patient and will hopefully help boost their immune system’s ability to fight the virus and provide long-term protection.

Whenever you can tell someone who calls you, desperately looking for help, that you have something that might be able to help them, you can hear the relief on the other end of the line. Of course, we explain that these are only early-stage clinical trials and that we don’t know if they’ll work. But for someone who up until that point felt they had no options and, often, no hope, it’s welcome and encouraging news that progress is being made.

 

 

Lights, Camera, Stem Cells! How photo-responsive hydrogels can improve stem cell therapies

Watching a movie in IMAX 3D.

These days, going to the movie theater is like riding the wildest rollercoaster at your local theme park. It can be an IMAX 3D, surround sound, vibrating seat experience that makes you feel like you’re living the actual movie.

As the entertainment industry evolves towards more intense, realistic cinematic experiences, scientists are following a similar path towards 3D technologies that will improve stem cell-based therapies for biomedical applications. One such technology is called a hydrogel. Hydrogels are biological materials made of either synthetic polymers or natural molecules that scientists use to simulate the native environment in which cells and tissues develop.

Growing stem cells on a flat surface, such as a culture dish, is like watching a movie in a standard, less immersive 2D theater – the stem cells aren’t in their typical 3D environment where they receive biochemical and physical cues to develop into the appropriate cell types of the tissue they are destined to become.

With hydrogels, scientists can more closely mimic a stem cell’s natural environment, or what is called the “stem cell niche”. A lot of research has been dedicated towards fine-tuning hydrogels in a way that can control how stem cells behave and mature. We’ve blogged on this topic previously, and today we bring you an update on a new type of hydrogel that improves upon current technologies.

Scientists from The Hong Kong University of Science and Technology created photo-responsive or light-sensitive hydrogels that they used to grow human mesenchymal stem cells in 3D cultures. These hydrogels contain a vitamin B12-dependent, photo-responsive protein called CarHC. In the dark, coenzyme B12 binds to CarHC and triggers the protein to self-assemble into polymers that create an elastic hydrogel structure. When exposed to light, B12 is absorbed and can no longer bind CarHC, causing the hydrogel structure to dissolve into a liquid solution.

A hydrogel containing mesenchymal stem cells. (Image courtesy of Harvard Paulson School).

This photo-responsive hydrogel is the equivalent of a light-sensing switch that allows the scientists to capture or release stem cells without damaging them or affecting their viability. Senior author on the study, Dr. Fei Sun, elaborated in an interview with Phys.org,

“The resulting hydrogel composed of physically self-assembled CarHC polymers exhibited a rapid gel-solultion transition on light exposure, which enabled the facile release/recovery of 3T3 fibroblasts and human mesenchymal stem cells (hMSCs) from 3D cultures while maintaining their viability.”

Sun’s team is one of the first to report the development of photo-sensitive “smart” hydrogels for stem cell research applications. Looking forward, Sun believes that their technology will be useful for making “tunable materials” that will aid in the development of stem cell-based therapies.

He concluded,

“Given the growing demand for creating stimuli-responsive “smart” hydrogels, the direct assembly of stimuli-responsive proteins into hydrogels represents a versatile strategy for designing dynamically tunable materials.”

License to heal: UC Davis deal looks to advance stem cell treatment for bone loss and arthritis

Nancy Lane

Wei Yao and Nancy Lane of UC Davis: Photo courtesy UC Davis

There are many challenges in taking even the most promising stem cell treatment and turning it into a commercial product approved by the Food and Drug Administration (FDA). One of the biggest is expertise. The scientists who develop the therapy may be brilliant in the lab but have little experience or expertise in successfully getting their work through a clinical trial and ultimately to market.

That’s why a team at U.C. Davis has just signed a deal with a startup company to help them move a promising stem cell treatment for arthritis, osteoporosis and fractures out of the lab and into people.

The licensing agreement combines the business acumen of Regenerative Arthritis and Bone Medicine (RABOME) with the scientific chops of the UC Davis team, led by Nancy Lane and Wei Yao.

They plan to test a hybrid molecule called RAB-001 which has shown promise in helping direct mesenchymal stem cells (MSCs) – these are cells typically found in the bone marrow and fat tissue – to help stimulate bone growth and increase existing bone mass and strength. This can help heal people suffering from conditions like osteoporosis or hard to heal fractures. RAB-001 has also shown promise in reducing inflammation and so could prove helpful in treating people with inflammatory arthritis.

Overcoming problems

In a news article on the UC Davis website, Wei Yao, said RAB-001 seems to solve a problem that has long puzzled researchers:

“There are many stem cells, even in elderly people, but they do not readily migrate to bone.  Finding a molecule that attaches to stem cells and guides them to the targets we need provides a real breakthrough.”

The UC Davis team already has approval to begin a Phase 1 clinical trial to test this approach on people with osteonecrosis, a disease caused by reduced blood flow to bones. CIRM is funding this work.

The RABOME team also hopes to test RAB-001 in clinical trials for healing broken bones, osteoporosis and inflammatory arthritis.

CIRM solution

To help other researchers overcome these same regulatory hurdles in developing stem cell therapies CIRM created the Stem Cell Center with QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider that has deep experience and therapeutic expertise. The Stem Cell Center will help researchers overcome the challenges of manufacturing and testing treatments to meet FDA standards, and then running a clinical trial to test that therapy in people.

Pregnant women’s stem cells could help battle brittle bone diseases like osteoporosis

pregnant

Sometimes I wonder how a scientist ever came up with an idea for a potential treatment. Case in point is a study in the journal Scientific Reports, where researchers use stem cells from the amniotic fluid of a pregnant woman to cure osteoporosis in mice! What researcher, seeing a pregnant woman, thought to her or himself “I wonder if…..”

Regardless of how they came up with the idea, we might be glad they did because this study showed that those stem cells could reduce the number of fractures in mice with brittle bone disease by 78 percent. And that’s raising hopes they might one day be able to do the same for people.

Researchers at University College London took mesenchymal stem cells (MSCs) that had been shed by babies into the amniotic fluid of their mother, and injected them into mice with brittle bone disease. Previous studies had suggested that MSCs, taken at such an early age, might be more potent than similar cells taken from adults. That certainly seems to have been the case here where the treated mice had far fewer fractures than untreated mice.

Pascale Guillot, the lead researcher of the study, told the Guardian newspaper:

“The stem cells we’ve used are excellent at protecting bones. The bones become much stronger and the way the bone is organised internally is of much higher quality.”

 

What was also interesting was not just what they did but how they did it. You might think that the injected stem cells helped reduce fractures by forming new bones. You might think that, but you’d be wrong. Instead, the stem cells seem to have worked by releasing growth factors that stimulated the mouse’s own bone cells to kick into a higher gear, and help build stronger bones.

In the study the researchers say using MSCs from amniotic fluid has a number of distinct advantages over using MSCs from adults:

  • They are easier to expand into large numbers needed for therapies
  • They don’t create tumors
  • The body’s immune system won’t attack them
  • They are smaller and so can move around with greater ease
  • They are easier to reprogram into different kinds of cells

Next Guillot and his team want to explore if this approach could be used to treat children and adults with brittle bone disease, and to help adults with osteoporosis, a problem that affects around 44 million people in the US.

 “The discovery could have a profound effect on the lives of patients who have fragile bones and could stop a large number of their painful fractures.”

Stem cell stories that caught our eye: fashionable stem cells, eliminating HIV, cellular Trojan horse fights cancer

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.

Stem cell fashion for a cause. Science and art are not mutually exclusive subjects. I know plenty of scientists who are talented painters or designers. But you don’t often see science being displayed in an artistic way or art being used to help explain complex scientific topics. I think that in the future, this will change as both subjects have a lot to offer one another.

Stem cell ties are in fashion!

Stem cell ties are in fashion!

Take this story from the University of Michigan for instance. Designer Dominic Pangborn has joined forces with the Heinz C. Prechter Bipolar Research Fund at the University of Michigan (UOM) to design fashionable scarves and ties featuring beautiful pictures of stem cells. The goal of the Prechter Fund scarf and tie project is to raise awareness for mental health research.

The scarves and ties feature pictures of brain stem cells taken by UOM scientists who are studying them to understand the mechanisms behind bipolar disorder. These stem cells were generated from induced pluripotent stem cells or iPS cells that were derived from donated skin biopsies of patients with bipolar disease. Studying these diseased brain cells in a dish revealed that the nerve cells from bipolar patients were misbehaving, sending out electrical signals more frequently compared to healthy nerve cells.

Dr. Melvin McInnis, the Prechter Fund research director, explained:

“By understanding the causes of bipolar disorder, we will be able to develop new treatments for the illness and most importantly, we’ll be able to prevent destructive mood episodes. Our ultimate goal is to allow people to live happy, normal lives.”

Pangborn is passionate about using art to reflect an important cause.

“I decided to add butterflies to the design because they signify metamorphosis. Our society is finally at a point where mental illness is openly talked about and research is taking a turn for the better.”

He plans to release his collection in time for National Mental Health Awareness month in May. All proceeds will go to the Prechter bipolar research projects at UOM.

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

New stem cell therapy could eliminate HIV for good

The stem cells therapies being developed to cure HIV are looking more promising every day. A few are already being tested in clinical trials, and CIRM is funding two of them (you can read more about them here). News came out this week about a new trial conducted at the City of Hope’s CIRM Alpha Stem Cell Clinic. They reported in a news release that they’ve treated their first patient. His name is Aaron Kim, and he’s had HIV since he was born. In 1983, he and his twin sister were born prematurely and due to a complication, Aaron had to get a blood transfusion that unfortunately gave him HIV.

Aaron Kim with nurse. (City of Hope)

Aaron Kim with nurse. (City of Hope)

Aaron thought he would live with this disease the rest of his life, but now he has a chance at being cured. In March, Aaron received a transplant of his own bone marrow stem cells that were genetically engineered to have a modified version of the CCR5 gene that makes his cells resistant to HIV infection. CCR5 is a is a protein receptor on the surface of blood cells that acts as a gateway for HIV entry. The hope is that his reengineered stem cells will populate his immune system with HIV-resistant cells that can eliminate the virus completely.

Dr. John Zaia who is the director the the City of Hope Alpha Clinic explained,

“The stem cell therapy Aaron received is one of more than 20 cure strategies for HIV. It may not cure him, but our goal is to reduce or even halt Aaron’s reliance on HIV drugs, potentially eliminating the virus completely.”

My favorite part of this story was that it acknowledged how importance it is for patients to participate in clinical trials testing promising new stem cell therapies where the outcomes aren’t always known. Brave patients such as Aaron make it possible for scientists to make progress and develop better and safer treatments for patients in the future.

Dr. Zaia commented, “It’s a wonderful and generous humanitarian gesture on Aaron’s part to participate in this trial.”

Stem cell Trojan horse fights cancer

Chemotherapy is great at killing cancer cells, but unfortunately, it’s also great at killing healthy cells too. To combat this issue, scientists are developing new delivery methods that can bring high doses of chemotherapy drugs to the cancer tumors and minimize exposure of healthy tissues.

Mesenchymal stem cells loaded with drug-containing microparticles. Credit: Jeff Karp and Oren Levy, Brigham and Women's Hospital

Mesenchymal stem cells loaded with drug-containing microparticles.
Credit: Jeff Karp and Oren Levy, Brigham and Women’s Hospital

A study published this week in Biomaterials, describes a new drug delivery method that has the potential to be an effective treatment for prostate cancer. Researchers from the Brigham and Women’s Hospital and Johns Hopkins University developed a drug delivery platform using mesenchymal stem cells. They packaged a non-active, prodrug version of a potent prostate cancer chemotherapy drug into microparticles that they loaded into MSCs. When the MSCs and prostate cancer cells were cultured together in a dish, the MSCs released their prodrug cargo, which was then internalized by the prostate cancer cells. The prodrug was then metabolized into its active, cancer-killing form and was very effective at killing the cancer cells.

In a news release picked up by Science Daily, one of the lead scientists on the study, Dr. Oren Levy, further explained the stem cell Trojan horse concept:

“Mesenchymal stem cells represent a potential vehicle that can be engineered to seek out tumors. Loading those cells with a potent chemotherapeutic drug is a promising cell-based Trojan horse approach to deliver drugs to sites of cancer.”

If all goes well, the teams plan to develop different versions of their stem cell-based drug delivery method that target different cancers and other diseases.

Students use a 3D printer to sink their teeth into stem cell research

Student winners

L-R Alan Tan, Sid Bommakanti, Daniel Chae – prize winning science students

A 3D printer, some old teeth, and some terrific science were enough to help three high school students develop a new way of growing bone and win a $30,000 prize in a national competition.

The three teamed up for the Siemens Competition in Math, Science & Technology, which bills itself as “the nation’s premier research competition for high school students”.

The trio includes two from the San Francisco Bay area, where we are based; Sid Bommakanti from Amador Valley High School in Pleasanton, and Alan Tan, from Irvington High School in Fremont. The third member of the team, Daniel Chae, goes to Thomas Jefferson High School for Science and Technology in Alexandria, Virginia.

The three used mesenchymal stem cells – which are capable of being turned into muscle, cartilage or bone – which they got from the dental pulp found in wisdom teeth that had been extracted.

In a story posted on the KQED website Tan says they thought it would be cool to take something that is normally thrown away, and recycle it:

“When we learned we could take stem cells from teeth—it’s actually part of medical waste—we realized could turn this into bone cells,”

The students used a 3D printer to create a kind of scaffold out of a substance called polylatctic acid – it’s an ingredient found in corn starch or sugar cane. The scaffold had a rough surface, something they hoped would help stimulate the dental pulp to grow on it and become bone.

That’s what happened. The students were able to show that their work produced small clusters of cells that were growing on the scaffold, cells that were capable of maturing into bone. This could be used to create dental implants to replace damaged teeth, and, according to Alan Tan, to repair other injuries:

“We used dental pulp stem cells so that we could regenerate bones in various parts of our body so for example we could fix bones in your jaw and tibia and other places.”

The beauty of this approach is that the scaffold and bone could be implanted in, say, the mouth and then as the scaffold disintegrates the new bone would be left in place.

While they didn’t take the top prize (a $100,000 scholarship) they did have to see off some serious competition from nearly 1,800 other student project submissions to win a Team scholarship award.

The students say they learned a lot working together, and encouraged other high school students who are interested in science to take part in competitions like this one.

Sid Bommakanti “Both me, Alan and our other partner are interested in medicine as a whole and we wanted to make an impact on other people’s lives.”

Alan Tan: “I would say get into science early. Don’t be afraid to put yourself out there and talk to professors, talk to people, competitions like this are beneficial because they encourage students to get out there and interact with the real world.”

CIRM is helping students like these through its Stem Cell Education Portal,  which includes the materials and resources that teachers need to teach high school students about stem cells. All the materials meet both state and federal guidelines.

 

 

Cell survival strategy gives mesenchymal stem cells their “paramedic” properties

Electron micrograph of a human mesenchymal stem cells (Credit: Robert M. Hunt)

Electron micrograph of a human mesenchymal stem cells (Image credit: Robert M. Hunt)

A cell for all therapies
Type “mesenchymal stem cells” into the federal online database of registered clinical trials, and you’ll get a sprawling list of 527 trials testing treatments for diabetes, multiple sclerosis as well as diseases of the kidney, lung, and heart, to name just a few. Mesenchymal stem cells (MSCs) have the capacity to specialize into bone, cartilage, muscle and fat cells but their popularity as a therapeutic agent mostly comes from their ability to reduce inflammation and to help repair tissues.

MSCs may be great tools for scientists to fight disease, but what is it about their natural function that make MSCs – as UC Davis researcher Jan Nolta likes to calls them – the body’s “paramedics”? A fascinating study reported yesterday in Nature Communications by scientists at the Florida campus of The Scripps Research Institute (TSRI) and the University of Pittsburgh suggest that it’s a trait the cells gain as a result of their complex cell survival mechanisms.

The TSRI team came to this conclusion by studying how MSCs respond to oxygen-related stress. MSCs reside in the bone marrow where they help maintain and regulate blood stem cells. The bone marrow is naturally a hypoxic, or low oxygen, environment. Growing MSCs in the lab at oxygen levels found in the air we breathe are much higher than what is found in the marrow. This creates oxidative stress in which the excess oxygen leads to unwanted chemical reactions which disrupt a cell’s molecules.

One cell’s trash is another’s treasure
One result of this oxidative stress is damage to the MSCs’ mitochondria, structures responsible for generating the energy needs of a cell. The team found that MSCs package the faulty mitochondria into sacs, or vesicles, which travel to the cell surface to be dumped out of the cell. At this point, another resident of the bone marrow comes into the picture: the macrophage. Previous research has shown that macrophages and MSCs work closely together to maintain the health of the blood stem cells in the bone marrow.

Screen Shot 2015-11-04 at 9.58.48 AM

White arrow shows vesicles (red) carrying mitochondra (green) to the surface of the MSC  and being ingested by a macrophage (round shape in lower half) – (From Fig 2 Nat Commun. 2015 Oct 7;6:8472)

In a high oxygen stress environment, the team observed that MSCs can recruit macrophages to engulf the damaged mitochondria-containing vesicles and repurpose them for their own use. In fact, the researchers measured improved energy production in the macrophages after ingesting the MSCs’ mitochondria. Blocking the transfer of the damaged mitochondria from MSCs to macrophages caused the MSCs to die, confirming that this off-loading of mitochondria to macrophages is critical for MSC survival.

Evolving tricks for cell survival
Macrophages (macro=big; phages=eaters), key players of the immune system and the inflammation response, also rid the body of invading bacteria or damaged cells by devouring them. To avoid being swallowed up by the macrophage while donating its mitochondria, the stressed MSCs have another trick up their sleeve. The research team identified the release of other vesicles from the MSCs that contain molecules called microRNAs which stimulate anti-inflammatory properties in the macrophages. This prevented the macrophages from attacking and eating the MSCs.

And there you have it: as a result of relying on macrophages to survive stressful environments, MSCs appear to have evolved anti-inflammatory activities that turn out to be a handy tool for numerous ongoing and future cell therapy trials.

In a TSRI press release picked up by Newswise, professor Donald Phinney co-leader of study points out the groundbreaking aspect of the study:

Donald G. Phinney

Donald Phinney (photo: TSRI)

“This is the first time anyone has shown how mesenchymal stem cells provide for their own survival by recruiting and then suppressing normal macrophage activity.”