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

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.

 

 

 

 

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The life of a sleeping muscle stem cell is very busy

For biological processes, knowing when to slow down is as important as knowing when to step on the accelerator. Take for example muscle stem cells. In a healthy state, these cells mostly lay quiet and rarely divide but upon injury, they bolt into action by dividing and specializing into new muscle cells to help repair damaged muscle tissue. Once that mission is accomplished, the small pool of muscle stem cells is replenished through self-renewal before going back into a dormant, or quiescent, state.

muscle stem cell

Muscle stem cell (pink with green outline) sits along a muscle fiber. Image: Michael Rudnicki/OIRM

“Dormant” may not be the best way to describe it because a lot of activity is going on within the cells to maintain its sleepy state. And a better understanding of the processes at play in a dormant state could reveal insights about treating aging or diseased muscles which often suffer from a depletion of muscle stem cells. One way to analyze cellular activity is by examining RNA transcripts which are created when a gene is turned “on”. These transcripts are the messenger molecules that provide a gene’s instructions for making a particular protein.

By observing something, you change it
In order to carry out the RNA transcript analyses in animal studies, researchers must isolate and purify the stem cells from muscle tissue. The worry here is that all of the necessary poking of prodding of the cells during the isolation method will alter the RNA transcripts leading to a misinterpretation of what is actually happening in the native muscle tissue. To overcome this challenge, Dr. Thomas Rando and his team at Stanford University applied a recently developed technique that allowed them to tag and track the RNA transcripts within living mice.

The CIRM-funded study reported today in Cell Reports found that there are indeed significant differences in results when comparing the standard in vitro lab method to the newer in vivo method. As science writer Krista Conger summarized in a Stanford Medical School press release, those differences led to some unexpected results that hadn’t been observed previously:

“The researchers were particularly surprised to learn that many of the RNAs made by the muscle stem cells in vivo are either degraded before they are made into proteins, or they are made into proteins that are then rapidly destroyed — a seemingly shocking waste of energy for cells that spend most of their lives just cooling their heels along the muscle fiber.”

It takes a lot of energy to stay ready
Dr. Rando thinks that these curious observations do not point to an inefficient use of a cell’s resources but instead, “it’s possible that this is one way the cells stay ready to undergo a rapid transformation, either by blocking degradation of RNA or proteins or by swiftly initiating translation of already existing RNA transcripts.”

The new method provides Rando’s team a whole new perceptive on understanding what’s happening behind the scenes during a muscle stem cell’s “dormant” state. And Rando thinks the technique has applications well beyond this study:

Rando

Thomas Rando

“It’s so important to know what we are and are not modeling about the state of these cells in vivo. This study will have a big impact on how researchers in the field think about understanding the characteristics of stem cells as they exist in their native state in the tissue.”

 

 

Clever technique uncovers role of stem cells in cartilage repair

Over 50 million adults in the U.S. are estimated to be affected by some form of arthritis, a very painful, debilitating condition in which the cartilage that provides cushioning within bone joints gradually degrades. Health care costs of treating arthritis in California alone has been estimated at over $12 billion and that figure is already over a decade old. Unfortunately, the body doesn’t do a good job at healing cartilage in the joint so doctors rely mostly on masking symptoms with pain management therapy and, in severe cases, resorting to surgery.

Illustration of damaged cartilage within an osteoarthritic hip joint Image: Wikipedia/Open Stax

Mesenchymal stem cells (MSCs) – found in bone marrow, fat and blood – give rise to several cell types including cartilage-producing cells called chondrocytes. For that reason, they hold a lot of promise to restore healthy joints for arthritis sufferers. While there is growing evidence that injection of MSCs into joint cartilage is effective, it is still not clear how exactly the stem cells work. Do they take up residence in the cartilage, and give rise to new cartilage production in the joint? Or do they simply release proteins and molecules that stimulate other cells within the joint to restore cartilage? These are important questions to ask when it comes to understanding what tweaks you can make to your cell therapy to optimize its safety and effectiveness. Using some clever genetic engineering techniques in animal models, a research team at the University of Veterinary Medicine in Vienna, Austria report this week in JCI Insights that they’ve uncovered an answer.

Tracking the fate of a stem cell treatment after they’ve been injected into an animal, requires the attachment of some sort of “beacon” to the cells. A number of methods exist to accomplish this feat and they all rely on creating transgenic animals engineered to carry a gene that produces a protein label on the cells. For instance, cells from mice or rats engineered to carry the luciferase gene from fireflies, will glow and can be tracked in live animals. So, in this scenario, MSCs from a genetically-engineered donor animal are injected into the joints of a recipient animal which lacks this protein marker. This technique allows the researchers to observe what happens to the labeled cells.

There’s a catch, though. The protein marker carried along with the injected cells is seen as foreign to the immune system of the animal that receives the cells. As a result, the cells will be rejected and destroyed. To get around that problem, the current practice is to use recipient animals bred to have a limited immune response so that the injected cells survive. But solving this problem adds yet another: the immune system plays a key role in the mechanisms of arthritis so removing the effects of it in this experiment will likely lead to misinterpretations of the results.

So, the research team did something clever. They genetically engineered both the donor and recipient mice to carry the same protein marker but with an ever-so-slight difference in their genetic code. The genetic difference in the protein marker was large enough to allow the team to track the donor stem cells in the recipient animals, but similar enough to avoid rejection from the immune system. With all these components of the experiment in place, the researchers were able to show that the MSCs release protein factors to help the body repair its own cartilage damage and not by directly replacing the cartilage-producing cells.

An unexpected link: immune cells send muscle injury signal to activate stem cell regeneration

We’ve written many blogs over the years about research focused on muscle stem cell function . Those stories describe how satellite cells, another name for muscle stem cells, lay dormant but jump into action to grow new muscle cells in response to injury and damage. And when satellite function breaks down with aging as well as with diseases like muscular dystrophy, the satellite cells drop in number and/or lose their capacity to divide, leading to muscle degeneration.

Illustration of satellite cells within muscle fibers. Image source: APSU Biology

One thing those research studies don’t focus on is the cellular and molecular signals that cause the satellite cells to say, “Hey! We need to start dividing and regenerating!” A Stanford research team examining this aspect of satellite cell function reports this week in Nature Communications that immune cells play an unexpected role in satellite cell activation. This study, funded in part by CIRM, provides a fundamental understanding of muscle regeneration and repair that could aid the development of novel treatments for muscle disorders.

ADAMTS1: a muscle injury signal?
To reach this conclusion, the research team drew upon previous studies that indicated a gene called Adamts1 was turned on more strongly in the activated satellite cells compared to the dormant satellite cells. The ADAMTS1 protein is a secreted protein so the researchers figured it’s possible it could act as a muscle injury signal that activates satellites cells. When ADAMTS1 was applied to mouse muscle fibers in a petri dish, satellite cells were indeed activated.

Next, the team examined ADAMTS1 in a mouse model of muscle injury and found the protein clearly increased within one day after muscle injury. This timing corresponds to when satellite cells drop out of there dormant state after muscle injury and begin dividing and specializing into new muscle cells. But follow up tests showed the satellite cells were not the source of ADAMTS1. Instead, a white blood cell called a macrophage appeared to be responsible for producing the protein at the site of injury. Macrophages, which literally means “big eaters”, patrol our organs and will travel to sites of injury and infection to keep them clean and healthy by gobbling up dead cells, bacteria and viruses. They also secrete various proteins to alert the rest of the immune system to join the fight against infection.

Immune cell’s double duty after muscle injury: cleaning up the mess and signaling muscle regeneration
To confirm the macrophages’ additional role as the transmitter of this ADAMTS1 muscle injury signal, the researchers generated transgenic mice whose macrophages produce abnormally high levels of ADAMTS1. The activation of satellite cells in these mice was much higher than in normal mice lacking this boost of ADAMTS1 production. And four months after birth, the increased activation led to larger muscles in the transgenic mice. In terms of muscle regeneration, one-month old transgenic mice recovered from muscle injury faster than normal mice. Stanford professor Brian Feldman, MD, PhD, the senior author of the study, described his team’s initial reaction to their findings in an interview with Scope, Stanford Medicine’s blog:

“While, in retrospect, it might make intuitive sense that the same cells that are sent into a site of injury to clean up the mess also carry the tools and signals needed to rebuild what was destroyed, it was not at all obvious how, or if, these two processes were biologically coupled. Our data show a direct link in which the clean-up crew releases a signal to launch the rebuild. This was a surprise.”

Further experiments showed that ADAMTS1 works by chopping up a protein called NOTCH that lies on the surface of satellite cells. NOTCH provides signals to the satellite cell to stay in a dormant state. So, when ADAMTS1 degrades NOTCH, the dormancy state of the satellite cells is lifted and they begin to divide and transform into muscle cells.

A pathway to novel muscle disorder therapies?
One gotcha with the ADAMTS1 injury signal is that too much activation can lead to a depletion of satellite cells. In fact, after 8 months, muscle regeneration actually weakened in the transgenic mice that were designed to persistently produce the protein. Still, this novel role of macrophages in stimulating muscle regeneration via the secreted ADAMTS1 protein opens a door for the Stanford team to explore new therapeutic approaches to treating muscle disorders:

“We are excited to learn that a single purified protein, that functions outside the cell, is sufficient to signal to muscle stem cells and stimulate them to differentiate into muscle,” says Dr. Feldman. “The simplicity of that type of signal in general and the extracellular nature of the mechanism in particular, make the pathway highly tractable to manipulation to support efforts to develop therapies that improve health.”

Confusing cancer to kill it

Kipps

Thomas Kipps, MD, PhD: Photo courtesy UC San Diego

Confusion is not a state of mind that we usually seek out. Being bewildered is bad enough when it happens naturally, so why would anyone actively pursue it? But now some researchers are doing just that, using confusion to not just block a deadly blood cancer, but to kill it.

Today the CIRM Board approved an investment of $18.29 million to Dr. Thomas Kipps and his team at UC San Diego to use a one-two combination approach that we hope will kill Chronic Lymphocytic Leukemia (CLL).

This approach combines two therapies, cirmtuzumab (a monoclonal antibody developed with CIRM funding, hence the name) and Ibrutinib, a drug that has already been approved by the US Food and Drug Administration (FDA) for patients with CLL.

As Dr. Maria Millan, our interim President and CEO, said in a news release, the need for a new treatment is great.

“Every year around 20,000 Americans are diagnosed with CLL. For those who have run out of treatment options, the only alternative is a bone marrow transplant. Since CLL afflicts individuals in their 70’s who often have additional medical problems, bone marrow transplantation carries a higher risk of life threatening complications. The combination approach of  cirmtuzumab and Ibrutinib seeks to offer a less invasive and more effective alternative for these patients.”

Ibrutinib blocks signaling pathways that leukemia cells need to survive. Disrupting these pathways confuses the leukemia cell, leading to its death. But even with this approach there are cancer stem cells that are able to evade Ibrutinib. These lie dormant during the therapy but come to life later, creating more leukemia cells and causing the cancer to spread and the patient to relapse. That’s where cirmtuzumab comes in. It works by blocking a protein on the surface of the cancer stem cells that the cancer needs to spread.

It’s hoped this one-two punch combination will kill all the cancer cells, increasing the number of patients who go into complete remission and improve their long-term cancer control.

In an interview with OncLive, a website focused on cancer professionals, Tom Kipps said Ibrutinib has another advantage for patients:

“The patients are responding well to treatment. It doesn’t seem like you have to worry about stopping therapy, because you’re not accumulating a lot of toxicity as you would with chemotherapy. If you administered chemotherapy on and on for months and months and years and years, chances are the patient wouldn’t tolerate that very well.”

The CIRM Board also approved $5 million for Angiocrine Bioscience Inc. to carry out a Phase 1 clinical trial testing a new way of using cord blood to help people battling deadly blood disorders.

The standard approach for this kind of problem is a bone marrow transplant from a matched donor, usually a family member. But many patients don’t have a potential donor and so they often have to rely on a cord blood transplant as an alternative, to help rebuild and repair their blood and immune systems. However, too often a single cord blood donation does not have enough cells to treat an adult patient.

Angiocrine has developed a product that could help get around that problem. AB-110 is made up of cord blood-derived hematopoietic stem cells (these give rise to all the other types of blood cell) and genetically engineered endothelial cells – the kind of cell that lines the insides of blood vessels.

This combination enables the researchers to take cord blood cells and greatly expand them in number. Expanding the number of cells could also expand the number of patients who could get these potentially life-saving cord blood transplants.

These two new projects now bring the number of clinical trials funded by CIRM to 35. You can read about the other 33 here.

 

 

 

Reprogramming cells with a nanochip, electricity and DNA to help the body to heal itself

The axolotl, a member of the salamander family, has amazing regenerative abilities. You can cut off its limbs or crush its spinal cord and it will repair itself with no scarring. A human’s healing powers, of course, are much more limited.

To get around this unfortunate fact, the field of regenerative medicine aims to develop stem cell-based therapies that provide the body with that extra oomph of regenerative ability to rid itself of disease or injury. But most of the current approaches in development rely on complex and expensive manufacturing processes in clinical labs before the cells can be safely transplanted in a patient’s body. Wouldn’t it be nice if we could just give the cells already in our bodies some sort of spark to allow them to repair other diseased or damaged cells?

A research team at Ohio State University have taken a fascinating step toward that seemingly science fiction scenario. Reporting this week in Nature Nanotechnology, the scientists describe a technique that – with some DNA, a nanochip and an electric current placed on the skin – can help mice regrow blood vessels to restore dying tissue.

Researchers demonstrate a process known as tissue nanotransfection (TNT). In laboratory tests, this process was able to heal the badly injured legs of mice in just three weeks with a single touch of this chip. The technology works by converting normal skin cells into vascular cells, which helped heal the wounds. Photo: Wexner Medical Center/The Ohio State University

The foundation of this technique is cellular reprogramming. Induced pluripotent stem cells are the most well-known example of reprogramming in which adult cells, like skin or blood, are converted, in a lab dish, to an embryonic stem cell-like state by introducing a set of reprogramming genes into the cells. From there, the stem cells can be specialized into any cell type.

Now, you wouldn’t want to convert skin or blood cells inside the body into quasi embryonic stem cells because they could generate tumors due to their limitless ability to multiply. In this study, the researchers rely on a related method, direct reprogramming, that skips the stem cell step and uses a different set of genes to directly convert one cell type into another. They focused on the direct reprogramming of skin cells to endothelial cells, a key component of blood vessels, in mice that were given symptoms mimicking those seen in human injury-induced limb ischemia. This condition leads to a risk of gangrene and amputation when severely injured limbs deteriorate due to blocked blood vessels.

It’s one thing to introduce, or transfect, reprogramming genes into cells that are grown in the very controlled environment of a petri dish. But how the heck does one get DNA into skin cells on the leg of a mouse? That’s where the team’s tissue nano-transfection (TNT) approach comes into the picture. After rubbing off a small section of dead skin on the leg, the TNT device, composed of an nanochip electrode and tiny channels of liquid containing reprogramming DNA, is placed on the skin. A short pulse of electricity is applied which opens miniscule holes in the membranes of skin cells that are in contact with the electrode which allows the DNA to enter the cells. Here’s a short video describing the process:

Three weeks after the procedure, blood vessels had formed, blood flow was restored and the legs of the mice were saved. Team leader, Dr. Chandan Sen, described the results in an interview with National Public Radio:

“Not only did we make new cells, but those cells reorganized to make functional blood vessels that plumb with the existing vasculature and carry blood.”

It’s surprising that TNT reprogramming affects more than just the skin cells that were in contact with the device. But it appears the reprogramming instructions from the introduced DNA was somehow spread to other cells through tiny vesicles called exosomes. When Sen’s team extracted those exosomes and introduced them to skin cells in a petri dish, those cells specialized into blood vessel cells.

This result did attract some skepticism from the field. In the NPR story, stem cell expert Dr. Sean Morrison had this to say:

“There are all manners of claims of these vesicles. It’s not clear what these things are, and if it’s a real biological process or if it’s debris.”

Clearly, more work is needed before TNT is ready for clinical trials in humans. But if it holds up, the technique could bring us closer to the incredible self-healing powers of the axolotl.

One man’s journey with leukemia has turned into a quest to make bone marrow stem cell transplants safer

Dr. Lukas Wartman in his lab in March 2011 (left), before he developed chronic graft-versus-host disease, and last month at a physical therapy session (right). (Photo by Whitney Curtis for Science Magazine)

I read a story yesterday in Science Magazine that really stuck with me. It’s about a man who was diagnosed with leukemia and received a life-saving stem cell transplant that is now threatening his health.

The man is name Lukas Wartman and is a doctor at Washington University School of Medicine in St. Louis. He was first diagnosed with a type of blood cancer called acute lymphoblastic leukemia (ALL) in 2003. Since then he has taken over 70 drugs and undergone two rounds of bone marrow stem cell transplants to fight off his cancer.

The first stem cell transplant was from his brother, which replaced Wartman’s diseased bone marrow, containing blood forming stem cells and immune cells, with healthy cells. In combination with immunosuppressive drugs, the transplant worked without any complications. Unfortunately, a few years later the cancer returned. This time, Wartman opted for a second transplant from an unrelated donor.

While the second transplant and cancer-fighting drugs have succeeded in keeping his cancer at bay, Wartman is now suffering from something equally life threatening – a condition called graft vs host disease (GVHD). In a nut shell, the stem cell transplant that cured him of cancer and saved his life is now attacking his body.

GVHD, a common side effect of bone marrow transplants

GVHD is a disease where donor transplanted immune cells, called T cells, expand and attack the cells and tissues in your body because they see them as foreign invaders. GVHD occurs in approximately 50% of patients who receive bone marrow, peripheral blood or cord blood stem cell transplants, and typically affects the skin, eyes, mouth, liver and intestines.

The main reason why GVHD is common following blood stem cell transplants is because many patients receive transplants from unrelated donors or family members who aren’t close genetic matches. Half of patients who receive these types of transplants develop an acute form of GVHD within 100 days of treatment. These patients are put on immunosuppressive steroid drugs with the hope that the patient’s body will eventually kill off the aggressive donor T cells.

This was the case for Wartman after the first transplant from his brother, but the second transplant from an unrelated donor eventually caused him to develop the chronic form of GVHD. Wartman is now suffering from weakened muscles, dry eyes, mouth sores and skin issues as the transplanted immune cells slowly attack his body from within. Thankfully, his major organs are still untouched by GVHD, but Wartman knows it could be only a matter of time before his condition worsens.

Dr. Lukas Wartman has to use eye drops every 20 minutes to deal with dry eyes caused by GVHD. (Photo by Whitney Curtis for Science Magazine)

Hope for GVHD sufferers

Wartman along with other GVHD patients are basically guinea pigs in a field where effective drugs are still being developed and tested. Many of these patients, including Wartman, have tried many unproven treatments or drugs for other disease conditions in desperate hope that something will work. It’s a situation that is heartbreaking not only for the patient but also for their families and doctors.

There is hope for GVHD patients however. Science Magazine mentioned two promising drugs for GVHD, ibrutinib and ruxolitinib. Both received breakthrough therapy designation from the US Food and Drug Administration and could be the first approved treatments for GVHD.

Another promising therapy is called Prochymal. It’s a stem cell therapy developed by former CIRM President and CEO, Dr. Randy Mills, at Osiris Therapeutics. Prochymal is already approved to treat the acute form of GVHD in Canada, and is currently being tested in phase 3 trials in the US in young children and adults.

While CIRM isn’t currently funding clinical trials for GVHD, we are funding a trial out of Stanford University led by Dr. Judy Shizuru that aims to improve the outcome of bone marrow stem cell transplants in patients. Shizuru says that these transplants are “the most powerful form of cell therapy out there, for cancers or deficiencies in blood formation” but they come with their own set of potentially deadly side effects such as GVHD.

Shizuru is testing an antibody drug that blocks a signaling protein called CD117, which sits on the surface of blood stem cells and acts as an elimination signal. By turning off this protein, her team improved the engraftment of bone marrow stem cells in mice that had leukemia and removed their need for chemotherapy treatment. The therapy is in a Phase 1 trial for patients with an immune disease called severe combined immunodeficiency (SCID) who receive bone marrow transplants, but Shizuru said that her hope is the drug could also treat patients with certain cancers or blood diseases.

Advocating for better GVHD treatments

The reason the article in Science Magazine spoke to me is because of the power of Wartman’s story. Wartman’s battle with ALL and now GVHD has transformed him into one of the strongest patient voices advocating for the development of new GVHD treatments. Jon Cohen, the author of the Science Magazine article, explained:

“The urgency of his case has turned Wartman into one of the world’s few patients who advocate for GVHD research, prevention, and treatment. ‘Most people it affects suffer quietly,” says Wartman. ‘They’re grateful they’re alive, and they’re beaten down. It’s the paradox of being cured and dying of the cure. Even if you can get past that, you don’t have the energy to advocate, and that’s really tragic.’”

Patients like Wartman are an inspiration not only to other people with GVHD, but also to funding agencies and scientists working to advance GVHD research towards a cure. We don’t want these patients to suffer quietly. Wartman’s story is an important reminder that there’s a lot more work to do to make bone marrow transplants safer – so that they save lives without later putting those lives at risk.

One day, scientists could grow the human cardiovascular system from stem cells

The human cardiovascular system is an intricate, complex network of blood vessels that include arteries, capillaries and veins. These structures distribute blood from the heart to all parts of the body, from our head to our toes, and back again.

This week, two groups of scientists published studies showing that they can create key components of the human cardiovascular system from human pluripotent stem cells. These technologies will not only be valuable for modeling the cardiovascular system, but also for developing transplantable tissues to treat patients with cardiovascular or vascular diseases.

Growing capillaries using 3D printers

Scientists from Rice University and the Baylor College of Medicine are using 3D printers to make functioning capillaries. These are tiny, thin vessels that transport blood from the arteries to the veins and facilitate the exchange of oxygen, nutrients and waste products between the blood and tissues. Capillaries are made of a single layer of endothelial cells stitched together by cell structures called tight junctions, which create an impenetrable barrier between the blood and the body.

In work published in the journal Biomaterials Science, the scientists discovered two materials that coax human stem cell-derived endothelial cells to develop into capillary-like structures. They found that adding mesenchymal stem cells to the process, improved the ability of the endothelial cells to form into the tube-like structures resembling capillaries. Lead author on the study, Gisele Calderon, explained their initial findings in an interview with Phys.org,

“We’ve confirmed that these cells have the capacity to form capillary-like structures, both in a natural material called fibrin and in a semisynthetic material called gelatin methacrylate, or GelMA. The GelMA finding is particularly interesting because it is something we can readily 3-D print for future tissue-engineering applications.”

Scientists grow capillaries from stem cells using 3D gels. (Image Credit: Jeff Fitlow/Rice University)

The team will use their 3D printing technology to develop more accurate models of human tissues and their vast network of capillaries. Their hope is that these 3D printed tissues could be used for more accurate drug testing and eventually as implantable tissues in the clinic. Co-senior author on the study, Jordan Miller, summarized potential future applications nicely.

“Ultimately, we’d like to 3D print with living cells … to create fully vascularized tissues for therapeutic applications. You could foresee using these 3D printed tissues to provide a more accurate representation of how our bodies will respond to a drug. The potential to build tissue constructs made from a particular patient represents the ultimate test bed for personalized medicine. We could screen dozens of potential drug cocktails on this type of generated tissue sample to identify candidates that will work best for that patient.”

Growing functioning arteries

In a separate study published in the journal PNAS, scientists from the University of Wisconsin-Madison and the Morgridge Institute reported that they can generate functional arterial endothelial cells, which are cells that line the insides of human arteries.

The team used a lab technique called single-cell RNA sequencing to identify important signaling factors that coax human pluripotent stem cells to develop into arterial endothelial cells. The scientists then used the CRISPR/Cas9 gene editing technology to develop arterial “reporter cell lines”, which light up like Christmas trees when candidate factors are successful at coaxing stem cells to develop into arterial endothelial cells.

Arterial endothelial cells derived from human pluripotent stem cells. (The Morgridge Institute for Research)

Using this two-pronged strategy, they generated cells that displayed many of the characteristic functions of arterial endothelial cells found in the body. Furthermore, when they transplanted these cells into mice that suffered a heart attack, the cells helped form new arteries and improved the survival rate of these mice significantly. Mice who received the transplanted cells had an 83% survival rate compared to untreated mice who only had a 33% survival rate.

In an interview with Genetic Engineering & Biotechnology News, senior author on the study James Thomson, explained the significance of their findings,

“Our ultimate goal is to apply this improved cell derivation process to the formation of functional arteries that can be used in cardiovascular surgery. This work provides valuable proof that we can eventually get a reliable source for functional arterial endothelial cells and make arteries that perform and behave like the real thing.”

In the future, the scientists have set their sights on developing a universal donor cell line that can treat large populations of patients without fear of immune rejection. With cardiovascular disease being the leading cause of death around the world, the demand for such a stem cell-based therapy is urgent.

Stories that caught our eye: smelling weight gain, colon cancer & diet and diabetes & broken bones

How smelling your food could cause weight gain (Karen Ring).
Here’s the headline that caught my eye this week: “Smelling your food first can make you fat…”

It’s a bizarre statement, but the claim is backed by scientific research coming from a new study in Cell Metabolism by researchers at the University of California Berkeley. The team found that obese mice who smelled their food before eating it were more likely to gain weight compared to obese mice that couldn’t smell their food.

Their experiments revealed a connection between the olfactory system, which is responsible for our sense of smell, and how the mice metabolize food into energy. Obese mice that lost their ability to smell actually lost weight on a high-fat diet, burned more fat, and became more sensitive to the hormone insulin. Insulin regulates how much glucose, or sugar, is in the blood by facilitating the absorption of glucose by fat, liver and muscle cells. In obese individuals, insulin resistance can occur where their cells are no longer sensitive to the hormone and therefore can’t regulate how much glucose is in the blood.

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Both mice in this picture were fed the same high-fat diet. The only difference: the lower mouse’s sense of smell was temporarily blocked. Image: UC Berkeley

For obese mice that could smell their food, the same high fat diet given to the “no-smellers” resulted in massive weight gain in the “smellers” because their metabolism was impaired. Even more interesting is the fact that other types of smells unrelated to food, such as the scent of other mice, influenced weight gain in the “smellers”.

The authors concluded that the centers in our brain that are responsible for smell (the olfactory system) and metabolism (the hypothalamus) are connected and that manipulating smell could be a future strategy to influence how the brain controls the balance of energy during food consumption.

In an interview with Tech Times, senior author on the study, Dr. Andrew Dillin, explained how their research could potentially lead to a new strategy to promote weight loss,

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Andrew Dillin. Image: HHMI

“Sensory systems play a role in metabolism. Weight gain isn’t purely a measure of the calories taken in; it’s also related to how those calories are perceived. If we can validate this in humans, perhaps we can actually make a drug that doesn’t interfere with smell but still blocks that metabolic circuitry. That would be amazing.”

A link between colorectal cancer and a Western diet identified
Weight gain isn’t the only concern of a eating a high-fat diet. It’s thought that 80% of colorectal cases are associated with a high-fat, Western diet. The basis for this connection hasn’t been well understood. But this week, researchers at the Cleveland Clinic report in Stem Cell Reports that they’ve pinpointed a protein signaling network within cancer stem cells as a possible source of the link.

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Cancer stem cells have properties that resemble embryonic stem cells and are thought to be the source of a cancer’s unlimited growth and spread. A cancer stem cell maintains its properties by exploiting various cell signaling processes that when functioning abnormally can lead to inappropriate cell division and tumor growth. In this study, the team focused on one cell signaling process carried out by a protein called STAT3, known to promote tumor growth in a mouse model of colon cancer. When the team blocked STAT3 activity, high fat diet-induced cancer stem cell growth subsided.

In a press release, Dr. Matthew Kalady, a colorectal surgeon at the Cleveland Clinic and an author on this study, explained how this new insight can open new therapeutic avenues:

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Matthew Kalady. Image: Cleveland Clinic

“We have known the influence of diet on colorectal cancer. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk.”

 

 

Scientists connect dots between diabetes and broken bones.
Type 2 diabetes carries a whole host of long-term complications including heart disease, nerve damage, kidney dysfunction and even an increased risk for bone fractures. The connection between diabetes and fragile bones has not been well understood. But this week, researchers at New York University of Dentistry, Stanford University and China’s Dalian Medical University published a report, funded in part by CIRM, in this week’s Nature Communications showing a biochemical basis for this connection. The new insight may lead to treatment options to prevent fractures.

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Chemical structure of succinate.
Image: Wikimedia Commons.

Fundamentally, diabetes is a disease that causes hyperglycemia, or abnormally high levels of blood sugar. The team ran a systematic analysis of hyperglycemia’s effects on bone metabolism using bone marrow samples from diabetic and healthy mice. They found that the levels of succinate, a key molecule involved in energy production, are over 20 times higher in the diabetic mice. In turns out that succinate also acts as a stimulator of bone breakdown. Now, bone is continually in a process of turnover and, in a healthy state, the breakdown of old bone is balanced with the formation of new bone. So, it appears that the huge increase of succinate is tipping the balance of bone turnover. In fact, the team found that the porous, yet strong inner region of bone, called trabecular bone, was significantly reduced in the diabetic mice, making them more susceptible to fractures.

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The density of spongy bone, or trabecular bone, is reduced in type 2 diabetes.
Image: Wikimedia commons

Dr. Xin Li, the study’s lead scientist, explained the importance of these new insights for people living with type 2 diabetes in a press release:

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Xin Li.
Image: NYU Dentistry

“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed. In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], which outpaced the formation of new bone. This has implications for bone protection, as well as for the treatment of diabetes-associated collateral bone damage.”

 

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.”