UCLA scientists begin a journey to restore the sense of touch in paralyzed patients

Yesterday, CIRM-funded scientists at UCLA published an interesting study that sheds light on the development of sensory neurons, a type of nerve cell that is damaged in patients with spinal cord injury. Their early-stage findings could potentially, down the road, lead to the development of stem cell-based treatments that rebuild the sensory nervous system in paralyzed people that have lost their sense of touch.

Dr. Samantha Butler, a CIRM grantee and professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, led the study, which was published in the journal eLife.

Restoring sensation

Butler and her team were interested in understanding the basic development of sensory interneurons in the spinal cord. These are nerve cells in the spinal cord that receive sensory signals from the environment outside the body (like heat, pain and touch) and relay these signals to the brain where the senses are then perceived.

Developing spinal cord injury treatments often focus on the loss of movement caused by damage to the motor neurons in the spine that control our muscles. However, the damage caused to sensory neurons in the spine can be just as debilitating to people with paralysis. Without being able to feel whether a surface is hot or cold, paralyzed patients can sustain serious burn injuries.

Butler commented in a UCLA news release that attempting to restoring sensation in paralyzed patients is just as important as restoring movement:

Samantha Butler

“The understanding of sensory interneuron development has lagged far behind that of another class of neurons—called motor neurons—which control the body’s ability to move. This lack in understanding belies the importance of sensation: it is at the core of human experience. Some patients faced with the reality of paralysis place the recovery of the sense of touch above movement.”

BMPs are important for sensory neuron development

To restore sensation in paralyzed patients, scientists need to replace the sensory neurons that are damaged in the spine. To create these neurons, Butler looked to proteins involved in the early development of the spinal cord called bone morphogenetic proteins or BMPs.

BMPs are an important family of signaling proteins that influence development of the embryo. Their signaling can determine the fate or identity of cells including cells that make up the developing spinal cord.

It was previously thought that the concentration of BMPs determined what type of sensory neuron a stem cell would develop into, but Butler’s team found the opposite in their research. By studying developing chick embryos, they discovered that the type, not the concentration, of BMP matters when determining what subtype of sensory neuron is produced. Increasing the amount of a particular BMP in the chick spinal cord only produced more of the same type of sensory interneuron rather than creating a different type.

Increasing the concentration of a certain type of BMP increases the production of the same categories of sensory interneurons (red and green). (Image credit: UCLA)

The scientists confirmed these findings using mouse embryonic stem cells grown in the lab. Interestingly a different set of BMPs were responsible for deciding sensory neuron fate in the mouse stem cell model compared to the chick embryo. But the finding that different BMPs determine sensory neuron identity was consistent.

So what and what’s next?

While this research is still in its early stages, the findings are important because they offer a better understanding of sensory neuron development in the spinal cord. This research also hints at the potential for stem cell-based therapies that replace or restore the function of sensory neurons in paralyzed patients.

Madeline Andrews, the first author of the study, concluded:

“Central nervous system injuries and diseases are particularly devastating because the brain and spinal cord are unable to regenerate. Replacing damaged tissue with sensory interneurons derived from stem cells is a promising therapeutic strategy. Our research, which provides key insights into how sensory interneurons naturally develop, gets us one step closer to that goal.”

The next stop on the team’s research journey is to understand how BMPs influence sensory neuron development in a human stem cell model. The UCLA news release gave a sneak preview of their plans in the coming years.

“Butler’s team now plans to apply their findings to human stem cells as well as drug testing platforms that target diseased sensory interneurons. They also hope to investigate the feasibility of using sensory interneurons in cellular replacement therapies that may one day restore sensation to paralyzed patients.”

Advertisements

Stem Cell Stories That Caught our Eye: Insights into a healthy brain, targeting mutant cancers and commercializing cell therapies

Here’s your weekly roundup of interesting stem cell stories!

Partnership for a healthy brain. To differentiate or not to differentiate. That is the question the stem cells in our tissues and organs face.

In the case of the brain, neural precursor cells can either remain in a stem cell state or they can differentiate into mature brain cells called neurons and astrocytes. Scientists are interested in understanding how the brain maintains the balance between these different cell states in order to understand how disruption to this balance are associated with psychiatric and neurodegenerative diseases.

Scientists from the Salk Institute, led by Genetics Professor Rusty Gage, published a study this week in Cell Stem Cell that sheds light on how this imbalance can cause brain disease. They found that a partnership between two proteins determines whether a neural precursor develops into a neuron or an astrocyte.

One of these proteins is called Nup153. It’s a protein that’s part of the nuclear pore complex, which sits on the surface of the nuclear membrane and controls the entry and exit of various proteins and molecules. In collaboration with another Salk team under the leadership of Martin Hetzer, Gage discovered that Nup153 was expressed at different levels depending on the cell type. Neural precursors had high levels of Nup153 protein, immature neurons had what they defined as an intermediate level while astrocytes had the lowest level.

When they blocked the function of Nup153, neural precursors differentiated, which led them to conclude that the levels of Nup153 can influence the fate of neural precursor cells. The teams also discovered that Nup153 interacts with the transcription factor Sox2 and that the levels of Sox2 in the different cell types was similar to the levels of Nup153.

A fluorescent microscopy image shows Nup153 (red) in pore complexes encircling and associating with Sox2 (green) in a precursor cell nucleus. Credit: Salk Institute/Waitt Center

In a Salk News release, first author on the study, Tomohisa Toda, explained how their findings shed light on basic cellular processes:

“The fact that we were able to connect transcription factors, which are mobile switches, to the pore complex, which is a very stable structure, offers a clue as to how cells maintain their identity through regulated gene expression.”

Gage’s team will next study how this partnership between the nuclear pore complex and transcription factors can influence the function of neurons in hopes of gaining more understanding of how an imbalance in these interactions can lead to neurological diseases.

“Increasingly, we are learning that diseases like schizophrenia, depression and Alzheimer’s all have a cellular basis. So we are eager to understand how specific brain cells develop, what keeps them healthy and why advancing age or other factors can lead to disease.”

Tomohisa Toda and Rusty Gage. Credit: Salk Institute

Targeting KRAS Mutant Cancer.

CIRM-funded scientists at UC San Diego School of Medicine have developed a new strategy to target cancers that are caused by a mutation in the KRAS gene. Their findings were published in the journal Cancer Discovery.

The KRAS protein is essential for normal signaling processes in tissues, but mutant versions of this protein can cause cancer. According to a UC San Diego Health news release about the study, “there are currently no effective treatments for the 95 percent of pancreatic cancers and up to 30 percent of non-small cell lung cancers with KRAS mutations.”

To address this need, the team identified a biomarker called αvb3 that is associated with cancers dependent on the KRAS mutation. They observed that a protein called Galectin-3 binds to αvb3, which is an integrin receptor on the surface of cancer cells, to promote mutant KRAS’s cancer-causing ability.

This realization offered the team a path towards potential treatments. By inhibiting Galectin-3 with a drug called GCS-100, the scientists would make KRAS-addicted cancers go cold turkey. Senior author on the study, David Cheresh, explained,

“This may be among the first approaches to successfully target KRAS mutant cancers. Previously, we didn’t understand why only certain KRAS-initiated cancers would remain addicted to the mutation. Now we understand that expression of integrin αvb3 creates the addiction to KRAS. And it’s those addicted cancers that we feel will be most susceptible to targeting this pathway using Galectin-3 inhibitors.”

Cheresh concluded that this novel approach could pave the way for a personalized medicine approach for KRAS-addicted cancers.

“KRAS mutations impact a large number of patients with cancer. If a patient has a KRAS mutant cancer, and the cancer is also positive for αvb3, then the patient could be a candidate for a therapeutic that targets this pathway. Our work suggests a personalized medicine approach to identify and exploit KRAS addicted tumors, providing a new opportunity to halt the progression of tumors that currently have no viable targeted therapeutic options.”

Commercializing cell therapy.

Our friends at RegMedNet made an infographic that illustrates how cell therapies have developed over time and how these therapies are advancing towards commercialization.

The infographic states, “The cell therapy industry is rapidly evolving, with new techniques, technology and applications being developed all the time. After some high-profile failures, all eyes are on regulating existing therapies to ensure patient safety is paramount. Legislators, regulators and other stakeholders around the world are navigating a difficult line between hope, hype and the scientific evidence.”

Check out their timeline below and visit the RegMedNet website for more news and information about the regenerative medicine field.

CIRM-funded scientists discover a new way to make stem cells using antibodies

Just as learning a new skill takes time to hone, scientific discoveries take time to perfect. Such is the case with induced pluripotent stem cells (iPSCs), the Nobel Prize winning technology that reprograms mature adult cells back into a pluripotent stem cell state. iPSCs are a powerful tool because they can develop into any cell found in the body. Scientists use iPSCs to model diseases in a dish, screen for new drugs, and to develop stem cell-based therapies for patients.

iPSCs grown in a cell culture dish.

The original iPSC technology, discovered by Dr. Shinya Yamanaka in 2006, requires viral delivery of four transcription factor genes, Oct4, Sox2, Klf4, and c-Myc, into the nucleus of an adult cell. These genes are inserted into the genome where they are activated to churn out their respective proteins. The combined expression of these four factors (OSKM) turns off the genetic programming of an adult cell and turns on the programming for a pluripotent stem cell.

The technology is pretty neat and allows scientists to make iPSCs from patients using a variety of different tissue sources including skin, blood, and even urine. However, there is a catch. Inserting reprogramming genes into a cell’s genome can be disruptive if the reprogramming genes fail to switch off or can cause cancer if nefarious oncogenes are turned on.

In response to this concern, scientists are developing alternative methods for making iPSCs using non-invasive methods. A CIRM-funded team from The Scripps Research Institute (TSRI) published such a study yesterday in the journal Nature Biotechnology.

Led by senior author and CIRM grantee Dr. Kristin Baldwin, the TSRI team screened a large library of antibodies – proteins that recognize and bind to specific molecules – to identify ones that could substitute for the OSKM reprogramming factors. The hope was that some of these antibodies would bind to proteins on the surface of cells and turn on a molecular signaling cascade from the outside that would turn on the appropriate reprogramming genes from the inside of the cell.

The scientists screened over 100 million antibodies and found ones that could replace three of the four reprogramming factors (Oct4, Sox2, and c-Myc) when reprogramming mouse skin cells into iPSCs. They were unable to find an antibody to replace Klf4 in the current study but have it on their to-do list for future studies.

Dr. Baldwin explained how her team’s findings improve upon previous reprogramming methods in a TSRI news release,

Kristen Baldwin

“This result suggests that ultimately we might be able to make IPSCs without putting anything in the cell nucleus, which potentially means that these stem cells will have fewer mutations and overall better properties.”

 

Other groups have published other non-invasive iPSC reprogramming methods using cocktails of chemicals, proteins or microRNAs in place of virally delivering genes to make iPSCs. However, Baldwin’s study is the first (to our knowledge) to use antibodies to achieve this feat.

An added benefit to antibody reprogramming is that the team was able to learn more about the signaling pathways that were naturally activated by the iPSC reprogramming antibodies.

“The scientists found that one of the Sox2-replacing antibodies binds to a protein on the cell membrane called Basp1. This binding event blocks Basp1’s normal activity and thus removes the restraints on WT1, a transcription factor protein that works in the cell nucleus. WT1, unleashed, then alters the activity of multiple genes, ultimately including Sox2’s, to promote the stem cell state using a different order of events than when using the original reprogramming factors.”

iPSCs made by antibody reprogramming could address some of the long-standing issues associated with more traditional reprogramming methods and could offer further insights into the complex signaling required to turn adult cells back into a pluripotent state. Baldwin and her team are now on the hunt for antibodies that will reprogram human (rather than mouse) cells into iPSCs. Stay tuned!

Stem Cell Stories That Caught our Eye: Duchenne muscular dystrophy and short telomeres, motor neurons from skin, and students today, stem cell scientists tomorrow

Short telomeres associated with Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is a severe muscle wasting disease that typically affects young men. There is no cure for DMD and the average life expectancy is 26. These are troubling facts that scientists at the University of Pennsylvania are hoping to change with their recent findings in Stem Cell Reports.

Muscle stem cells with telomeres shown in red. (Credit: Penn Medicine)

The team discovered that the muscle stem cells in DMD patients have shortened telomeres, which are the protective caps on the ends of chromosomes that prevent the loss of precious genetic information during cell division. Each time a cell divides, a small section of telomere is lost. This typically isn’t a problem because telomeres are long enough to protect cells through many divisions.

But it turns out this is not the case for the telomeres in the muscle stem cells of DMD patients. Because DMD patients have weak muscles, they experience constant muscle damage and their muscle stem cells have to divide more frequently (basically non-stop) to repair and replace muscle tissue. This is bad news for the telomeres in their muscle stem cells. Foteini Mourkioti, senior author on the study, explained in a news release,

“We found that in boys with DMD, the telomeres are so short that the muscle stem cells are probably exhausted. Due to the DMD, their muscle stem cells are constantly repairing themselves, which means the telomeres are getting shorter at an accelerated rate, much earlier in life. Future therapies that prevent telomere loss and keep muscle stem cells viable might be able to slow the progress of disease and boost muscle regeneration in the patients.”

With these new insights, Mourkioti and his team believe that targeting muscle stem cells before their telomeres become too short is a good path to pursue for developing new treatments for DMD.

“We are now looking for signaling pathways that affect telomere length in muscle stem cells, so that in principle we can develop drugs to block those pathways and maintain telomere length.”

Making Motor Neurons from Skin.

Skin cells and brain cells are like apples and oranges, they look completely different and have different functions. However, in the past decade, researchers have developed methods to transform skin cells into neurons to study neurodegenerative disorders and develop new strategies to treat brain diseases.

Scientists at Washington University School of Medicine in St. Louis published new findings on this topic yesterday in the journal Cell Stem Cell. In a nut shell, the team discovered that a specific combination of microRNAs (molecules involved in regulating what genes are turned on and off) and transcription factors (proteins that also regulate gene expression) can turn human skin cells into motor neurons, which are the brain cells that degenerate in neurodegenerative diseases like ALS, also known as Lou Gehrig’s disease.

Human motor neurons made from skin. (Credit: Daniel Abernathy)

This magical cocktail of factors told the skin cells to turn off genes that make them skin and turn on genes that transformed them into motor neurons. The scientists used skin cells from healthy individuals but will soon use their method to make motor neurons from patients with ALS and other motor neuron diseases. They are also interested in generating neurons from older patients who are more advanced in their disease. Andrew Yoo, senior author on the study, explained in a news release,

“In this study, we only used skin cells from healthy adults ranging in age from early 20s to late 60s. Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons. In the future, we would like to study skin cells from patients with disorders of motor neurons. Our conversion process should model late-onset aspects of the disease using neurons derived from patients with the condition.”

This research will make it easier for other scientists to grow human motor neurons in the lab to model brain diseases and potentially develop new treatments. However, this is still early stage research and more work should be done to determine whether these transformed motor neurons are the “real deal”. A similar conclusion was shared by Julia Evangelou Strait, the author of the Washington University School of Medicine news release,

“The converted motor neurons compared favorably to normal mouse motor neurons, in terms of the genes that are turned on and off and how they function. But the scientists can’t be certain these cells are perfect matches for native human motor neurons since it’s difficult to obtain samples of cultured motor neurons from adult individuals. Future work studying neuron samples donated from patients after death is required to determine how precisely these cells mimic native human motor neurons.”

Students Today, Scientists Tomorrow.

What did you want to be when you were growing up? For Benjamin Nittayo, a senior at Cal State University Los Angeles, it was being a scientist researching a cure for acute myeloid leukemia (AML), a form of blood cancer that took his father’s life. Nittayo is making his dream into a reality by participating in a summer research internship through the Eugene and Ruth Roberts Summer Student Academy at the City of Hope in Duarte California.

Nittayo has spent the past two summers doing cancer research with scientists at the Beckman Research Institute at City of Hope and hopes to get a PhD in immunology to pursue his dream of curing AML. He explained in a City of Hope news release,

“I want to carry his memory on through my work. Being in this summer student program helped me do that. It influenced the kind of research I want to get into as a scientist and it connected me to my dad. I want to continue the research I was able to start here so other people won’t have to go through what I went through. I don’t wish that on anybody.”

The Roberts Academy also hosts high school students who are interested in getting their first experience working in a lab. Some of these students are part of CIRM’s high school educational program Summer Program to Accelerate Regenerative Medicine Knowledge or SPARK. The goal of SPARK is to train the next generation of stem cell scientists in California by giving them hands-on training in stem cell research at leading institutes in the state.

This year, the City of Hope hosted the Annual SPARK meeting where students from the seven different SPARK programs presented their summer research and learned about advances in stem cell therapies from City of Hope scientists.

Ashley Anderson, a student at Mira Costa High School in Manhattan Beach, had the honor of giving the City of Hope SPARK student talk. She shared her work on Canavan’s disease, a progressive genetic disorder that damages the brain’s nerve cells during infancy and can cause problems with movement and muscle weakness.

Under the guidance of her mentor Yanhong Shi, Ph.D., who is a Professor of Developmental and Stem Cell Biology at City of Hope, Ashley used induced pluripotent stem cells (iPSCs) from patients with Canavan’s to generate different types of brain cells affected by the disease. Ashley helped develop a protocol to make large quantities of neural progenitor cells from these iPSCs which the lab hopes to eventually use in clinical trials to treat Canavan patients.

Ashley has always been intrigued by science, but thanks to SPARK and the Roberts Academy, she was finally able to gain actual experience doing science.

“I was looking for an internship in biosciences where I could apply my interest in science more hands-on. Science is more than reading a textbook, you need to practice it. That’s what SPARK has done for me. Being at City of Hope and being a part of SPARK was amazing. I learned so much from Dr. Shi. It’s great to physically be in a lab and make things happen.”

You can read more about Ashley’s research and those of other City of Hope SPARK students here. You can also find out more about the educational programs we fund on our website and on our blog (here and here).

Stem cell therapy for Parkinson’s disease shows promise in monkeys

Tremors, muscle stiffness, shuffling, slow movement, loss of balance. These are all symptoms of Parkinson’s disease (PD), a neurodegenerative disorder that progressively destroys the dopamine-producing neurons in the brain that control movement.

While there is no cure for Parkinson’s disease, there are drugs like Levodopa and procedures like deep brain stimulation that alleviate or improve some Parkinsonian symptoms. What they don’t do, however, is slow or reverse disease progression.

Scientists are still trying to figure out what causes Parkinson’s patients to lose dopaminergic neurons, and when they do, they hope to stop the disease in its early stages before it can cause the debilitating symptoms mentioned above. In the meantime, some researchers see hope for treating Parkinson’s in the form of stem cell therapies that can replace the brain cells that are damaged or lost due to the disease.

Dopaminergic neurons derived from induced pluripotent stem cells. (Xianmin Zeng, Buck Institute)

Promising results in monkeys

This week, a team of Japanese scientists reported in the journal Nature that they treated monkeys with Parkinson’s-like symptoms by transplanting dopaminergic neurons made from human stem cells into their brains. To prevent the monkeys from rejecting the human cells, they were treated with immunosuppressive drugs. These transplanted neurons survived for more than two years without causing negative side effects, like tumor growth, and also improved PD symptoms, making it easier for the monkeys to move around.

The neurons were made from induced pluripotent stem cells (iPSCs), which are stem cells that can become any cell type in the body and are made by transforming mature human cells, like skin, back to an embryonic-like state. The scientists transplanted neurons made from the iPSCs of healthy people and PD patients into the monkeys and saw that both types of neurons survived and functioned properly by producing dopamine in the monkey brains.

Experts in the field spoke to the importance of these findings in an interview with Nature News. Anders Bjorklund, a neuroscientist at Lund University in Sweden, said “it’s addressing a set of critical issues that need to be investigated before one can, with confidence, move to using the cells in humans,” while Lorenz Studer, a stem-cell scientist at the Memorial Sloan Kettering Cancer Center in New York City, said that “there are still issues to work out, such as the number of cells needed in each transplant procedure. But the latest study is ‘a sign that we are ready to move forward.’”

Next stop, human trials

Jun Takahashi

Looking ahead, Jun Takahashi, the senior author on the study, explained that his team hopes to launch a clinical trial testing this iPSC-based therapy by the end of 2018. Instead of developing personalized iPSC therapies for individual PD patients, which can be time consuming and costly, Takahashi plans to make special donor iPSC lines (called human leukocyte antigen or HLA-homozygous iPSCs) that are immunologically compatible with a larger population of patients.

In a separate study published at the same time in Nature Communications, Takahashi and colleagues showed that transplanting neurons derived from immune-matched monkey iPSCs improved their survival and dampened the immune response.

The Nature News article does a great job highlighting the findings and significance of both studies and also mentions other research projects using stem cells to treat PD in clinical trials.

“Earlier this year, Chinese researchers began a Parkinson’s trial that used a different approach: giving patients neural-precursor cells made from embryonic stem cells, which are intended to develop into mature dopamine-producing neurons. A year earlier, in a separate trial, patients in Australia received similar cells. But some researchers have expressed concerns that the immature transplanted cells could develop tumour-causing mutations.

Meanwhile, researchers who are part of a Parkinson’s stem-cell therapy consortium called GForce-PD, of which Takahashi’s team is a member, are set to bring still other approaches to the clinic. Teams in the United States, Sweden and the United Kingdom are all planning trials to transplant dopamine-producing neurons made from embryonic stem cells into humans. Previously established lines of embryonic stem cells have the benefit that they are well studied and can be grown in large quantities, and so all trial participants can receive a standardized treatment.”

You can read more coverage on these research studies in STATnews, The San Diego Union Tribune, and Scientific American.

For a list of projects CIRM is funding on Parkinson’s disease, visit our website.

Stem cell treatment helps puppies born with spina bifida walk again

Just when you thought puppies couldn’t get any cuter, this video appears in your twitter feed.

These adorable English bulldog puppies are named Darla and Spanky, and they were born with a birth defect called spina bifida where the bones and tissue surrounding the spinal cord fail to fuse completely. Spina bifida occurs in 1500-2000 children in the US each year and can cause serious problems such as paralysis and issues with walking, cognition, and bladder or bowel control. Dogs born with this condition usually cannot use their hind legs, and as a sad consequence, are typically put down at a young age.

Cutting edge research from UC Davis is now giving these unfortunate puppies hope. Diana Farmer, a fetal surgeon at UC Davis Health, and scientists from the university’s Veterinary Institute for Regenerative Cures have developed a combination surgery and stem cell transplant, using placenta-derived mesenchymal stromal cells (PMSCs), to treat puppies with spina bifida. Because prenatal screening for spina bifida is not done in dogs, Darla and Spanky received the treatment when they were ten weeks old.

With funding from a CIRM preclinical development award, Farmer has done similar surgeries in lambs that are still in the womb. A UC Davis news release provided historical background on Farmer’s work on spina bifida,

“Farmer pioneered the use of surgery prior to birth to improve brain development in children with spina bifida. She later showed that prenatal surgery combined with human placenta-derived mesenchymal stromal cells (PMSCs), held in place with a cellular scaffold, helped research lambs born with the disorder walk without noticeable disability.”

As you can see from the video, the surgeries were a success. Darla and Spanky are now able to live up to their full puppy potential and will live happily ever after with their adoptive family in New Mexico.

Looking forward, Farmer and her team would like to treat more dogs with spina bifida so they can improve another negative consequence of spina bifida called incontinence, or an uncontrollable bladder. The UC Davis release explained that, “while Darla and Spanky are very mobile and doing well on their feet, they still require diapers.” (Side note: this video proves that puppies can make anything look cute, even dirty diapers.)

Additionally, the team is hoping to receive regulatory approval from the US Food and Drug Administration to launch a clinical trial testing this therapy in humans. If this stem cell treatment proves to be both safe and effective in clinical trials, it could potentially prevent spina bifida from ever happening in animals and in humans.

English Bulldog undergoing spina bifida surgery at UC Davis Veterinary Medical Teaching Hospital. (Gregory Urquiaga/UC Davis)

New research suggests taking a daily dose of vitamin C could prevent leukemia

Did you take your vitamins today? It’s not always easy to remember with such busy lives, but after you read this blog, you’ll be sure to make vitamins part of your daily routine if you haven’t already!

Two recent studies, published in the journals Nature and Cell, reported that vitamin C has a direct impact on the function of blood forming, or hematopoietic stem cells, and can be used to protect mice from getting a blood cancer called leukemia.

Science reporter Bradley Fikes compared the findings of the two studies yesterday in the San Diego Union Tribune. According to Fikes, the Nature study, which was conducted by scientists at UT Southwestern, “found that human and mouse hematopoietic stem cells absorb unusually large amounts of vitamin C. When the cells were depleted of vitamin C, they were more likely to turn into leukemia cells.”

As for the Cell study, scientists from NYU Langone Health “found that high doses of vitamin C can cause leukemic cells to die, potentially making it a useful and safe chemotherapy agent.” For more details on this particular study, see our blog from last week and the video below.

Dr. Benjamin Neel, director of NYU Langone’s Perlmutter Cancer Center, discusses how vitamin C may “tell” faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers.

Vitamin C levels are crucial for preventing leukemia

The common factor between the two studies is a gene called Tet2, which is turned on in blood stem cells and protects them from over-proliferating and acquiring genetic mutations that transform them into leukemia cells. If one copy of the Tet2 gene is genetically mutated, treating blood stem cells with vitamin C can make up for this partial loss in Tet2 function. However, if both copies of Tet2 are mutated, its protective functions are completely lost and blood stem cells can turn cancerous.

Fikes reached out to Sean Morrison, senior author on the Nature study, for an explanation about the relationship between vitamin C and Tet2, and how it can be leveraged to prevent or treat leukemia:

Sean Morrison

“The Cell study showed that high doses of vitamin C can compensate for Tet2 mutations, restoring normal function, Morrison said. Usually, transformation of normal cells into leukemic cells is irreversible, but the study demonstrated that’s not true when the leukemia is driven by Tet2 mutations.”

“The Nature study demonstrated that vitamin C is a limiting factor in the proper function of Tet2, Morrison said. People have two copies of the gene, one from each parent. When one of the genes is disabled, it’s important to take the full recommended dose of vitamin C so the remaining gene can exert its full tumor-suppressing effect.”

Before you place your bulk order of vitamin C on amazon, you should be aware that Morrison and his colleagues found that giving mice super doses of the supplement failed to further reduce their risk of getting leukemia. Thus, it seems that having the right levels of vitamin C in blood stem cells and healthy copies of the Tet2 gene are vital for preventing leukemia.

Vitamin C, a panacea for cancer?

These two studies raise important questions. Do vitamin C levels play a role in the development of other cancer cells and could this supplement be used as a treatment for other types of cancers?

Since the 1970’s, scientists (including the famous American scientist Linus Pauling) and doctors have pursued vitamin C as a potential cancer treatment. Early stage research revealed that vitamin C plays a role in slowing the growth of various types of cancer cells including prostate, colon and brain cancer cells. More recently, some of this research has progressed to clinical trials that are testing high-doses of vitamin C either by itself or in combination with chemotherapy drugs in cancer patients. Some of these trials have reported an improved quality of life and increased average survival time in patients, but more research and trials are necessary to determine whether vitamin C is a truly effective anti-cancer therapy.

Now that Morrison and his team have a better understanding of how vitamin C levels affect cancer risk, they plan to address some of these outstanding questions in future studies.

“Our data also suggest that probably not all cancers are increased by vitamin C depletion. We particularly would predict that certain leukemias would be increased in the absence of vitamin C. We’re collaborating with the Centers for Disease Control right now to look more carefully at the epidemiological data that have been collected over decades, to understand more precisely which cancers are at increased risk in people that have lower levels of vitamin C.”

Targeting hair follicle stem cells could be the key to fighting hair loss

Chia Pets make growing hair look easy. You might not be familiar with these chia plant terracotta figurines if you were born after the 80s, but I remember watching commercials growing up and desperately wanting a “Chia Pet, the pottery that grows!”

My parents eventually caved and got me a Chia teddy bear, and I was immediately impressed by how easy it was for my bear to grow “hair”. All I needed to do was to sprinkle water over the chia seeds and spread them over my chia pet, and in three weeks, voila, I had a bear that had sprouted a lush, thick coat of chia leaves.

These days, you can order Chia celebrities and even Chia politicians. If only treating hair loss in humans was as easy as growing sprouts on the top of Chia Mr. T’s head…

Activating Hair Follicle Stem Cells, the secret to hair growth?

That day might come sooner than we think thanks to a CIRM-funded study by UCLA scientists.

Published today in Nature Cell Biology, the UCLA team reported a new way to boost hair growth that could eventually translate into new treatments for hair loss. The study was spearheaded by senior authors Heather Christofk and William Lowry, both professors at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Christofk and Lowry were interested in understanding the biology of hair follicle stem cells (HFSCs) and how their metabolism (the set of chemical changes required for a cell to sustain itself) plays a role in hair growth. HFSCs are adult stem cells that live in the hair follicles of our skin. They are typically inactive but can quickly “wake up” and actively divide when a new hair growth cycle is initiated. When HFSCs fail to activate, hair loss occurs.

A closer look at HFSCs in mice revealed that these stem cells are dependent on the products of the glycolytic pathway, a metabolic pathway that converts the nutrient glucose into a metabolite called pyruvate, to stimulate their activation. The HFSCs have a choice, they can either give the pyruvate to their mitochondria to produce more energy, or they can break down the pyruvate into another metabolite called lactate.

The scientists found that if they tipped the balance towards producing more lactate, the HFSCs activated and induced hair growth. On the other hand, if they blocked lactate production, HFSCs couldn’t activate and new hair growth was blocked.

In a UCLA news release, Lowry explained the novel findings of their study,

“Before this, no one knew that increasing or decreasing the lactate would have an effect on hair follicle stem cells. Once we saw how altering lactate production in the mice influenced hair growth, it led us to look for potential drugs that could be applied to the skin and have the same effect.”

New drugs for hair loss?

In the second half of the study, the UCLA team went on the hunt for drugs that promote lactate production in HFSCs in hopes of finding new treatment strategies to battle hair loss. They found two drugs that boosted lactate production when applied to the skin of mice. One was called RCGD423, which activates the JAK-Stat signaling pathway and stimulates lactate production. The other drug, UK5099, blocks the entry of pyruvate into the mitochondria, thereby forcing HFSCs to turn pyruvate into lactate resulting in hair growth. The use of both drugs for boosting hair growth are covered by provisional patent applications filed by the UCLA Technology Development Group.

Untreated mouse skin showing no hair growth (left) compared to mouse skin treated with the drug UK5099 (right) showing hair growth. Credit: UCLA Broad Stem Cell Center/Nature Cell Biology

Aimee Flores, the first author of the study, concluded by explaining why using drugs to target the HFSC metabolism is a promising approach for treating hair loss.

“Through this study, we gained a lot of interesting insight into new ways to activate stem cells. The idea of using drugs to stimulate hair growth through hair follicle stem cells is very promising given how many millions of people, both men and women, deal with hair loss. I think we’ve only just begun to understand the critical role metabolism plays in hair growth and stem cells in general; I’m looking forward to the potential application of these new findings for hair loss and beyond.”

If these hair growth drugs pan out, scientists might give Chia Pets a run for their money.

High school students SPARK an interest in stem cell research

SPARK students at the 2017 Annual Meeting at the City of Hope.

High school is a transformative time for any student. It marks the transition from childhood to adulthood and requires discipline, dedication and determination to excel and get into their desired college or university.

The barrier to entry for college now seems much higher than when I was eighteen, but I am not worried for the current generation of high school students. That’s because I’ve met some of the brightest young minds this past week at the 2017 CIRM SPARK meeting.

SPARK is CIRM’s high school education program, which gives underprivileged students in California the opportunity to train as stem cell scientists for the summer. Students participate in a summer research internship at one of seven programs at leading research institutes in the state. They attend scientific lectures, receive training in basic lab techniques, and do an eight-week stem cell research project under the guidance of a mentor.

At the end of the summer, SPARK students congregate at the annual SPARK poster meeting where they present the fruits of their labor. Meeting these students in person is my favorite time of the year. Their enthusiasm for science and stem cell research is contagious. And when you engage them or listen to them talk about their project, it’s hard to remember that they are still teenagers and not graduate level scientists.

What impresses me most about these students is their communication skills. Each summer, I challenge SPARK students to share their summer research experience through social media and blogging, and each time they go above and beyond with their efforts. Training these students as effective science communicators is important to me. They are the next generation of talented scientists who can help humanize research for the public. They have the power to change the perception of science as a field to be embraced and one that should receive proper funding.

It’s also inspiring to me that this young generation can effectively educate their friends, family and the public about the importance of stem cell research and how it will help save the lives of patients who currently don’t have effective treatments. If you haven’t already, I highly recommend checking out the #CIRMSPARKlab hashtag on Instagram to get a taste of what this year’s group of students accomplished during their internships.

Asking students, many of whom are learning to do research for the first time, to post on Instagram once a week and write a blog about their internship is a tall task. And I believe with any good challenge, there should be a reward. Therefore, at this year’s SPARK meeting held at the City of Hope in Duarte, California, I handed out prizes.

It was very difficult to pick winners for our presentation, social media and blogging awards because honestly, all our students were excellent this year. Even Kevin McCormack, Director of CIRM’s Communications, who helped me read the students’ blogs said,

“This was really tough. The standard of the blogs this year was higher than ever; and previous years had already set the bar really high. It was really difficult deciding which were really good and which were really, really good.”

Ok, enough with the hype, I know you want to read these award-winning blogs so I’ve shared them below. I hope that they inspire you as much as they have inspired me.


Amira Hirara

Amira Hirara (Children’s Hospital Oakland Research Institute)

It was a day like any other. I walked into the room, just two minutes past 10:30am, ready for another adventurous day in the lab. Just as I settle down, I am greeted by my mentor with the most terrifying task I have ever been asked to perform, “Will you passage the cells for me…alone?” Sweat begins to pour down my cemented face as I consider what is at stake.

The procedure was possibly thirty steps long and I have only executed it twice, with the supervision of my mentor of course. To be asked to do the task without the accompaniment of an experienced individual was unthought-of. I feel my breath begin to shorten as I mutter the word “Ok”. Yet it wasn’t just the procedure that left me shaking like a featherless bird, it was the location of my expedition as well. The dreaded tissue culture room. If even a speck of dirt enters the circulating air of the biosafety cabinet, your cells are at risk of death…death! I’ll be a cell murderer. “Alright”, she said, “I’ll just take a look at the cells then you’ll be on your way.” As we walk down the hallway, my eyes began to twitch as I try to recall the first steps of the procedure. I remember freezing our plates with Poly-ornithine and laminin, which essentially simulates the extracellular environment and allows adhesion between the cell and the plate itself. I must first add antibiotics to rid the frozen plate of potential bacteria. Then I should remove my cells from the incubator, and replace the old solution with accutase and new media, to nourish the cells, as well as unbind them from the plate before. Passaging is necessary when the cell density gets too high, as the cells must be relocated to a roomier environment to better promote survival. As we approach the tissue culture room, my jaw unclenches, as I realize the whirlwind of ideas meant I know more than I thought. My mentor retrieves our cells, views them under the microscope, and deems them ‘ready for passaging’.

“Good luck Amira” she says to me with a reassuring smile. I enter the room ready for battle. Placing first my gloves and coat, I then spray my hands and all things placed in the cabinet with 70% ethanol, to insure a sterile work environment. Back to the procedure, I’ll place the cellular solution of accutase and media into a covalent tube. After, I’ll centrifuge it for two minutes until a cellular pellet forms at the bottom, then dissolve the cells in fresh media, check its density using a cell counter, and calculate the volume of cellular solution needed to add to my once frozen plates. Wait, once I do that, I’ll be all done. I eagerly execute all the steps, ensuring both accuracy and sterility in my work. Pride swells within me as I pipette my last milliliter of solution into my plate. The next day, my mentor and I stop by to check on how our sensitive neural stem cells are doing. “Wow Amira, I am impressed, your cells seem very confluent in their new home, great job!” I smile slyly and begin to nod my head. I now walk these hallways, with a puffed chest, brightened smile, and eagerness to learn. My stem cells did not die, and having the amazing opportunity to master their treatment and procedures, is something I can never forget.

 

Gaby Escobar

Gaby Escobar (Stanford University)

Walking into the lab that would become my home for the next 8 weeks, my mind was an empty canvas.  Up to that point, my perception of the realm of scientific research was one-sided. Limited to the monotonous textbook descriptions of experiments that were commonplace in a laboratory, I wanted more. I wanted to experience the alluring call of curiosity. I wanted to experience the flash of discovery and the unnerving drive that fueled our pursuit of the unknown. I was an empty canvas looking for its first artistic stroke.

Being part of the CIRM Research program, I was lucky enough to have been granted such opportunity. Through the patient guidance of my mentor, I was immersed into the limitless world of stem cell biology. From disease modeling to 3D bioprinting, I was in awe of the capabilities of the minds around me. The energy, the atmosphere, the drive all buzzed with an inimitable quest for understanding. It was all I had imagined and so, so much more.

However, what many people don’t realize is research is an arduous, painstaking process. Sample after sample day after day, frustration and doubt loomed above our heads as we tried to piece together a seemingly pieceless puzzle.  Inevitably, I faced the truth that science is not the picture-perfect realm I had imagined it to be. Rather, it is tiring, it is relentless, and it is unforgiving. But at the same time, it is incomparably gratifying. You see, the innumerable samples, the countless gels and PCRS, all those futile attempts to fruitlessly make sense of the insensible, have meaning. As we traversed through the rollercoaster ride of our project, my mentor shared a personal outlook that struck very deeply with me: her motivation to work against obstacle after obstacle comes not from the recognition or prestige of discovering the next big cure but rather from the notion that one day, her perseverance may transform someone’s life for the good.  And in that, I see the beauty of research and science: the coming together of minds and ideas and bewildering intuitions all for the greater good.

As I look back, words cannot express the gratitude I feel for the lessons I have learned. Undoubtedly, I have made countless mistakes (please don’t ask how many gels I’ve contaminated or pipettes I have dropped) but I’ve also created the most unforgettable of memories. Memories that I know I will cherish for the journey ahead of me. Having experienced the atmosphere of a vibrant scientific community, I have found a second home, a place that I can explore and question and thrive. And although not every day will hold the cure to end all diseases or hand an answer on a silver platter, every day is another opportunity.  And with that, I walk away perhaps not with the masterpiece of art that I had envisioned in my mind but rather with a burning spark of passion, ready to ignite.

 

Anh Vo

Ahn Vo (UC Davis)

With college selectivity increasing and acceptance rates plummeting, the competitive nature within every student is pushed to the limit. In high school, students are expected to pad up their resumes and most importantly, choose an academic path sooner rather than later. However, at 15, I felt too young to experience true passion for a field. As I tried to envision myself in the future, I wondered, would I be someone with the adrenaline and spirit of someone who wants to change the world or one with hollow ambitions, merely clinging onto a paycheck with each day passing? At the very least, I knew that I didn’t want to be the latter.

The unrelenting anxiety induced by the uncertainty of my own ambitions was intoxicating. As my high school career reached its halfway mark, I felt the caving pressure of having to choose an academic path.

“What do you want to be?” was one of the first questions that my mentor, Whitney Cary, asked me. When I didn’t have an answer, she assured me that I needed to keep my doors open, and the SPARK program was the necessary first step that I needed to take to discovering my passion.

As I reflected on my experience, the SPARK program was undoubtedly the “first step”. It was the first step into a lab and above all, into a community of scientists, who share a passion for research and a vehement resolve to contribute to scientific merit. It was the integration into a cohort of other high school students, whose brilliance and kindness allowed us to forge deeper bonds with each other that we will hold onto, even as we part ways. It was the first nervous step into the bay where I met the Stem Cell Core, a team, whose warm laughter and vibrancy felt contagious. Finally, it was the first uncertain stumble into the tissue culture room, where I conceived a curiosity for cell culture that made me never stop asking, “Why?”

With boundless patience, my mentor and the Stem Cell Core strove to teach me techniques, such as immunocytochemistry and continually took the time out of their busy day to reiterate concepts. Despite my initial blunders in the hood, I found myself in a place without judgement, and even after discouraging incidents, I felt a sense of consolation in the witty and good-humored banter among the Stem Cell Core. At the end of every day, the unerring encouragement from my mentor strengthened my resolve to continue improving and incited an earnest excitement in me for the new day ahead. From trembling hands, nearly tipping over culture plates and slippery gloves, overdoused in ethanol, I eventually became acquainted with daily cell culture, and most importantly, I gained confidence and pride in my work.

I am grateful to CIRM for granting me this experience that has ultimately cultivated my enthusiasm for science and for the opportunity to work alongside remarkable people, who have given me new perspectives and insights. I am especially thankful to my mentor, whose stories of her career journey have inspired me to face the future with newfound optimism in spite of adversity.

As my internship comes to a close, I know that I have taken my “first step”, and with a revived mental acquisitiveness, I eagerly begin to take my second.

Other 2017 SPARK Awards

Student Speakers: Candler Cusato (Cedars-Sinai), Joshua Ren (Stanford)

Instagram/Social Media: Jazmin Aizpuru (UCSF), Emily Beckman (CHORI), Emma Friedenberg (Cedars-Sinai)

Poster Presentations: Alexander Escudero (Stanford), Jamie Kim (CalTech), Hector Medrano (CalTech), Zina Patel (City of Hope)


Related Links:

Stem cell stories that caught our eye: skin grafts fight diabetes, reprogramming the immune system, and Asterias expands spinal cord injury trial sites

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

Skin grafts fight diabetes and obesity.

An interesting new gene therapy strategy for fighting type 1 diabetes and obesity surfaced this week. Scientists from the University of Chicago made genetically engineered skin grafts that secrete a peptide hormone called glucagon-liked peptide-1 (GLP-1). This peptide is released by cells in the intestine and can lower blood sugar levels by stimulating pancreatic islet cells to secrete insulin (a hormone that promotes the absorption of glucose from the blood).

The study, which was published in the journal Cell Stem Cell, used CRISPR gene editing technology to introduce a mutation to the GLP-1 gene in mouse and human skin stem cells. This mutation stabilized the GLP-1 peptide, allowing it to hang around in the blood for longer. The team matured these stem cells into skin grafts that secreted the GLP-1 into the bloodstream of mice when treated with a drug called doxycycline.

When fed a high-fat diet, mice with a skin graft (left), genetically altered to secrete GLP-1 in response to the antibiotic doxycycline, gained less weight than normal mice (right). (Image source: Wu Laboratory, the University of Chicago)

On a normal diet, mice that received the skin graft saw a rise in their insulin levels and a decrease in their blood glucose levels, proving that the gene therapy was working. On a high fat diet, mice with the skin graft became obese, but when they were treated with doxycycline, GLP-1 secreted from their grafts reduced the amount of weight gain. So not only does their engineered skin graft technology look like a promising new strategy to treat type 1 diabetes patients, it also could be used to control obesity. The beauty of the technology is in its simplicity.

An article in Genetic Engineering and Biotechnology News that covered this research explained that Xiaoyang Wu, the senior author on the study, and his team “worked with skin because it is a large organ and easily accessible. The cells multiply quickly and are easily transplanted. And, transplanted cells can be removed, if needed. “Skin is such a beautiful system,” Wu says, noting that its features make it a perfect medium for testing gene therapies.”

Wu concluded that, “This kind of therapy could be potentially effective for many metabolic disorders.” According to GenBio, Wu’s team “is now testing the gene-therapy technique in combination with other medications.” They also hope that a similar strategy could be used to treat patients that can’t make certain proteins like in the blood clotting disorder hemophilia.

How to reprogram your immune system (Kevin McCormack)

When your immune system goes wrong it can cause all manner of problems, from type 1 diabetes to multiple sclerosis and cancer. That’s because an overactive immune system causes the body to attack its own tissues, while an underactive one leaves the body vulnerable to outside threats such as viruses. That’s why scientists have long sought ways to correct those immune dysfunctions.

Now researchers at the Gladstone Institutes in San Francisco think they have found a way to reprogram specific cells in the immune system and restore a sense of health and balance to the body. Their findings are published in the journal Nature.

The researchers identified a drug that targets effector T cells, which get our immune system to defend us against outside threats, and turns them into regulatory T cells, which control our immune system and stops it from attacking our own body.

Why would turning one kind of T cell into another be helpful? Well, in some autoimmune diseases, the effector T cells become overly active and attack healthy tissues and organs, damaging and even destroying them. By converting them to regulatory T cells you can prevent that happening.

In addition, some cancers can hijack regulatory T cells and suppress the immune system, allowing the disease to spread. By turning those cells into effector T cells, you can boost the immune system and give it the strength to fight back and, hopefully, kill the cancer.

In a news release, Gladstone Senior Investigator Sheng Ding, the lead scientists on the study, said their findings could have several applications:

“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies.” 

Gladstone scientists Sheng Ding (right) and Tao Xu (left) discovered how to reprogram cells in our immune system. (Gladstone Institutes)

CIRM-funded spinal cord injury trial expands clinical sites

We have another update from CIRM’s clinical trial front. Asterias Biotherapeutics, which is testing a stem cell treatment for complete cervical (neck) spinal cord injury, is expanding its clinical sites for its CIRM-funded SCiStar Phase 1/2a trial. The company is currently treating patients at six sites in the US, and will be expanding to include two additional sites at Thomas Jefferson University Hospital in Philadelphia and the UC San Diego Medical Center, which is part of the UCSD Health CIRM Alpha Stem Cell Clinic.

In a company news release, Ed Wirth, Chief Medical Officer of Asterias said,

Ed Wirth

“We are excited about the clinical site openings at Thomas Jefferson University Hospital and UC San Diego Health. These sites provide additional geographical reach and previous experience with spinal cord injury trials to our SCiStar study. We have recently reported completion of enrollment in four out of five cohorts in our SCiStar study so we hope these institutions will also participate in a future, larger study of AST-OPC1.”

The news release also gave a recap of the trial’s positive (but still preliminary) results this year and their plans for completing trial enrollment.

“In June 2017, Asterias reported 9 month data from the AIS-A 10 million cell cohort that showed improvements in arm, hand and finger function observed at 3-months and 6-months following administration of AST-OPC1 were confirmed and in some patients further increased at 9-months. The company intends to complete enrollment of the entire SCiStar study later this year, with multiple safety and efficacy readouts anticipated during the remainder of 2017 and 2018.”