ViaCyte Advances Cell Replacement Therapy for High Risk Type 1 Diabetes

San Diego regenerative medicine company ViaCyte announced this week that the Food and Drug Administration (FDA) approved their Investigational New Drug (IND) Application for PEC-Direct, a cell-based therapy to treat patients at risk for severe complications caused by type 1 diabetes. In the US, IND approval is the final regulatory step required before a therapy can be tested in clinical trials.

PEC-Direct is a combination therapy consisting of cells encapsulated in a device that aims to replace the insulin-producing islet cells of the pancreas destroyed in patients with type 1 diabetes. The device contains human stem cell-derived pancreatic progenitor cells that develop into insulin-secreting cells when the device is placed under the patient’s skin. Ports on the surface of the device allow blood vessels from the host to directly contact the cells within, allowing for engraftment of the transplanted cells and for their maturation into islet cells.  These cells can sense and regulate blood glucose levels by secreting the hormones found in islets, including insulin.

ViaCyte’s PEC-Direct device allows a patient’s blood vessels to integrate and make contact with the transplanted cells.

Because PEC-Direct allows for “direct vascularization”, in effect connecting the device to the blood system, patients will need to take immunosuppressive drugs to prevent rejection of the donor cells. ViaCyte is therefore testing this therapy in patients who are at risk for serious complications associated with type 1 diabetes like severe hypoglycemia where a patient’s blood sugar is so low they need immediate medical assistance.

Severe hypoglycemia can occur because people with diabetes must inject insulin to control elevated blood sugar, but the injections can exceed the patients’ needs. The resulting low blood sugar can lead to dizziness, irregular heartbeat, and unconsciousness, even death. In some cases, sufferers are not aware of their hypoglycemia symptoms, putting them at increased risk of these life-threatening complications.

ViaCyte’s President and CEO, Dr. Paul Laikind, explained in a news release,

Paul Laikind

“While insulin therapy transformed type 1 diabetes from a death sentence to a chronic illness, it is far from a cure. Type 1 diabetes patients continue to deal with the daily impact of the disease and remain at risk for often severe long-term complications.  This is especially true for the patients with high-risk type 1 diabetes, who face challenges such as hypoglycemia unawareness and life-threatening severe hypoglycemic episodes.  These patients have a particularly urgent unmet medical need and could benefit greatly from cell replacement therapy.”

Approximately 140,000 people in the US and Canada suffer from this form of high-risk diabetes. These patients qualify for islet transplants from donated cadaver tissue. But because donor islets are in limited supply, ViaCyte Clinical Advisor, Dr. James Shapiro at the University of Alberta, believes PEC-Direct will address this issue by providing an unlimited supply of cells.

“Islet transplants from scarce organ donors have offered great promise for those with unstable, high-risk type 1 diabetes, but the procedure has many limitations.  With an unlimited supply of new islets that the stem cell-derived therapy promises, we have real potential to benefit far more patients with islet cell replacement.”

The company’s preclinical research on PEC-Direct, leading up to the FDA’s IND approval, was funded by a CIRM late stage preclinical grant. ViaCyte now plans to launch a clinical trial this year that will evaluate the safety and efficacy of PEC-Direct in the US and Canada. They will enroll approximately 40 patients at multiple clinical trial centers including the University of Alberta in Edmonton, the University of Minnesota, and UC San Diego. The trial will test whether the device is safe and whether the transplanted cells can produce enough insulin to relieve patients of insulin injections and hypoglycemic events.

ViaCyte has another product called PEC-Encap, a different implantable device that contains the same cells but protects these cells from the patient’s immune system. The device is being tested in a CIRM-funded Phase 1/2a trial, and ViaCyte is currently collaborating with W. L. Gore & Associates to improve the design of PEC-Encap to improve consistency of engraftment in patients.

Stem cell stories that caught our eye: lab-grown blood stem cells and puffer fish have the same teeth stem cells as humans

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Scientists finally grow blood stem cells in the lab!

Two exciting stem cell studies broke through the politics-dominated headlines this week. Both studies, published in the journal Nature, demonstrated that human hematopoietic or blood stem cells can be grown in the lab.

This news is a big deal because scientists have yet to make bonafide blood stem cells from pluripotent stem cells or other human cells. These stem cells not only create all the cells in our blood and immune systems, but also can be used to develop therapies for patients with blood cancers and genetic blood disorders.

But to do these experiments, you need a substantial source of blood stem cells – something that has eluded scientists for decades. That’s where these two studies come to the rescue. One study was spearheaded by George Daley at the Boston Children’s Hospital in Massachusetts and the other was led by Shahin Rafii at the Weill Cornell Medical College in New York City.

Researchers have made blood stem cells and progenitor cells from pluripotent stem cells. Credit: Steve Gschmeissner Getty Images

George Daley and his team developed a strategy that matured human induced pluripotent stem cells (iPS cells) into blood-forming stem and progenitor cells. It’s a two-step process that first uses a cocktail of chemicals to make hemogenic endothelium, the embryonic tissue that generates blood stem cells. The second step involved treating these intermediate cells with a combination of seven transcription factors that directed them towards a blood stem cell fate.

These modified human blood stem cells were then transplanted into mice where they developed into blood stem cells that produced blood and immune cells. First author on the study, Ryohichi Sugimura, explained the applications that their technology could be used for in a Boston Children’s Hospital news release,

“This step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect and make functional blood cells. This also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions.”

The second study by Shahin Rafii and his team at Cornell used a different strategy to generate blood-forming stem cells. Instead of genetically manipulating iPS cells, they selected a more mature cell type to directly reprogram into blood stem cells. Using four transcription factors, they successfully reprogrammed mouse endothelial cells, which line the insides of blood vessels, into blood-forming stem cells that repopulated the blood and immune systems of irradiated mice.

Raffii believe his method is simpler and more efficient than Daley’s. In coverage by Nature News, he commented,

“Using the most efficient method to generate stem cells matters because every time a gene is added to a batch of cells, a large portion of the batch fails to incorporate it and must be thrown out. There is also a risk that some cells will mutate after they are modified in the lab, and could form tumors if they are implanted into people.”

To play devil’s advocate, Daley’s technique might appeal more to some because the starting source of iPS cells is much easier to obtain and culture in the lab than endothelial cells that have to be extracted from the blood vessels of animals or people. Furthermore, Daley argued that his team’s method could “be made more efficient, and [is] less likely to spur tumor growth and other abnormalities in modified cells.”

The Nature News article compares the achievements of both studies and concluded,

“Time will determine which approach succeeds. But the latest advances have buoyed the spirits of researchers who have been frustrated by their inability to generate blood stem cells from iPS cells.”

 

Humans and puffer fish have the same tooth-making stem cells.

Here’s a fun fact for your next blind date: humans and puffer fish share the same genes that are responsible for making teeth. Scientists from the University of Sheffield in England discovered that the stem cells that make teeth in puffer fish are the same stem cells that make the pearly whites in humans. Their work was published in the journal PNAS earlier this week.

Puffer fish. Photo by pingpogz on Flickr.

But if you look at this puffer fish, you’ll see a dramatic difference between its smile and ours – their teeth look more like a beak. Research has shown that the tooth-forming stem cells in puffer fish produce tooth plates that form a beak-like structure, which helps them crush and consume their prey.

So why is this shared evolution between humans and puffer fish important when our teeth look and function so differently? The scientists behind this research believe that studying the pufferfish could unearth answers about tooth loss in humans. The lead author on the study, Dr. Gareth Fraser, concluded in coverage by Phys.org,

“Our study questioned how pufferfish make a beak and now we’ve discovered the stem cells responsible and the genes that govern this process of continuous regeneration. These are also involved in general vertebrate tooth regeneration, including in humans. The fact that all vertebrates regenerate their teeth in the same way with a set of conserved stem cells means that we can use these studies in more obscure fishes to provide clues to how we can address questions of tooth loss in humans.”

Bridging the Gap: Regenerating Injured Bones with Stem Cells and Gene Therapy

Scientists from Cedars-Sinai Medical Center have developed a new stem cell-based technology in animals that mends broken bones that can’t regenerate on their own. Their research was published today in the journal Science Translational Medicine and was funded in part by a CIRM Early Translational Award.

Over two million bone grafts are conducted every year to treat bone fractures caused by accidents, trauma, cancer and disease. In cases where the fractures are small, bone can repair itself and heal the injury. In other cases, the fractures are too wide and grafts are required to replace the missing bone.

It sounds simple, but the bone grafting procedure is far from it and can cause serious problems including graft failure and infection. People that opt to use their own bone (usually from their pelvis) to repair a bone injury can experience intense pain, prolonged recovery time and are at risk for nerve injury and bone instability.

The Cedars-Sinai team is attempting to “bridge the gap” for people with severe bone injuries with an alternative technology that could replace the need for bone grafts. Their strategy combines “an engineering approach with a biological approach to advance regenerative engineering” explained co-senior author Dr. Dan Gazit in a news release.

Gazit’s team developed a biological scaffold composed of a protein called collagen, which is a major component of bone. They implanted these scaffolds into pigs with fractured leg bones by inserting the collagen into the gap created by the bone fracture. Over a two-week period, mesenchymal stem cells from the animal were recruited into the collagen scaffolds.

To ensure that these stem cells generated new bone, the team used a combination of ultrasound and gene therapy to stimulate the stem cells in the collagen scaffolds to repair the bone fractures. Ultrasound pulses, or high frequency sound waves undetectable by the human ear, temporarily created small holes in the cell membranes allowing the delivery of the gene therapy-containing microbubbles into the stem cells.

Image courtesy of Gazit Group/Cedars-Sinai.

Animals that received the collagen transplant and ultrasound gene therapy repaired their fractured leg bones within two months. The strength of the newly regenerated bone was comparable to successfully transplanted bone grafts.

Dr. Gadi Pelled, the other senior author on this study, explained the significance of their research findings for treating bone injuries in humans,

“This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal’s own stem cells can effectively be used to treat non-healing bone fractures. It addresses a major orthopedic unmet need and offers new possibilities for clinical translation.”

You can learn more about this study by watching this research video provided by the Gazit Group at Cedars-Sinai.


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Kidney Disease: There’s an Organ-on-a-Chip for That

“There’s an app for that” is a well-known phrase trademarked by Apple to promote how users can do almost anything they do on a computer on their mobile phone. Apps are so deeply ingrained in everyday life that it’s hard for some people to imagine living without them. (I know I’d be lost without google maps or my Next Bus app!)

An estimated 2.2 million mobile apps exist for iPhones. Imagine if this multitude of apps were instead the number of stem cell models available for scientists to study human biology and disease. Scientists dream of the day when they can respond to questions about any disease and say, “there’s a model for that.” However, a future where every individual or disease has its own personalized stem cell line is still far away.

In the meantime, scientists are continuing to generate stem cell-based technologies that answer important questions about how our tissues and organs function and what happens when they are affected by disease. One strategy involves growing human stem cells on microchips and developing them into miniature organ systems that function like the organs in our bodies.

Kidney-on-a-chip

A group of scientists from Harvard’s Wyss Institute are using organ-on-a-chip technology to model a structure in the human kidney, called a glomerulus, that’s essential for filtering the body’s blood. It’s made up of a meshwork of blood vessels called capillaries that remove waste, toxic products, and excess fluid from the blood by depositing them into the urine.

The glomerulus also contains cells called podocytes that wrap around the capillaries and leave thin slits for blood to filter through. Diseases that affect podocytes or the glomerulus structure can cause kidney failure early or later in life, which is why the Harvard team was so interested to model this structure using their microchip technology.

They developed a method to mature human pluripotent stem cells into podocytes by engineering an environment similar to that of a real kidney on a microchip. Using a combination of kidney-specific factors and extracellular matrix molecules, which form a supportive environment for cells within tissues and organs, the team generated mature podocytes from human stem cells in three weeks. Their study was published in Nature Biomedical Engineering and was led by Dr. Donald Ingber, Founding Director of the Wyss Institute.

3D rendering of the glomerulus-on-a-chip derived from human stem cells. (Wyss Institute at Harvard University)

First author, Samaira Musah, explained how their glomerulus-on-a-chip works in a news release,

“Our method not only uses soluble factors that guide kidney development in the embryo, but, by growing and differentiating stem cells on extracellular matrix components that are also contained in the membrane separating the glomerular blood and urinary systems, we more closely mimic the natural environment in which podocytes are induced and mature. We even succeeded in inducing much of this differentiation process within a channel of the microfluidic chip, where by applying cyclical motions that mimic the rhythmic deformations living glomeruli experience due to pressure pulses generated by each heartbeat, we achieve even greater maturation efficiencies.”

Over 90% of stem cells successfully developed into functional podocytes that could properly filter blood by selectively filtering different blood proteins. The podocytes also were susceptible to a chemotherapy drug called doxorubicin, proving that they are suitable for modeling the effects of drug toxicity on kidneys.

Kidney podocyte derived from human stem cells. (Wyss Institute)

Ingber highlighted the potential applications of their glomerulus-on-a-chip technology,

Donald Ingber, Wyss Institute

“The development of a functional human kidney glomerulus chip opens up an entire new experimental path to investigate kidney biology, carry out highly personalized modeling of kidney diseases and drug toxicities, and the stem cell-derived kidney podocytes we developed could even offer a new injectable cell therapy approach for regenerative medicine in patients with life-threatening glomerulopathies in the future.”

There’s an organ-on-a-chip for that!

The Wyss Institute team has developed other organ-on-chips including lungs, intestine, skin and bone marrow. These miniature human systems are powerful tools that scientists hope will “revolutionize drug development, disease modeling and personalized medicine” by reducing the cost of research and the reliance on animal models according to the Wyss Institute technology website.

What started out as a microengineering experiment in Ingber’s lab a few years ago is now transforming into a technology “that is now poised to have a major impact on society” Ingber further explained. If organs-on-chips live up to these expectations, you might one day hear a scientist say, “Don’t worry, there’s an organ-on-a-chip for that!”


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Engineered bone tissue improves stem cell transplants

Bone marrow transplants are currently the only approved stem cell-based therapy in the United States. They involve replacing the hematopoietic, or blood-forming stem cells, found in the bone marrow with healthy stem cells to treat patients with cancers, immune diseases and blood disorders.

For bone marrow transplants to succeed, patients must undergo radiation therapy to wipe out their diseased bone marrow, which creates space for the donor stem cells to repopulate the blood system. Radiation can lead to complications including hair loss, nausea, fatigue and infertility.

Scientists at UC San Diego have a potential solution that could make current bone marrow transplants safer for patients. Their research, which was funded in part by a CIRM grant, was published yesterday in the journal PNAS.

Engineered bone with functional bone marrow in the center. (Varghese Lab)

Led by bioengineering professor Dr. Shyni Varghese, the team engineered artificial bone tissue that contains healthy donor blood stem cells. They implanted the engineered bone under the skin of normal mice and watched as the “accessory bone marrow” functioned like the real thing by creating new blood cells.

The implant lasted more than six months. During that time, the scientists observed that the cells within the engineered bone structure matured into bone tissue that housed the donor bone marrow stem cells and resembled how bones are structured in the human body. The artificial bones also formed connections with the mouse circulatory system, which allowed the host blood cells to populate the implanted bone tissue and the donor blood cells to expand into the host’s bloodstream.

Normal bone structure (left) and engineered bone (middle) are very similar. Bone tissue shown on top right and bone marrow cells on bottom right. (Varghese lab)

The team also implanted these artificial bones into mice that received radiation to mimic the procedures that patients typically undergo before bone marrow transplants. The engineered bone successfully repopulated the blood systems of the irradiated mice, similar to how blood stem cell functions in normal bone.

In a UC San Diego news release, Dr. Varghese explained how their technology could be translated into the clinic,

“We’ve made an accessory bone that can separately accommodate donor cells. This way, we can keep the host cells and bypass irradiation. We’re working on making this a platform to generate more bone marrow stem cells. That would have useful applications for cell transplantations in the clinic.”

The authors concluded that engineered bone tissue would specifically benefit patients who needed bone marrow transplants for non-cancerous bone marrow-related diseases such as sickle cell anemia or thalassemia where there isn’t a need to destroy cancer-causing cells.

Keeping intestinal stem cells in their prime

Gut stem cells (green) in the small intestine of a mouse.

The average length of the human gut is 25 feet long. That’s equivalent to four really tall people or five really short people lined up head to toe. Intestinal stem cells have the fun job of regenerating and replacing ALL the cells that line the gut. Therefore, it’s important for these stem cells to be able to self-renew, a process that replenishes the stem cell population. If this important biological process is disrupted, the intestine is at risk for diseases like inflammatory bowel disease and cancer.

This week, Stanford Medicine researchers published new findings about the biological processes responsible for regulating the regenerative capacity of intestinal stem cells. Their work, which was partially funded by CIRM, was published in the journal Nature.

Priming gut stem cells to self-renew

Scientists know that the self-renewal of intestinal stem cells is very important for a happy, functioning gut, but the nuances of what molecules and signaling pathways regulate this process have yet to be figured out. The Stanford team, led by senior author and Stanford Professor Dr. Calvin Kuo, studied two signaling pathways, Wnt and R-Spondin, that are involved in the self-renewal of intestinal stem cells in mice.

Dr. Calvin Kuo, Stanford Medicine.

“The cascade of events comprising the Wnt signaling pathway is crucial to stem cell self-renewal,” Dr. Kuo explained in an email exchange. “The Wnt pathway can be induced by either hormones classified as “Wnts” or “R-spondins”.  However, it is not known if Wnts or R-spondins cooperate to induce Wnt signaling, and if these Wnts and R-spondins have distinct functions or if they can mutually substitute for each other.   We explored how Wnts and R-spondins might cooperate to regulate intestinal stem cells – which are extremely active and regenerate the 25-foot lining of the human intestine every week.”

The team used different reagents to activate or block Wnt or R-spondin signaling and monitored the effects on intestinal stem cells. They found that both were important for the self-renewal of intestinal stem cells, but that they played different roles.

“Our work revealed that Wnts and R-spondins are not equivalent and that they have very distinct functions even though they both trigger the Wnt signaling cascade,” said Dr. Kuo. “Both Wnts and R-spondins are required to maintain intestinal stem cells.  However, Wnts perform more of a subservient “priming” function, where they prepare intestinal stem cells for the action of R-spondin, which is the active catalyst for inducing intestinal stem cells to divide.”

The authors believe that this multi-step regulation, involving priming and self-renewal factors could apply to stem cell systems in other organs and tissues in the body. Some of the researchers on this study including Dr. Kuo are pursuing this idea through a new company called Surrozen, which produces artificial bioengineered Wnt molecules that don’t require activation like natural Wnt molecules. These Wnt molecules were used in the current study and are explained in more detail in a separate Nature article published at the same time.

The company believes that artificial Wnts will be useful for understanding stem cell biology and potentially for therapeutic applications. Dr. Kuo explained,

“The new surrogate Wnts are easily produced and can circulate in the bloodstream, unlike natural Wnts.  There may be medical applications of these bioengineered Wnt surrogates in stimulating various stem cell compartments of the body, given the wide range of stem cells that are governed by natural Wnts.”

Capricor reports positive results on CIRM-funded stem cell trial for Duchenne Muscular Dystrophy

Capricor Therapeutics, a Los Angeles-based company, published an update about its CIRM-funded clinical trial for patients with Duchenne muscular dystrophy (DMD), a devastating degenerative muscle disease that significantly reduces life expectancy.

The company reported positive results from their Phase I/II HOPE trial that’s testing the safety of their cardiosphere stem cell-based therapy called CAP-1002. The trial had 25 patients, 13 of which received the cells and 12 who received normal treatment. No serious adverse effects were observed suggesting that the treatment is “generally safe” thus far.

Patients given a single dose of CAP-1002 showed improvements “in certain measures of cardiac and upper limb function” after six months. They also experienced a reduction of cardiac scar tissue and a thickening of the heart’s left ventricle wall, which is typically thinned in DMD patients.

Capricor shared more details on their six-month trial results in a webcast this week, and you can read about them in this blog by Rare Disease Report.

Leading cause of death for DMD patients

DMD is a severe form of muscular dystrophy caused by a recessive genetic mutation in the dystrophin gene on the X chromosome. Consequently, men are much more likely to get the disease than women. Symptoms of DMD start with muscle weakness as early as four years of age, which then leads to deterioration of both skeletal and heart muscle. Heart disease is the leading cause of death in DMD patients – a fact that Capricor hopes to change with its clinical trial.

Capricor’s CEO, Dr. Linda Marbán, commented in a press release that the trial’s results support the findings of other researchers.

“These initial positive clinical results build upon a large body of preclinical data which illustrate CAP-1002’s potential to broadly improve the condition of those afflicted by DMD, as they show that cardiosphere-derived cells exert salutary effects on cardiac and skeletal muscle.”

Also quoted in the press release was Pat Furlong, DMD patient advocate and CEO of Parent Project Muscular Dystrophy.

Pat Furlong

“I’m excited to see these data, especially given the advanced nature of the patients in the HOPE trial. It is also gratifying to see the field of cell therapy making progress after more than two decades in development. It is our hope that CAP-1002 will have broad potential to improve the lives of patients with Duchenne muscular dystrophy.”

Pat recently spoke at the 2nd Annual CIRM Alpha Stem Cell Clinics meeting about her heartbreaking experience of losing two sons to DMD, both at a very young age. You can watch her speech below. We also featured her story and her inspiring efforts to promote DMD awareness in our 2016 Annual Report.

What to HOPE for next?

The trial is a year-long study and Capricor will report 12-month results at the end of 2017. In the meantime, Dr. Marbán and her team have plans to talk with the US Food and Drug Administration (FDA) about the regulatory options for getting CAP-1002 approved and on the market for DMD patients. She explained,

Linda Marban, CEO of Capricor Therapeutics

“We have submitted an FDA meeting request to discuss these results as well as next steps in our development of CAP-1002 for Duchenne muscular dystrophy, which includes our plan to begin a clinical trial of intravenously-administered CAP-1002 in the latter half of this year. We believe the interim HOPE results may enable us to pursue one of the FDA’s Expedited Programs for Serious Conditions, and we will apply for either or both of the Breakthrough Therapy and Regenerative Medicine Advanced Therapy (RMAT) designations for CAP-1002.”


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Scientists make stem cell-derived nerve cells damaged in spinal cord injury

The human spinal cord is an information highway that relays movement-related instructions from the brain to the rest of the body and sensory information from the body back to the brain. What keeps this highway flowing is a long tube of nerve cells and support cells bundled together within the spine.

When the spinal cord is injured, the nerve cells are damaged and can die – cutting off the flow of information to and from the brain. As a result, patients experience partial or complete paralysis and loss of sensation depending on the extent of their injury.

Unlike lizards which can grow back lost tails, the spinal cord cannot robustly regenerate damaged nerve cells and recreate lost connections. Because of this, scientists are looking to stem cells for potential solutions that can rebuild injured spines.

Making spinal nerve cells from stem cells

Yesterday, scientists from the Gladstone Institutes reported that they used human pluripotent stem cells to create a type of nerve cell that’s damaged in spinal cord injury. Their findings offer a new potential stem cell-based strategy for restoring movement in patients with spinal cord injury. The study was led by Gladstone Senior Investigator Dr. Todd McDevitt, a CIRM Research Leadership awardee, and was published in the journal Proceedings of the National Academy of Sciences.

The type of nerve cell they generated is called a spinal interneuron. These are specialized nerve cells in the spinal cord that act as middlemen – transporting signals between sensory neurons that connect to the brain to the movement-related, or motor, neurons that connect to muscles. Different types of interneurons exist in the brain and spinal cord, but the Gladstone team specifically created V2a interneurons, which are important for controlling movement.

V2a interneurons extend long distances in the spinal cord. Injuries to the spine can damage these important cells, severing the connection between the brain and the body. In a Gladstone news release, Todd McDevitt explained why his lab is particularly interested in making these cells to treat spinal cord injury.

Todd McDevitt, Gladstone Institutes

“Interneurons can reroute after spinal cord injuries, which makes them a promising therapeutic target. Our goal is to rewire the impaired circuitry by replacing damaged interneurons to create new pathways for signal transmission around the site of the injury.”

 

Transplanting nerve cells into the spines of mice

After creating V2a interneurons from human stem cells using a cocktail of chemicals in the lab, the team tested whether these interneurons could be successfully transplanted into the spinal cords of normal mice. Not only did the interneurons survive, they also set up shop by making connections with other nerve cells in the spinal cord. The mice that received the transplanted cells didn’t show differences in their movement suggesting that the transplanted cells don’t cause abnormalities in motor function.

Co-author on the paper, Dylan McCreedy, described how the transplanted stem cell-derived cells behaved like developing V2a interneurons in the spine.

“We were very encouraged to see that the transplanted cells sprouted long distances in both directions—a key characteristic of V2a interneurons—and that they started to connect with the relevant host neurons.”

Todd McDevitt (right), Jessica Butts (center) and Dylan McCreedy (left) created a special type of neuron from human stem cells that could potentially repair spinal cord injuries. (Photo: Chris Goodfellow, Gladstone)

A new clinical strategy?

Looking forward, the Gladstone team plans to test whether these V2a interneurons can improve movement in mice with spinal cord injury. If results look promising in mice, this strategy of transplanting V2a interneurons could be translated into human clinic trials although much more time and research are needed to get there.

Trials testing stem cell-based treatments for spinal cord injury are already ongoing. Many of them involve transplanting progenitor cells that develop into the different types of cells in the spine, including nerve and support cells. These progenitor cells are also thought to secrete important growth factors that help regenerate damaged tissue in the spine.

CIRM is funding one such clinical trial sponsored by Asterias Biotherapeutics. The company is transplanting oligodendrocyte progenitor cells (which make nerve support cells called oligodendrocytes) into patients with severe spinal cord injuries in their neck. The trial has reported encouraging preliminary results in all six patients that received a dose of 10 million cells. You can read more about this trial here.

What the Gladstone study offers is a different stem cell-based strategy for treating spinal cord injury – one that produces a specific type of spinal nerve cell that can reestablish important connections in the spinal cord essential for movement.

For more on this study, watch the Gladstone’s video abstract “Discovery Offers New Hope to Repair Spinal Cord.


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Stem cell stories that caught our eye: developing the nervous system, aging stem cells and identical twins not so identical

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

New theory for how the nervous system develops.

There’s a new theory on the block for how the nervous system is formed thanks to a study published yesterday by UCLA stem cell scientists in the journal Neuron.

The theory centers around axons, thin extensions projecting from nerve cells that transmit electrical signals to other cells in the body. In the developing nervous system, nerve cells extend axons into the brain and spinal cord and into our muscles (a process called innervation). Axons are guided to their final destinations by different chemicals that tell axons when to grow, when to not grow, and where to go.

Previously, scientists believed that one of these important chemical signals, a protein called netrin 1, exerted its influence over long distances in a gradient-like fashion from a structure in the developing nervous system called the floor plate. You can think of it like a like a cell phone tower where the signal is strongest the closer you are to the tower but you can still get some signal even when you’re miles away.

The UCLA team, led by senior author and UCLA professor Dr. Samantha Butler, questioned this theory because they knew that neural progenitor cells, which are the precursors to nerve cells, produce netrin1 in the developing spinal cord. They believed that the netrin1 secreted from these progenitor cells also played a role in guiding axon growth in a localized manner.

To test their hypothesis, they studied neural progenitor cells in the developing spines of mouse embryos. When they eliminated netrin1 from the neural progenitor cells, the axons went haywire and there was no rhyme or reason to their growth patterns.

Left: axons (green, pink, blue) form organized patterns in the normal developing mouse spinal cord. Right: removing netrin1 results in highly disorganized axon growth. (UCLA Broad Stem Cell Research Center/Neuron)

A UCLA press release explained what the scientists discovered next,

“They found that neural progenitors organize axon growth by producing a pathway of netrin1 that directs axons only in their local environment and not over long distances. This pathway of netrin1 acts as a sticky surface that encourages axon growth in the directions that form a normal, functioning nervous system.”

Like how ants leave chemical trails for other ants in their colony to follow, neural progenitor cells leave trails of netrin1 in the spinal cord to direct where axons go. The UCLA team believes they can leverage this newfound knowledge about netrin1 to make more effective treatments for patients with nerve damage or severed nerves.

In future studies, the team will tease apart the finer details of how netrin1 impacts axon growth and how it can be potentially translated into the clinic as a new therapeutic for patients. And from the sounds of it, they already have an idea in mind:

“One promising approach is to implant artificial nerve channels into a person with a nerve injury to give regenerating axons a conduit to grow through. Coating such nerve channels with netrin1 could further encourage axon regrowth.”

Age could be written in our stem cells.

The Harvard Gazette is running an interesting series on how Harvard scientists are tackling issues of aging with research. This week, their story focused on stem cells and how they’re partly to blame for aging in humans.

Stem cells are well known for their regenerative properties. Adult stem cells can rejuvenate tissues and organs as we age and in response to damage or injury. However, like most house hold appliances, adult stem cells lose their regenerative abilities or effectiveness over time.

Dr. David Scadden, co-director of the Harvard Stem Cell Institute, explained,

“We do think that stem cells are a key player in at least some of the manifestations of age. The hypothesis is that stem cell function deteriorates with age, driving events we know occur with aging, like our limited ability to fully repair or regenerate healthy tissue following injury.”

Harvard scientists have evidence suggesting that certain tissues, such as nerve cells in the brain, age sooner than others, and they trigger other tissues to start the aging process in a domino-like effect. Instead of treating each tissue individually, the scientists believe that targeting these early-onset tissues and the stem cells within them is a better anti-aging strategy.

David Sadden, co-director of the Harvard Stem Cell Institute.
(Jon Chase/Harvard Staff Photographer)

Dr. Scadden is particularly interested in studying adult stem cell populations in aging tissues and has found that “instead of armies of similarly plastic stem cells, it appears there is diversity within populations, with different stem cells having different capabilities.”

If you lose the stem cell that’s the best at regenerating, that tissue might age more rapidly.  Dr. Scadden compares it to a game of chess, “If we’re graced and happen to have a queen and couple of bishops, we’re doing OK. But if we are left with pawns, we may lose resilience as we age.”

The Harvard Gazette piece also touches on a changing mindset around the potential of stem cells. When stem cell research took off two decades ago, scientists believed stem cells would grow replacement organs. But those days are still far off. In the immediate future, the potential of stem cells seems to be in disease modeling and drug screening.

“Much of stem cell medicine is ultimately going to be ‘medicine,’” Scadden said. “Even here, we thought stem cells would provide mostly replacement parts.  I think that’s clearly changed very dramatically. Now we think of them as contributing to our ability to make disease models for drug discovery.”

I encourage you to read the full feature as I only mentioned a few of the highlights. It’s a nice overview of the current state of aging research and how stem cells play an important role in understanding the biology of aging and in developing treatments for diseases of aging.

Identical twins not so identical (Todd Dubnicoff)

Ever since Takahashi and Yamanaka showed that adult cells could be reprogrammed into an embryonic stem cell-like state, researchers have been wrestling with a key question: exactly how alike are these induced pluripotent stem cells (iPSCs) to embryonic stem cells (ESCs)?

It’s an important question to settle because iPSCs have several advantages over ESCs. Unlike ESCs, iPSCs don’t require the destruction of an embryo so they’re mostly free from ethical concerns. And because they can be derived from a patient’s cells, if iPSC-derived cell therapies were given back to the same patient, they should be less likely to cause immune rejection. Despite these advantages, the fact that iPSCs are artificially generated by the forced activation of specific genes create lingering concerns that for treatments in humans, delivering iPSC-derived therapies may not be as safe as their ESC counterparts.

Careful comparisons of DNA between iPSCs and ESCs have shown that they are indeed differences in chemical tags found on specific spots on the cell’s DNA. These tags, called epigenetic (“epi”, meaning “in addition”) modifications can affect the activity of genes independent of the underlying genetic sequence. These variations in epigenetic tags also show up when you compare two different preparations, or cell lines, of iPSCs. So, it’s been difficult for researchers to tease out the source of these differences. Are these differences due to the small variations in DNA sequence that are naturally seen from one cell line to the other? Or is there some non-genetic reason for the differences in the iPSCs’ epigenetic modifications?

Marian and Vivian Brown, were San Francisco’s most famous identical twins. Photo: Christopher Michel

A recent CIRM-funded study by a Salk Institute team took a clever approach to tackle this question. They compared epigenetic modifications between iPSCs derived from three sets of identical twins. They still found several epigenetic variations between each set of twins. And since the twins have identical DNA sequences, the researchers could conclude that not all differences seen between iPSC cell lines are due to genetics. Athanasia Panopoulos, a co-first author on the Cell Stem Cell article, summed up the results in a press release:

“In the past, researchers had found lots of sites with variations in methylation status [specific term for the epigenetic tag], but it was hard to figure out which of those sites had variation due to genetics. Here, we could focus more specifically on the sites we know have nothing to do with genetics. The twins enabled us to ask questions we couldn’t ask before. You’re able to see what happens when you reprogram cells with identical genomes but divergent epigenomes, and figure out what is happening because of genetics, and what is happening due to other mechanisms.”

With these new insights in hand, the researchers will have a better handle on interpreting differences between individual iPSC cell lines as well as their differences with ESC cell lines. This knowledge will be important for understanding how these variations may affect the development of future iPSC-based cell therapies.

Live streaming genes in living cells coming to a computer near you!

Christmas has come early to scientists at the University of Virginia School of Medicine. They’ve developed a technology that allows you to watch how individual genes move and interact in living cells. You can think of it as Facebook’s live streaming meets the adventurous Ms. Frizzle and her Magic School Bus.

Using a gene editing system called CRISPR/Cas9, the team tagged genes of interest with fluorescent proteins that light up under a microscope – allowing them to watch in real time where these genes are in a cell’s nucleus and how they interact with other genes in the genome. This research, which was funded in part by a CIRM Research Leadership award, was published in the journal Nature Communications.

Watching genes in living cells

Traditional methods for observing the locations of genes within cells, such as fluorescent in situ hybridization (FISH), kill the cells – giving scientists only a snapshot of the complex interactions between genes. With this new technology, scientists can track genes in living cells and generate a 3D map of where genes are located within chromatin (the DNA/protein complex that makes up our chromosomes) during the different stages of a cell’s existence. They can also use these maps to understand changes in gene interactions caused by diseases like cancer.

Senior author on the study, Dr. Mazhar Adli, explained in a news release:

Mazhar Adli (Josh Barney, UVA Health System)

“This has been a dream for a long time. We are able to image basically any region in the genome that we want, in real time, in living cells. It works beautifully. With the traditional method, which is the gold standard, basically you will never be able to get this kind of data, because you have to kill the cells to get the imaging. But here we are doing it in live cells and in real time.”

Additionally, this new technique helps scientists conceptualize the position of genes in a 3D rather than in a linear fashion.

“We have two meters of DNA folded into a nucleus that is so tiny that 10,000 of them will fit onto the tip of a needle,” Adli explained. “We know that DNA is not linear but forms these loops, these large, three-dimensional loops. We want to basically image those kind of interactions and get an idea of how the genome is organized in three-dimensional space, because that’s functionally important.”

Not only can this CRISPR technology light up specific genes of interest, but it can also turn their activity on or off, allowing the scientists to observe the effects of one gene’s activity on others. The flexibility of this approach for visualizing genes in live cells is something that the research world currently lacks.

“We were told we would never be able to do this. There are some approaches that let you look at three-dimensional organization. But you do that experiment on hundreds of millions of cells, and you have to kill them to do it. Here, we can look at the single-cell level, and the cell is still alive, and we can take movies of what’s happening inside.”

This is a pretty nifty imaging tool for scientists that allows them to watch where genes are located and how they move as a cell develops and matures. Live-streaming the components of the genetic engine that keeps a cell running could also provide new insights into why certain genetic diseases occur and potentially open doors for developing better treatments.

Scientists tracked specific genomic locations in a living cell over time using their CRISPR/Cas9 technology. (Nature communications)