CIRM-funded research is helping unlock the secrets behind “chemo brain”

chemo brain

Every year millions of Americans undergo chemotherapy. The goal of the treatment is to destroy cancer, but along the way more than half of the people treated lose something else. They suffer from something called “chemo brain” which causes problems with thinking and memory. In some cases it can be temporary, lasting a few months. In others it can last years.

Now a CIRM-funded study by researchers at Stanford has found what may be behind chemo brain and identifying potential treatments.

In an article on the Stanford Medicine News Center, senior author Michelle Monje said:

“Cognitive dysfunction after cancer therapy is a real and recognized syndrome. In addition to existing symptomatic therapies — which many patients don’t know about — we are now homing in on potential interventions to promote normalization of the disorders induced by cancer drugs. There’s real hope that we can intervene, induce regeneration and prevent damage in the brain.”

The team first looked at the postmortem brains of children, some of whom had undergone chemotherapy and some who had not. The chemotherapy-treated brains had far fewer oligodendrocyte cells, a kind of cell important in protecting nerve cells in the brain.

Next the team injected methotrexate, a commonly used chemotherapy drug, into mice and then several weeks later compared the brains of those mice to untreated mice. They found that the brains of the treated mice had fewer oligodendrocytes and that the ones they had were in an immature state, suggested the chemo was blocking their development.

The inner changes were also reflected in behavior. The treated mice had slower movement, showed more anxiety, and impaired memory compared to untreated mice; symptoms that persisted for up to six months after the injections.

As if that wasn’t enough, they also found that the chemo affected other cells in the brain, creating a kind of cascade effect that seemed to amplify the impaired memory and other cognitive functions.

However, there is some encouraging news in the study, which is published in the journal Cell. The researchers gave the treated mice a drug to reverse some of the side effects of methotrexate, and that seemed to reduce some of the cognitive problems the mice were having.

Monje says that’s where her research is heading next.

“If we understand the cellular and molecular mechanisms that contribute to cognitive dysfunction after cancer therapy, that will help us develop strategies for effective treatment. It’s an exciting moment.”

 

Japanese scientists implant first Parkinson’s patient with replacement neurons derived from stem cells

Parkinsons

Neurons derived from stem cells.Credit: Silvia Riccardi/SPL

Currently, more than 10 million people worldwide live with Parkinson’s disease (PD). By 2020, in the US alone, people living with Parkinson’s are expected to outnumber the cases of multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined.

There is no cure for Parkinson’s and treatment options consist of medications that patients ultimately develop tolerance to, or surgical therapies that are expensive. Therefore, therapeutic options that offer long-lasting treatment, or even a cure, are essential for treating PD.

Luckily for patients, Jun Takahashi’s team at Kyoto University has pioneered a stem cell based therapy for PD patients.

To understand their treatment strategy, however, we first have to understand what causes this disease. Parkinson’s results from decreased numbers of neurons that produce dopamine, a molecule that helps control muscle movements. Without proper dopamine production, patients experience a wide range of movement abnormalities, including the classic tremors that are associated with PD.

The current treatment options only target the symptoms, as opposed to the root cause of the disease. Takashi’s group decided to go directly to the source and improve dopamine production in these patients by correcting the dopaminergic neuron shortage.

The scientists harvested skin cells from a healthy donor and reprogrammed them to become induced pluripotent stem cells (iPSCs), or stem cells that become any type of cell. These iPSCs were then turned into the precursors of dopamine-producing neurons and implanted into 12 brain regions known to be hotspots for dopamine production.

The procedure was carried out in October and the patient, a male in his 50s, is still healthy. If his symptoms continue to improve and he doesn’t experience any bad side effects,  he will receive a second dose of dopamine-producing stem cells. Six other patients are scheduled to receive this same treatment and Takashi hopes that, if all goes well, this type of treatment can be ready for the general public by 2023.

This treatment was first tested in monkeys, where the researchers saw that not only did the implanted stem cells improve Parkinson’s symptoms and survive in the brain for at least two years, but they also did not cause any negative side effects.

This is only the third time iPSCs have been used as a treatment option in humans. The first was for macular degeneration in 2014.

CIRM is funding a similar, albeit earlier-stage program, with Jeanne Loring at Scripps.

 

Why having a wrinkled brain is a good thing

Brain_01

We normally associate wrinkles with aging, such as wrinkled skin. But there’s one organ that is wrinkled right from the time we are born. It’s our brain. And new research shows those wrinkles are not a sign of age but are, in fact, a sign of just how large and complex our brains are.

The wrinkles, according to U.C. Santa Barbara (UCSB) postdoctoral scholar Eyal Karzbrun, are vital to our development because they create a greater surface area giving our neurons, or brain nerve cells, more space to create connections and deliver information.

In an article in UCSB’s Daily Nexus, Karzbrun says while our knowledge of the brain is increasing there are still many things we don’t understand:

“The brain is a complex organ whose organization is essential to its function. Yet it is ‘assembled by itself’. How this assembly takes place and what physics come into play is fundamental to our understanding of the brain.”

Eyal Karzbrun

Eyal Karzbrun: Photo courtesy UCSB

Karzbrun used stem cells to create 3D clusters of brain cells, to better understand how they organize themselves. He said brains are like computers in the way they rely on surface area to process information.

“In order to be computationally strong and quick, what your brain does is take a lot of surface area and put it in a small volume. The cerebral cortex, which occupies most of the volume in your brain, has a unique architecture in which neurons are layered on the outer surface of the brain, and the bulk of the brain is composed of axons, [or] biological wire which interconnect the neurons.”

Karzbrun says gaining a deeper understanding of how the brain is formed, and why it takes the shape it does, may help us develop new approaches to treating problems in the brain.

 

Using biological “codes” to generate neurons in a dish

BrainWavesInvestigators at the Scripps Research Institute are making brain waves in the field of neuroscience. Until now, neuroscience research has largely relied on a variety of animal models to understand the complexities of various brain or neuronal diseases. While beneficial for many reasons, animal models do not always allow scientists to understand the precise mechanism of neuronal dysfunction, and studies done in animals can often be difficult to translate to humans. The work done by Kristin Baldwin’s group, however, is revolutionizing this field by trying to re-create this complexity in a dish.

One of the primary hurdles that scientists have had to overcome in studying neuronal diseases, is the impressive diversity of neuronal cell types that exist. The exact number of neuronal subtypes is unknown, but scientists estimate the number to be in the hundreds.

While neurons have many similarities, such as the ability to receive and send information via chemical cues, they are also distinctly specialized. For example, some neurons are involved in sensing the external environment, whereas others may be involved in helping our muscles move. Effective medical treatment for neuronal diseases is contingent on scientists being able to understand how and why specific neuronal subtypes do not function properly.

In a study in the journal Nature, partially funded by CIRM, the scientists used pairs of transcription factors (proteins that affect gene expression and cell identity), to turn skin stem cells into neurons. These cells both physically looked like neurons and exhibited characteristic neuronal properties, such as action potential generation (the ability to conduct electrical impulses). Surprisingly, the team also found that they were able to generate neurons that had unique and specialized features based on the transcription factors pairs used.

The ability to create neuronal diversity using this method indicates that this protocol could be used to recapitulate neuronal diversity outside of the body. In a press release, Dr. Baldwin states:

KristinBaldwin

Kristin Baldwin, PhD

“Now we can be better genome detectives. Building up a database of these codes [transcription factors] and the types of neurons they produce can help us directly link genomic studies of human brain disease to a molecular understanding of what goes wrong with neurons, which is the key to finding and targeting treatments.”

These findings provide an exciting and promising tool to more effectively study the complexities of neuronal disease. The investigators of this study have made their results available on a free platform called BioGPS in the hopes that multiple labs will delve into the wealth of information they have opened up. Hopefully, this system will lead to more rapid drug discovery for disease like autism and Alzheimer’s

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.”

Stem cell agency funds Phase 3 clinical trial for Lou Gehrig’s disease

ALS

At CIRM we don’t have a disease hierarchy list that we use to guide where our funding goes. We don’t rank a disease by how many people suffer from it, if it affects children or adults, or how painful it is. But if we did have that kind of hierarchy you can be sure that Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, would be high on that list.

ALS is a truly nasty disease. It attacks the neurons, the cells in our brain and spinal cord that tell our muscles what to do. As those cells are destroyed we lose our ability to walk, to swallow, to talk, and ultimately to breathe.

As Dr. Maria Millan, CIRM’s interim President and CEO, said in a news release, it’s a fast-moving disease:

“ALS is a devastating disease with an average life expectancy of less than five years, and individuals afflicted with this condition suffer an extreme loss in quality of life. CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and, in keeping with this mission, our objective is to find a treatment for patients ravaged by this neurological condition for which there is currently no cure.”

Having given several talks to ALS support groups around the state, I have had the privilege of meeting many people with ALS and their families. I have seen how quickly the disease works and the devastation it brings. I’m always left in awe by the courage and dignity with which people bear it.

BrainStorm

I thought of those people, those families, today, when our governing Board voted to invest $15.9 million in a Phase 3 clinical trial for ALS run by BrainStorm Cell Therapeutics. BrainStorm is using mesenchymal stem cells (MSCs) that are taken from the patient’s own bone marrow. This reduces the risk of the patient’s immune system fighting the therapy.

After being removed, the MSCs are then modified in the laboratory to  boost their production of neurotrophic factors, proteins which are known to help support and protect the cells destroyed by ALS. The therapy, called NurOwn, is then re-infused back into the patient.

In an earlier Phase 2 clinical trial, NurOwn showed that it was safe and well tolerated by patients. It also showed evidence that it can help stop, or even reverse  the progression of the disease over a six month period, compared to a placebo.

CIRM is already funding one clinical trial program focused on treating ALS – that’s the work of Dr. Clive Svendsen and his team at Cedars Sinai, you can read about that here. Being able to add a second project, one that is in a Phase 3 clinical trial – the last stage before, hopefully, getting approval from the Food and Drug Administration (FDA) for wider use – means we are one step closer to being able to offer people with ALS a treatment that can help them.

Diane Winokur, the CIRM Board Patient Advocate member for ALS, says this is something that has been a long time coming:

CIRM Board member and ALS Patient Advocate Diane Winokur

“I lost two sons to ALS.  When my youngest son was diagnosed, he was confident that I would find something to save him.  There was very little research being done for ALS and most of that was very limited in scope.  There was one drug that had been developed.  It was being released for compassionate use and was scheduled to be reviewed by the FDA in the near future.  I was able to get the drug for Douglas.  It didn’t really help him and it was ultimately not approved by the FDA.

When my older son was diagnosed five years later, he too was convinced I would find a therapy.  Again, I talked to everyone in the field, searched every related study, but could find nothing promising.

I am tenacious by nature, and after Hugh’s death, though tempted to give up, I renewed my search.  There were more people, labs, companies looking at neurodegenerative diseases.

These two trials that CIRM is now funding represent breakthrough moments for me and for everyone touched by ALS.  I feel that they are a promising beginning.  I wish it had happened sooner.  In a way, though, they have validated Douglas and Hugh’s faith in me.”

These therapies are not a cure for ALS. At least not yet. But what they will do is hopefully help buy people time, and give them a sense of hope. For a disease that leaves people desperately short of both time and hope, that would be a precious gift. And for people like Diane Winokur, who have fought so hard to find something to help their loved ones, it’s a vindication that those efforts have not been in vain.

Scientist grow diseased brain cells in bulk to study Alzheimer’s and Parkinson’s disease

Daily trips to the local grocery store have become a thing of the past for many with the rise of wholesale stores like Costco and online giants like Amazon. Buying in bulk is attractive for people who lead busy lives, have large families, or just love having endless pairs of clean socks.

Scientists who study neurodegenerative diseases like Alzheimer’s and Parkinson’s use disease-in-a-dish models that are much like the daily visits to the nearby Safeway. They can make diseased brain cells, or neurons, from human pluripotent stem cells and study them in the lab. But often, they can’t generate large enough quantities of cells to do important experiments like test new drugs or develop diagnostic platforms to identify disease at an earlier age.

What scientists need is a Costco for brain cells, a source that can make diseased brain cells in bulk. Such a method would open a new avenue of research into what causes neurodegeneration and how the aging process affects its progression.

This week, this need was answered. A team of researchers from Lund University in Sweden developed a method that can efficiently generate neurons from patients with a range of neurodegenerative diseases including Parkinson’s, Huntington’s and Alzheimer’s disease. The study was published in EMBO Molecular Medicine and was led by senior author Dr. Malin Parmar.

Diseased neurons made by the Lund University team. (Photo, Kennet Ruona)

Parmar and her team took an alternative approach to making their neurons. Their technology involves converting human skin cells into neurons without reprogramming the skin cells back to a pluripotent stem cell state first. This process is called “direct conversion” and is considered an effective shortcut for generating mature cells like neurons in a dish. Direct conversion of skin cells into neurons was first published by Dr. Marius Wernig, a CIRM-grantee and professor at Stanford University.

There is also scientific evidence suggesting that reprogramming patient cells back to a pluripotent state wipes out the effects of aging in those cells and has a Benjamin Button-like effect on the resulting neurons. By directly converting patient skin cells into neurons, many of these aging “signatures” are retained and the resulting neurons are more representative of the aging brain.

So how did they make brain cells in bulk? Parmar explained their method in a Lund University news release,

Malin Parmar

“Primarily, we inhibited a protein, REST, involved in establishing identity in cells that are not nerve cells. After limiting this protein’s impact in the cells during the conversion process, we’ve seen completely different results.”

 

Besides blocking REST, the team also turned on the production of two proteins, Ascl1 and Brn2, that are important for the development of neurons. This combination of activating pro-neural genes and silencing anti-neural genes was successful at converting skin cells into neurons on a large scale. Parmar further explained,

“We’ve been playing around with changing the dosage of the other components in the previous method, which also proved effective. Overall, the efficiency is remarkable. We can now generate almost unlimited amounts of neurons from one skin biopsy.”

As mentioned previously, this technology is valuable because it provides better brain disease models for scientists to study and to screen for new drugs that could treat or delay disease onset. Additionally, scientists can study the effects of the aging in the brain at different stages of neurodegeneration. Aging is a well-known risk factor for many neurodegenerative diseases, especially Alzheimer’s, so the ability to make large quantities of brain cells from elderly Alzheimer’s patients will unlock new clues into how age influences disease.

Co-author Dr. Johan Jakobsson concluded,

Johan Jakobsson

“This takes us one step closer to reality, as we can now look inside the human neurons and see what goes on inside the cell in these diseases. If all goes well, this could fundamentally change the field of research, as it helps us better understand the real mechanisms of the disease. We believe that many laboratories around the world would like to start testing on these cells to get closer to the diseases.”

For more on this study, check out this short video provided by Lund University.

New stem cell technique gives brain support cells a starring role

Gage et al

The Salk team. From left: Krishna Vadodaria, Lynne Moore, Carol Marchetto, Arianna Mei, Fred H. Gage, Callie Fredlender, Ruth Keithley, Ana Diniz Mendes. Photo courtesy Salk Institute

Astrocytes are some of the most common cells in the brain and central nervous system but they often get overlooked because they play a supporting role to the more glamorous neurons (even though they outnumber them around 50 to 1). But a new way of growing those astrocytes outside the brain could help pave the way for improved treatments for stroke, Alzheimer’s and other neurological problems.

Astrocytes – which get their name because of their star shape (Astron – Greek for “star” and “kyttaron” meaning cell) – have a number of key functions in the brain. They provide physical and metabolic support for neurons; they help supply energy and fuel to neurons; and they help with detoxification and injury repair, particularly in terms of reducing inflammation.

Studying these astrocytes in the lab has not been easy, however, because existing methods of producing them have been slow, cumbersome and not altogether effective at replicating their many functions.

Finding a better way

Now a team at the Salk Institute, led by CIRM-funded Professor Fred “Rusty” Gage, has developed a way of using stem cells to create astrocytes that is faster and more effective.

Their work is published in the journal Stem Cell Reports. In a news release, Gage says this is an important discovery:

“This work represents a big leap forward in our ability to model neurological disorders in a dish. Because inflammation is the common denominator in many brain disorders, better understanding astrocytes and their interactions with other cell types in the brain could provide important clues into what goes wrong in disease.”

Stylized microscopy image of an astrocyte (red) and neuron (green). (Salk Institute)

In a step by step process the Salk team used a series of chemicals, called growth factors, to help coax stem cells into becoming, first, generic brain cells, and ultimately astrocytes. These astrocytes not only behaved like the ones in our brain do, but they also have a particularly sensitive response to inflammation. This gives the team a powerful tool in helping develop new treatment to disorders of the brain.

But wait, there’s more!

As if that wasn’t enough, the researchers then used the same technique to create astrocytes from induced pluripotent stem cells (iPSCs) – adult cells, such as skin, that have been re-engineered to have the ability to turn into any other kind of cell in the body. Those man-made astrocytes also showed the same characteristics as natural ones do.

Krishna Vadodaria, one of the lead authors on the paper, says having these iPSC-created astrocytes gives them a completely new tool to help explore brain development and disease, and hopefully develop new treatments for those diseases.

“The exciting thing about using iPSCs is that if we get tissue samples from people with diseases like multiple sclerosis, Alzheimer’s or depression, we will be able to study how their astrocytes behave, and how they interact with neurons.”

Stem cell-derived, 3D brain tissue reveals autism insights

Studying human brain disorders is one of the most challenging fields in biomedical research. Besides the fact that the brain is incredibly complex, it’s just plain difficult to peer into it.

It’s neither practical nor ethical to access the cells of the adult brain. Patrick J. Lynch, medical illustrator; C. Carl Jaffe, MD, cardiologist.

For one thing, it’s not practical, let alone ethical, to drill into an affected person’s skull and collect brain cells to learn about their disease. Another issue is that the faulty cellular and molecular events that cause brain disorders are, in many cases, thought to trace back to fetal brain development before a person is even born. So, just like a detective looking for evidence at the scene of a crime, neurobiologists can only piece together clues after the disease has already occurred.

The good news is these limitations are falling away thanks to human induced pluripotent stem cells (iPSCs), which are generated from an individual’s easily accessible skin cells. Last week’s CIRM-funded research report out of Stanford University is a great example of how this method is providing new human brain insights.

Using brain tissue grown from patient-derived iPSCs, Dr. Sergiu Pasca and his team recreated the types of nerve cell circuits that form during the late stages of pregnancy in the fetal cerebral cortex, the outer layer of the brain that is responsible for functions including memory, language and emotion. With this system, they observed irregularities in the assembly of brain circuitry that provide new insights into the cellular and molecular causes of neuropsychiatric disorders like autism.

Recreating interactions between different regions of the development from skin-derived iPSCs
Image: Sergui Pasca Lab, Stanford University

Holy Brain Balls! Recreating the regions of our brain with skin cells
Two years ago, Pasca’s group figured out a way grow iPSCs into tiny, three-dimensional balls of cells that mimic the anatomy of the cerebral cortex. The team showed that these brain spheres contain the expected type of nerve cells, or neurons, as well as other cells that support neuron function.

Still, the complete formation of the cortex’s neuron circuits requires connections with another type of neuron that lies in a separate region of the brain. These other neurons travel large distances in a developing fetus’ brain over several months to reach the cortical cortex. Once in place, these migrating neurons have an inhibitory role and can block the cortical cortex nerve signals. Turning off a nerve signal is just as important as turning one on. In fact, imbalances in these opposing on and off nerve signals are suspected to play a role in epilepsy and autism.

So, in the current Nature study, Pasca’s team devised two different iPSC-derived brain sphere recipes: one that mimics the neurons found in the cortical cortex and another that mimics the region that contains the inhibitory neurons. Then the researchers placed the two types of spheres in the same lab dish and within three days, they spontaneously fused together.

Under video microscopy, the migration of the inhibitory neurons into the cortical cortex was observed. In cells derived from healthy donors, the migration pattern of inhibitory neurons looked like a herky-jerkey car being driven by a student driver: the neurons would move toward the cortical cortex sphere but suddenly stop for a while and then start their migration again.

“We’ve never been able to recapitulate these human-brain developmental events in a dish before,” said Pasca in a press release, “the process happens in the second half of pregnancy, so viewing it live is challenging. Our method lets us see the entire movie, not just snapshots.”

New insights into Timothy Syndrome may also uncover molecular basis of autism
To study the migration of the inhibitory neurons in the context of a neuropsychiatric disease, iPSCs were generated from skin samples of patients with Timothy syndrome, a rare genetic disease which carries a wide-range of symptoms including autism as well as heart defects.

The formation of brain spheres from the patient-derived iPSCs proceeded normally. But the next part of the experiment revealed an abnormal migration pattern of the neurons.  The microscopy movies showed that the start and stop behavior of neurons happened more frequently but the speed of the migration slowed. The fascinating video below shows the differences in the migration patterns of a healthy (top) versus a Timothy sydrome-derived neuron (bottom). The end result was a disruption of the typically well-organized neuron circuitry.

Now, the gene that’s mutated in Timothy Syndrome is responsible for the production of a protein that helps shuttle calcium in and out of neurons. The flow of calcium is critical for many cell functions and adding drugs that slow down this calcium flux restored the migration pattern of the neurons. So, the researchers can now zero in their studies on this direct link between the disease-causing mutation and a specific breakdown in neuron function.

The exciting possibility is that, because this system is generated from a patient’s skin cells, experiments could be run to precisely understand each individual’s neuropsychiatric disorder. Pasca is eager to see what new insights lie ahead:

“Our method of assembling and carefully characterizing neuronal circuits in a dish is opening up new windows through which we can view the normal development of the fetal human brain. More importantly, it will help us see how this goes awry in individual patients.”

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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