Study shows connection between bipolar disorder and neuroinflammation

Astrocytes, which provide structural support and protection for neurons and also supply them with nutrients and oxygen.

Bipolar disorder (BPD) is a mental disorder that causes unusual shifts in mood, energy, activity levels, concentration, and the ability to carry out day-to-day tasks. In the United States, recent research has shown that 1.6% of the population has BPD, which is roughly over 4 million people. Those with BPD are more likely to have conditions associated with chronic inflammation such as hypertension and diabetes. It is because of this that scientists have been studying the connection between inflammation and BPD for quite some time.

In a new study, researchers at the Salk Institute for Biological Studies, UC San Diego, and the Institute of Psychiatry and Neuroscience of Paris have found evidence that astrocytes, a certain type of brain cell, can trigger inflammation more easily in those that have BPD. What’s more, these astrocytes can be linked to decreased brain activity that could be harmful to mental health.

Astrocytes are star shaped (as the word “astro” might suggest) and help support neurons, the cells that relay information around the brain. One of these supporting roles includes helping trigger inflammation in the brain and the surrounding nervous system to help with injury or infection. The researchers believe that this process can go wrong in people with BPD and that astrocytes can play a role in this dysfunctional inflammation.

For this study, the team used induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any type of cell, that they created from patients with BPD and patients without BPD. They converted these iPSCs into astrocytes and compared those that came from BPD patients to those that did not. What they found is that the astrocytes from patients with BPD were noticeably different. The BPD astrocytes had a higher expression of a protein that triggers an inflammatory response when compared to the non-BPD astrocytes. When they exposed neurons to the BPD astrocytes, the team saw decreased levels of neural activity compared to the non-BPD astrocytes. Lastly, when the researchers blocked the inflammatory protein, the neurons were less affected by the BPD astrocytes.

“Our study suggests that normal function of astrocytes is affected in bipolar disorder patients’ brains, contributing to neuroinflammation,” said Dr. Renata Santos, a researcher at the Salk Institute as well as the Institute of Psychiatry and Neuroscience of Paris, in a news release.

The team hopes that their findings can not only provide insight into BPD, but to other mental illnesses linked to inflammation such as schizophrenia. The ultimate goal is to help advance research into astrocytes and inflammation in order to develop treatments that might reverse the harmful bodily changes seen in those with BPD and other mental disorders.

The full study was published in Stem Cell Reports.

CIRM funded researchers discover link between Alzheimer’s gene and COVID-19

Dr. Yanhong Shi (left) and Dr. Vaithilingaraja Arumugaswami (right)

All this month we are using our blog and social media to highlight a new chapter in CIRM’s life, thanks to the voters approving Proposition 14. We are looking back at what we have done since we were created in 2004, and also looking forward to the future. Today we focus on groundbreaking CIRM funded research related to COVID-19 that was recently published.

It’s been almost a year since the world started hearing about SARS-CoV-2, the virus that causes COVID-19.  In our minds, the pandemic has felt like an eternity, but scientists are still discovering new things about how the virus works and if genetics might play a role in the severity of the virus.  One population study found that people who have ApoE4, a gene type that has been found to increase the risk of developing Alzheimer’s, had higher rates of severe COVID-19 and hospitalizations.

It is this interesting observation that led to important findings of a study funded by two CIRM awards ($7.4M grant and $250K grant) and conducted by Dr. Yanhong Shi at City of Hope and co-led by Dr. Vaithilingaraja Arumugaswami, a member of the UCLA Broad Stem Cell Research Center.  The team found that the same gene that increases the risk for Alzheimer’s disease can increase the susceptibility and severity of COVID-19.

At the beginning of the study, the team was interested in the connection between SARS-CoV-2 and its effect on the brain.  Due to the fact that patients typically lose their sense of taste and smell, the team theorized that there was an underlying neurological effect of the virus.  

The team first created neurons and astrocytes.  Neurons are cells that function as the basic working unit of the brain and astrocytes provide support to them.  The neurons and astrocytes were generated from induced pluripotent stem cells (iPSCs), which are a kind of stem cell that can become virtually any type of cell and can be created by “reprogramming” the skin cells of patients.  The newly created neurons and astrocytes were then infected with SARS-CoV-2 and it was found that they were susceptible to infection.

Next, the team used iPSCs to create brain organoids, which are 3D models that mimic certain features of the human brain.  They were able to create two different organoid models: one that contained astrocytes and one without them.  They infected both brain organoid types with the virus and discovered that those with astrocytes boosted SARS-CoV-2 infection in the brain model. 

The team then decided to further study the effects of ApoE4 on susceptibility to SARS-CoV-2.  They did this by generating neurons from iPSCs “reprogrammed” from the cells of an Alzheimer’s patient.  Because the iPSCs were derived from an Alzheimer’s patient, they contained ApoE4.  Using gene editing, the team modified some of the ApoE4 iPSCs created so that they contained ApoE3, which is a gene type considered neutral.  The ApoE3 and ApoE4 iPSCs were then used to generate neurons and astrocytes.

The results were astounding.  The ApoE4 neurons and astrocytes both showed a higher susceptibility to SARS-CoV-2 infection in comparison to the ApoE3 neurons and astrocytes.  Moreover, while the virus caused damage to both ApoE3 and ApoE4 neurons, it appeared to have a slightly more severe effect on ApoE4 neurons and a much more severe effect on ApoE4 astrocytes compared to ApoE3 neurons and astrocytes. 

“Our study provides a causal link between the Alzheimer’s disease risk factor ApoE4 and COVID-19 and explains why some (e.g. ApoE4 carriers) but not all COVID-19 patients exhibit neurological manifestations” says Dr. Shi. “Understanding how risk factors for neurodegenerative diseases impact COVID-19 susceptibility and severity will help us to better cope with COVID-19 and its potential long-term effects in different patient populations.”

In the last part of the study, the researchers tested to see if the antiviral drug remdesivir inhibits virus infection in neurons and astrocytes.  They discovered that the drug was able to successfully reduce the viral level in astrocytes and prevent cell death.  For neurons, it was able to rescue them from steadily losing their function and even dying. 

The team says that the next steps to build on their findings is to continue studying the effects of the virus and better understand the role of ApoE4 in the brains of people who have COVID-19.  Many people that developed COVID-19 have recovered, but long-term neurological effects such as severe headaches are still being seen months after. 

“COVID-19 is a complex disease, and we are beginning to understand the risk factors involved in the manifestation of the severe form of the disease” says Dr. Arumugaswami.  “Our cell-based study provides possible explanation to why individuals with Alzheimer’s’ disease are at increased risk of developing COVID-19.”

The full results to this study were published in Cell Stem Cell.

Genetic defect leads to slower production of brain cells linked to one form of autism

Child with Fragile X syndrome

Fragile X syndrome (FXS) is a genetic disorder that is the most common form of inherited intellectual disability in children, and has also been linked to a form of autism. Uncovering the cause of FXS could help lead to a deeper understanding of autism, what causes it and ultimately, it’s hoped, to treating or even preventing it.

Researchers at Children’s Hospital in Chicago looked at FXS at the stem cell level and found how a genetic defect has an impact on the development of neurons (nerve cells in the brain) and how that in turn has an impact on the developing brain in the fetus.

In a news release on Eurekalert, Dr. Yongchao Ma, the senior author of the study, says this identified a problem at a critical point in the development of the brain:

“During embryonic brain development, the right neurons have to be produced at the right time and in the right numbers. We focused on what happens in the stem cells that leads to slower production of neurons that are responsible for brain functions including learning and memory. Our discoveries shed light on the earliest stages of disease development and offer novel targets for potential treatments.”

The team looked at neural stem cells and found that a lack of one protein, called FMRP, created a kind of cascade that impacted the ability of the cells to turn into neurons. Fewer neurons meant impaired brain development. 

The findings, published in the journal Cell Reports, help explain how genetic information flows in cells in developing babies and, according to Dr. Ma, could lead to new ideas on how to treat problems.

“Currently we are exploring how to stimulate FMRP protein activity in the stem cell, in order to correct the timing of neuron production and ensure that the correct amount and types of neurons are available to the developing brain. There may be potential for gene therapy for fragile X syndrome.”

A new stem cell derived tool for studying brain diseases

Sergiu Pasca’s three-dimensional culture makes it possible to watch how three different brain-cell types – oligodendrocytes (green), neurons (magenta) and astrocytes (blue) – interact in a dish as they do in a developing human  brain.
Courtesy of the Pasca lab

Neurological diseases are among the most daunting diagnoses for a patient to receive, because they impact how the individual interacts with their surroundings. Central to our ability to provide better treatment options for these patients, is scientists’ capability to understand the biological factors that influence disease development and progression. Researchers at the Stanford University School of Medicine have made an important step in providing neuroscientists a better tool to understand the brain.

While animal models are excellent systems to study the intricacies of different diseases, the ability to translate any findings to humans is relatively limited. The next best option is to study human stem cell derived tissues in the laboratory. The problem with the currently available laboratory-derived systems for studying the brain, however, is the limited longevity and diversity of neuronal cell types. Dr. Sergiu Pasca’s team was able to overcome these hurdles, as detailed in their study, published in the journal Nature Neuroscience.

A new approach

Specifically, Dr. Pasca’s group developed a method to differentiate or transform skin derived human induced pluripotent stem cells (iPSCs – which are capable of becoming any cell type) into brain-like structures that mimic how oligodendrocytes mature during brain development. Oligodendrocytes are most well known for their role in myelinating neurons, in effect creating a protective sheath around the cell to protect its ability to communicate with other brain cells. Studying oligodendrocytes in culture systems is challenging because they arise later in brain development, and it is difficult to generate and maintain them with other cell types found in the brain.

These scientists circumvented this problem by using a unique combination of growth factors and nutrients to culture the oligodendrocytes, and found that they behaved very similarly to oligodendrocytes isolated from humans. Most excitingly, they observed that the stem cell-derived oligodendrocytes were able to myelinate other neurons in the culture system. Therefore they were both physically and functionally similar to human oligodendrocytes.

Importantly, the scientists were also able to generate astrocytes alongside the oligodendrocytes. Astrocytes perform many important functions such as providing essential nutrients and directing the electrical signals that help cells in the brain communicate with each other. In a press release, Dr. Pasca explains the importance of generating multiple cell types in this in vitro system:

“We now have multiple cell types interacting in one single culture. This permits us to look close-up at how the main cellular players in the human brain are talking to each other.”

This in vitro or laboratory-developed system has the potential to help scientists better understand oligodendrocytes in the context of diseases such as multiple sclerosis and cerebral palsy, both of which stem from improper myelination of brain nerve cells.

This work was partially supported by a CIRM grant.

Using 3D printer to develop treatment for spinal cord injury

3d-printed-device

3D printed device

Spinal cord injuries (SCIs) affect approximately 300,000 Americans, with about 18,000 new cases occurring per year. One of these patients, Jake Javier, who we have written about many times over the past several years, received ten million stem cells as part of a CIRM-funded clinical trial and a video about his first year at Cal Poly depicts how these injuries can impact someone’s life.

Currently, there is nothing that completely reverses SCI damage and most treatment is aimed at rehabilitation and empowering patients to lead as normal a life as possible under the circumstances. Improved treatment options are necessary both to improve patients’ overall quality of life, and to reduce associated healthcare costs.

Scientists at UC San Diego’s School of Medicine and Institute of Engineering in Medicine have made critical progress in providing SCI patients with hope towards a more comprehensive and longer lasting treatment option.

shaochen chen

Prof. Shaochen Chen and his 3D printer

In a study partially funded by CIRM and published in Nature Medicine, Dr. Mark Tuszynski’s and Dr. Shaochen Chen’s groups used a novel 3D printing method to grow a spinal cord in the lab.

Previous studies have seen some success in lab grown neurons or nerve cells, improving SCI in animal models. This new study, however, is innovative both for the speed at which the neurons are printed, and the extent of the neuronal network that is produced.

To achieve this goal, the scientists used a biological scaffold that directs the growth of the neurons so they grow to the correct length and generate a complete neuronal network. Excitingly, their 3D printing technology was so efficient that they were able to grow implants for an animal model in 1.6 seconds, and a human-sized implant in just ten minutes, showing that their technology is scalable for injuries of different sizes.

When they tested the spinal cord implants in rats, they found that not only did the implant repair the damaged spinal cord tissue, but it also provided sustained improvement in motor function up to six months after implantation.

Just as importantly, they also observed that blood vessels had infiltrated the implanted tissue. The absence of vascularized tissue is one of the main reasons engineered implants do not last long in the host, because blood vessels are necessary to provide nutrients and support tissue growth. In this case, the animal’s body solved the problem on its own.

In a press release, one of the co-first authors of the paper, Dr. Kobi Koffler, states the importance and novelty of this work:

“This marks another key step toward conducting clinical trials to repair spinal cord injuries in people. The scaffolding provides a stable, physical structure that supports consistent engraftment and survival of neural stem cells. It seems to shield grafted stem cells from the often toxic, inflammatory environment of a spinal cord injury and helps guide axons through the lesion site completely.”

In order to make this technology viable for human clinical trials, the scientists are testing their technology in larger animal models before moving into humans, as well as investigating how to improve the longevity of the neuronal network by introducing proteins into the scaffolds.

 

 

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.”