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:

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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

Straight to brain: A better approach to ALS cell therapies?

Getting the go ahead to begin a clinical trial by no means marks an end to a research team’s laboratory studies. A clinical trial is merely one experiment and is designed to answer a specific set of questions about a specific course of treatment. There will inevitably be more questions to pursue back in the lab in parallel with an ongoing clinical trial to potentially enhance the treatment.

That’s the scenario for Cedar-Sinai’s current CIRM-funded clinical trial testing a cell therapy for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Animal studies published this week in Stem Cells suggests that an additional route of therapy delivery may have potential and should also be considered.

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Microscopy image showing transplanted neural progenitor cells (green), the protein GDNF (red) and motor neurons (blue) together in brain tissue. Credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute

ALS is an incurable disease that destroys motor neurons responsible for communicating muscle movement between the brain and the rest of the body via the spinal cord. ALS sufferers lose the use of their limbs and eventually the muscles that control breathing. They rarely live more than 3 to 5 years after diagnosis.

The CIRM-funded trial uses neural progenitor cells – which are similar to stem cells but can only specialize into different types of brain cells – that are genetically engineered to release a protein called GDNF that helps protect the motor neurons from destruction. These cells are being transplanted into the spinal cords of the clinical trial participants.

While earlier animal studies showed that the GDNF-producing progenitor cells can protect motor neurons in the spinal cord, the researchers also recognized that motor neurons within the brain are also involved in ALS. So, for the current study, the team tested the effects of implanting the GDNF-producing cells into the brains of rats with symptoms mimicking an inherited form of ALS.

The team first confirmed that the cells survived, specialized into the right type of brain cells and released GDNF into the brain. More importantly, they went on to show that the transplanted cells not only protected the motor neurons in the brain but also delayed the onset of the disease and extended the survival of the ALS rats.

These results suggest that future clinical trials should test transplantation of the cells into the brain in addition to the spinal cord. The team will first need to carry out more animal studies to determine the cell doses that would be most safe and effective. As first author Gretchen Thomsen, PhD, mentions in a press release, the eventual benefit to patients could be enormous:

Gretchen-Miller-photo

Gretchen Thomsen

“If we are able in the future to reproduce our research results in humans, we could improve both the quality and length of life for patients diagnosed with this devastating disease.”

 

 

Stem Cell Round: Improving memory, building up “good” fat, nanomedicine

Stem Cell Photo of the Week

roundup03618In honor of brain awareness week, our featured stem cell photo is of the brain! Scientists at the Massachusetts General Hospital and Harvard Stem Cell Institute identified a genetic switch that could potentially improve memory during aging and symptoms of PTSD. Shown in this picture are dentate gyrus cells (DGC) (green) and CA3 interneurons (red) located in the memory-forming area of the brain known as the hippocampus. By reducing the levels of a protein called abLIM3 in the DGCs of older mice, the researchers were able to boost the connections between DGCs and CA3 cells, which resulted in an improvement in the memories of the mice. The team believes that targeting this protein in aging adults could be a potential strategy for improving memory and treating patients with post-traumatic stress disorder (PTSD). You can read more about this study in The Harvard Gazette.

New target for obesity.
Fat cells typically get a bad rap, but there’s actually a type of fat cell that is considered “healthier” than others. Unlike white fat cells that store calories in the form of energy, brown fat cells are packed with mitochondria that burn energy and produce heat. Babies have brown fat, so they can regulate their body temperature to stay warm. Adults also have some brown fat, but as we get older, our stores are slowly depleted.

In the fight against obesity, scientists are looking for ways to increase the amount of brown fat and decrease the amount of white fat in the body. This week, CIRM-funded researchers from the Salk Institute identified a molecule called ERRg that gives brown fat its ability to burn energy. Their findings, published in Cell Reports, offer a new target for obesity and obesity-related diseases like diabetes and fatty liver disease.

The team discovered that brown fat cells produce the ERRg molecule while white fat cells do not. Additionally, mice that couldn’t make the ERRg weren’t able to regulate their body temperature in cold environments. The team concluded in a news release that ERRg is “involved in protection against the cold and underpins brown fat identity.” In future studies, the researchers plan to activate ERRg in white fat cells to see if this will shift their identity to be more similar to brown fat cells.

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Mice that lack ERR aren’t able to regulate their body temperature and are much colder (right) than normal mice (left). (Image credit Salk Institute)

Tale of two nanomedicine stories: making gene therapies more efficient with a bit of caution (Todd Dubnicoff).
This week, the worlds of gene therapy, stem cells and nanomedicine converged for not one, but two published reports in the journal American Chemistry Society NANO.

The first paper described the development of so-called nanospears – tiny splinter-like magnetized structures with a diameter 5000 times smaller than a strand of human hair – that could make gene therapy more efficient and less costly. Gene therapy is an exciting treatment strategy because it tackles genetic diseases at their source by repairing or replacing faulty DNA sequences in cells. In fact, several CIRM-funded clinical trials apply this method in stem cells to treat immune disorders, like severe combined immunodeficiency and sickle cell anemia.

This technique requires getting DNA into diseased cells to make the genetic fix. Current methods have low efficiency and can be very damaging to the cells. The UCLA research team behind the study tested the nanospear-delivery of DNA encoding a gene that causes cells to glow green. They showed that 80 percent of treated cells did indeed glow green, a much higher efficiency than standard methods. And probably due to their miniscule size, the nanospears were gentle with 90 percent of the green glowing cells surviving the procedure.

As Steve Jonas, one of the team leads on the project mentions in a press release, this new method could bode well for future recipients of gene therapies:

“The biggest barrier right now to getting either a gene therapy or an immunotherapy to patients is the processing time. New methods to generate these therapies more quickly, effectively and safely are going to accelerate innovation in this research area and bring these therapies to patients sooner, and that’s the goal we all have.”

While the study above describes an innovative nanomedicine technology, the next paper inserts a note of caution about how experiments in this field should be set up and analyzed. A collaborative team from Brigham and Women’s Hospital, Stanford University, UC Berkeley and McGill University wanted to get to the bottom of why the many advances in nanomedicine had not ultimately led to many new clinical trials. They set out looking for elements within experiments that could affect the uptake of nanoparticles into cells, something that would muck up the interpretation of results.

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imaging of female human amniotic stem cells incubated with nanoparticles demonstrated a significant increase in uptake compared to male cells. (Green dots: nanoparticles; red: cell staining; blue: nuclei) Credit: Morteza Mahmoudi, Brigham and Women’s Hospital.

In this study, they report that the sex of cells has a surprising, noticeable impact on nanoparticle uptake. Nanoparticles were incubated with human amniotic stem cells derived from either males or females. The team showed that the female cells took up the nanoparticles much more readily than the male cells.  Morteza Mahmoudi, PhD, one of the authors on the paper, explained the implications of these results in a press release:

“These differences could have a critical impact on the administration of nanoparticles. If nanoparticles are carrying a drug to deliver [including gene therapies], different uptake could mean different therapeutic efficacy and other important differences, such as safety, in clinical data.”

 

Video illustrates potential path to stem cell repair for multiple sclerosis

“Can you imagine slowly losing the ability to live life as you know it? To slowly lose the ability to see, to walk, to grab an object, all the while experiencing pain, fatigue and depression?”

These sobering questions are posed at the beginning of a recent video produced by Youreka Science and Americans for Cures about multiple sclerosis (MS), a debilitating neurodegenerative disorder in which a person’s own immune system attacks cells that are critical for sending nerve signals from the brain and spinal cord to our limbs and the rest of our body.

In recognition of Multiple Sclerosis Awareness Week, today’s blog features this video. Using an easy to understand narrative and engaging hand-drawn illustrations, this whiteboard “explainer” video does a terrific job of describing the biological basis of multiple sclerosis. It also highlights promising research out of UC Irvine showing that stem cell-based therapies may one day help repair the damage caused by multiple sclerosis.

But don’t take my word for it, check out the five-minute video below:

Related Links:

Stem Cell Roundup: No nerve cells for you, old man; stem cells take out the trash; clues to better tattoo removal

Stem cell image of the week: Do they or don’t they? The debate on new nerve cell growth in adult brain rages on.

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Young neurons (green) are shown in the human hippocampus at the ages of (from left) birth, 13 years old and 35 years old. Images by Arturo Alvarez-Buylla lab

For the longest time, it was simply a given among scientists that once you reach adulthood, your brain’s neuron-making days were over. Then, over the past several decades, evidence emerged that the adult brain can indeed make new neurons, in a process called neurogenesis. Now the pendulum of understanding may be swinging back based on research reported this week out of Arturo Alvarez-Buylla’s lab at UCSF.

Through the careful examination of 59 human brain samples (from post mortem tissue and those collected during epilepsy surgery), Alvarez-Buylla’s team in collaboration with many other labs around the world, found lots of neurogenesis in neonatal and newborn brains. But after 1 year of age, a steep drop in the number of new neurons was observed. Those numbers continued to plummet through childhood and were barely detectable in samples from teens. New neurons were undetectable in adult brain samples.

This week’s stem cell image shows this dramatic decline of new neurons when comparing brain samples from a newborn, a 13 year-old and a 35 year-old.

It was no surprise that these surprising results, published in Nature, got quite a bit of attention by a wide range of news outlets including the LA Times, CNN, The Scientist and NPR to name just a few.

Limitless life of stem cells requires taking out the trash

It’s minding blowing to me that, given the proper nutrients, an embryonic stem cell in a lab dish can exist indefinitely. The legendary fountain of youth that Ponce de León searched in vain for is actually hidden inside these remarkable cells. So how do they do it? It’s a tantalizing question for researchers because the answers could lead to a better understanding of and eventually novel therapies for age-related diseases.

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Cartoon of a proteosome, the cell’s garbage disposal. Image: Wikipedia

A team from the University of Cologne reports this week on a connection between the removal of degraded proteins and the longevity of stem cells. Cells in general use special enzymes to tag wonky proteins for the cellular trash heap, called a proteasome. Without this ability to clean up, unwanted proteins can accumulate and make cells unhealthy, a scenario that is seen in age-related diseases like Alzheimer’s. The research team found that reducing the protein disposal activity in embryonic stem cells disrupted characteristics that are specific to these cells. So, one way stem cells may keep their youthful appearance is by being good about taking out their trash.

The study was published in Scientific Reports and picked up by Science Daily.

Why tattoos stay when your skin cells don’t ( by Kevin McCormack)

We replace our skin cells every two or three weeks. As each layer dies, the stem cells in the skin replace them with a new batch. With that in mind you’d think that a tattoo, which is just ink injected into the skin with a needle, would disappear as each layer of skin is replaced. But obviously it doesn’t. Now some French researchers think they have figured out why.

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Thank your macrophages for keeping your tattoo intact. Tattoo by: Sansanana

It’s not just fun science, published in the Journal of Experimental Medicine, it could also mean that that embarrassing tattoo you got saying you would love Fred or Freda forever, can one day be easily removed.

The researchers found that when the tattoo needle inflicts a wound on the skin, specialized cells called macrophages flock to the site and take up the ink. As those macrophages die, instead of the ink disappearing with them, new macrophages come along, gobble up the ink and so the tattoo lives on.

In an interview with Health News Digest, Bernard Malissen, one of the lead investigators, says the discovery, could help erase a decision made in a moment of madness:

“Tattoo removal can be likely improved by combining laser surgery with the transient ablation of the macrophages present in the tattoo area. As a result, the fragmented pigment particles generated using laser pulses will not be immediately recaptured, a condition increasing the probability of having them drained away via the lymphatic vessels.”

A Tribute to Stem Cells on Valentine’s Day

In case you forgot, today is Valentine’s Day. Whether you love, hate, or could care less about this day, you do have one thing in common with our other readers – you’re a fan of stem cells. (If you’re not, then why are you reading this blog??)

As a tribute to how awesome and important stem cell research is, I offer you a special Valentine’s Day-themed interview with the authors of the CIRM Stem Cellar blog.


What’s your favorite type of stem cell and why? 

Kevin: Embryonic stem cells. Without that one cell none of this work, none of us when you come to think of it, would be possible. Whenever I give talks to the public one of the first things I talk about when explaining what stem cells are and how they work is the cartoon from Piraro, the one featuring the snowmen who look up at snowflakes and say “oh look, stem cells”. For me that captures the power and beauty of these cells. Without them the snowmen/women would not exist. With them all is possible.

Karen: Neural stem cells (NSCs) for the win! First off, they created my brain, so I am truly in their debt. Second, NSCs and I have an intimate relationship. I spent eight years of my life (PhD and postdoc) researching these stem cells in the lab on an epic quest to understand what causes Alzheimer’s and Huntington’s disease. As you can see from the subject matter of my latest blogs (here, here, here), I am pretty stoked to write about NSCs any chance I get.

Microscopic image of a mini brain organoid, showing layered neural tissue and different groups of neural stem cells (in blue, red and magenta) giving rise to neurons (green). Image: Novitch laboratory/UCLA

Todd: Induced pluripotent stem cells (iPSCs) rule! They’re my favorite because they allow researchers to study poorly understood human diseases in a way that just wasn’t possible before iPSCs came on the scene in the late 2000’s. For instance, it’s neither practical nor ethical to study autism by taking cell samples out of the brains of affected children. But with iPSC technology, you can recover cells from an autistic child’s baby teeth after they fall out and grow them into nerve cells in the lab to more directly study the cellular causes of the disorder. I also like the fact that iPSCs are the ultimate in personalized medicine in that you could make a stem cell-based therapy from a person’s own cells.


What do you love most about your job at CIRM?

Kevin: That’s hard to say, it’s like asking which is your favorite child? I love getting to work with the team here at CIRM. It’s such an incredible group of individuals who are fiercely committed to this work, but who are also ridiculously smart and funny. It makes for a great work place and one I enjoy coming into every day.

I also love working with patient advocates. Their courage, compassion and commitment to the work that we do at CIRM is inspirational. If ever I think I am having a bad day I simply have to think about what these extraordinary people go through every day and it puts my day in perspective. They are the reason we do this work. They are the reason this work has value and purpose.

Karen: You know how some people have a hard time choosing what flavor of ice cream to get? I have the same issue with science. I enjoyed my time doing stem cell experiments in the lab but at the same time, I was frustrated that my research and communications was so narrowly focused. I joined CIRM because I love educating patients and the public about all types of stem cell research. I also am a self-professed multitasker and love that my job is to find new ways to connect with different audiences through social media, blogging, and whatever I can think of!

I guess if I really had to choose a favorite, it would be managing the SPARK high school educational program. Each year, I get to work with 60 high school students who spend their summers doing stem cell research in labs across California. They are extremely motivated and it’s easy to see by watching their journeys on instagram how these students will be the next generation of talented stem cell scientists.

Todd: My interests have always zig-zagged between the worlds of science and art. I love that my job allows me to embrace both equally. I could be writing a blog about stem cell-derived mini-intestines one moment, then in the next moment I’m editing video footage from an interview with a patient.

Speaking of patients, they’re the other reason I love my job. As a graduate student I worked in a fruit fly lab so it probably doesn’t surprise you that I had virtually no interactions with patients. But as a member of the science communications team at CIRM, I’ve been fortunate to hear firsthand from the patients and their caregivers who show so much courage in the face of their disease. It makes the work we do here all the more motivating.

CIRM communications team: Todd Dubnicoff, Kevin McCormack, Maria Bonneville, Karen Ring


Please share a poem inspired by your love for stem cell research

 Kevin: I’m from Ireland so obviously I wrote a limerick.

There was a young scientist at CIRM

Whose research made some people squirm

He took lots of cells

Fed them proteins and gels

Until they were grown to full-term

 Karen: I wrote a haiku because that was the only type of poem I received a good grade for in elementary school.

Pluripotency

One stem cell to rule them all

Many paths to choose

Todd: Limerick-shimerick, Kevin. Only true poets haiku!

Shape-shifting stem cell

Hero for those who suffer

Repairing lost hope


One year ago…

New Insights into Adult Neurogenesis

To be a successful scientist, you have to expect the unexpected. No biological process or disease mechanism is ever that simple when you peel off its outer layers. Overtime, results that prove a long-believed theory can be overturned by new results that suggest an alternate theory.

UCSF scientist Arturo Alvarez-Buylla is well versed with the concept of unexpected results. His lab’s research is focused on understanding adult neurogenesis – the process of creating new nerve cells (called neurons) from neural stem cells (NSCs).

For a long time, the field of adult neurogenesis has settled on the theory that brain stem cells divide asymmetrically to create two different types of cells: neurons and neural stem cells. In this way, brain stem cells populate the brain with new neurons and they also self-renew to maintain a constant stem cell supply throughout the adult animal’s life.

New Insights into Adult Neurogenesis

Last week, Alvarez-Buylla and his colleagues published new insights on adult neurogenesis in mice in the journal Cell Stem Cell. The study overturns the original theory of asymmetrical neural stem cell division and suggests that neural stem cells divide in a symmetrical fashion that could eventually deplete their stem cell population over the lifetime of the animal.

Arturo Alvarez-Buylla explained the study’s findings in an email interview with the Stem Cellar:

Arturo Alvarez-Bulla

“Our results are not what we expected. Our work shows that postnatal NSCs are not being constantly renewed by splitting them asymmetrically, with one cell remaining as a stem cell and the other as a differentiated cell. Instead, self-renewal and differentiation are decoupled and achieved by symmetric divisions.”

In brief, the study found that neural stem cells (called B1 cells) divide symmetrically in an area of the adult mouse brain called the ventricular-subventricular zone (V-SVZ). Between 70%-80% of those symmetric divisions produced neurons while only 20%-30% created new B1 stem cells. Alvarez-Buylla said that this process would result in the gradual depletion of B1 stem cells over time and seems to be carefully choreographed for the length of the lifespan of a mouse.

What does this mean?

I asked Alvarez-Buylla how his findings in mice will impact the field and whether he expects human adult neurogenesis to follow a similar process. He explained,

“The implications are quite wide, as it changes the way we think about neural stem cell retention and aging. The cells do not seem open ended with unlimited potential to be renewed, which results in a progressive decrease in NSC number and neurogenesis with time.  Understanding the mechanisms regulating proliferation of NSCs and their self-renewal also provides new insights into how the whole process of neurogenesis is choreographed over long periods by suggesting that differentiation (generation of neurons) is regulated separately from renewal.”

He further explained that mice generate new neurons in the V-SVZ brain region throughout their lifetime while humans only appear to generate new neurons during infancy in the equivalent region of the human brain called the SVZ. In humans, he said, it remains unclear where and how many neural stem cells are retained after birth.

I also asked him how these findings will impact the development of neural stem cell-based therapies for neurological or neurodegenerative diseases. Alvarez-Buylla shared interesting insights:

“Our data also indicate that upon a self-renewing division, sibling NSCs may not be equal to each other. While one NSC might stay quiescent [non-dividing] for an extended period of time, its sister cell might become activated earlier on and either undergo another round of self-renewal or differentiate. Thus, for cell-replacement therapies it will be important to understand which kind of neuron the NSC of interest can produce, and when. The use of NSCs for brain repair requires a detailed understanding of which NSC subset will be utilized for treatment and how to induce them to produce progeny. The study also suggests that factors that control NSC renewal may be separate from those that control generation of neurons.”

Scientists developing adult NSC-based therapies will definitely need to take note of Alvarez-Buylla’s findings as some NSC populations might be more successful therapeutically than others.

Neural Stem Cells in the Wild

I’ll conclude with a beautiful image that the study’s first author, Kirsten Obernier, shared with me. It’s shows the V-SVZ of the mouse brain and a neural stem cell in red making contact with a blood vessel in green and neurons in blue.

Image of the mouse brain with a neural stem cell in red. (Credit: Kirsten Obernier, UCSF)

Kirsten described the complex morphology of B1 NSCs in the mouse brain and their dynamic behavior, which Kirsten observed by taking a time lapsed video of NSCs dividing in the mouse V-SVZ. Obernier and Alvarez-Buylla hypothesize that these NSCs could be receiving signals from their surrounding environment that tell them whether to make neurons or to self-renew.

Clearly, further research is necessary to peel back the complex layers of adult neurogenesis. If NSC differentiation is regulated separately from self-renewal, their insights could shed new light on how conditions of unregulated self-renewal like brain tumors develop.

Stem Cell Roundup: Rainbow Sherbet Fruit Fly Brains, a CRISPR/iPSC Mash-up and more

This week’s Round Up is all about the brain with some CRISPR and iPSCs sprinkled in:

Our Cool Stem Cell Image of the Week comes from Columbia University’s Zuckerman Institute:

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(Credit: Jon Enriquez/Mann Lab/Columbia’s Zuckerman Institute).

This rainbow sherbet-colored scientific art is a microscopy image of a fruit fly nervous system in which brain cells were randomly labeled with different colors. It was a figure in a Neuron study published this week showing how cells derived from the same stem cells can go down very different developmental paths but then later are “reunited” to carry out key functions, such as in this case, the nervous system control of leg movements.


A new therapeutic avenue for Parkinson’s diseaseBuck Institute

Many animal models of Parkinson’s disease are created by mutating specific genes to cause symptoms that mimic this incurable, neurodegenerative disorder. But, by far, most cases of Parkinson’s are idiopathic, a fancy term for spontaneous with no known genetic cause. So, researchers at the Buck Institute took another approach: they generated a mouse model of Parkinson’s disease using the pesticide, paraquat, exposure to which is known to increase the risk of the idiopathic form of Parkinson’s.

Their CIRM-funded study in Cell Reports showed that exposure to paraquat leads to cell senescence – in which cells shut down and stop dividing – particularly in astrocytes, brain cells that support the function of nerve cells. Ridding the mice of these astrocytes relieved some of the Parkinson’s like symptoms. What makes these results so intriguing is the team’s analysis of post-mortem brains from Parkinson’s patients also showed the hallmarks of increased senescence in astrocytes. Perhaps, therapeutic approaches that can remove senescent cells may yield novel Parkinson’s treatments.


Discovery may advance neural stem cell treatments for brain disordersSanford-Burnham Prebys Medical Discovery Institute (via Eureka Alert)

Another CIRM-funded study published this week in Nature Neuroscience may also help pave the way to new treatment strategies for neurologic disorders like Parkinson’s disease. A team at Sanford Burnham Prebys Medical Discovery Institute (SBP) discovered a novel gene regulation system that brain stem cells use to maintain their ability to self-renew.

The study centers around messenger RNA, a molecular courier that transcribes a gene’s DNA code and carries it off to be translated into a protein. The team found that the removal of a chemical tag on mRNA inside mouse brain stem cells caused them to lose their stem cell properties. Instead, too many cells specialized into mature brain cells leading to abnormal brain development in animal studies. Team lead Jing Crystal Zhao, explained how this finding is important for future therapeutic development:

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Crystal Zhao

“As NSCs are increasingly explored as a cell replacement therapy for neurological disorders, understanding the basic biology of NSCs–including how they self-renew–is essential to harnessing control of their in vivo functions in the brain.”


Researchers Create First Stem Cells Using CRISPR Genome ActivationThe Gladstone Institutes

Our regular readers are most likely familiar with both CRISPR gene editing and induced pluripotent stem cell (iPSC) technologies. But, in case you missed it late last week, a Cell Stem Cell study out of Sheng Ding’s lab at the Gladstone Institutes, for the first time, combined the two by using CRISPR to make iPSCs. The study got a lot of attention including a review by Paul Knoepfler in his blog The Niche. Check it out for more details!

 

Stem cell stories that caught our eye: the tale of a tail that grows back and Zika’s devious Trojan Horse

The tale of a tail that grows back (Kevin McCormack)

Ask people what they know about geckos and the odds are they’ll tell you geckos have English accents and sell car insurance. Which tells you a lot more about the power of advertising than it does about the level of knowledge about lizards. Which is a shame, because the gecko has some amazing qualities, not the least of which is its ability to re-grow its tail. Now some researchers have discovered how it regenerates its tail, and what they’ve learned could one day help people with spinal cord injuries.

Geckos often detach a bit of their tail when being pursued by a predator, then grow a new one over the course of 30 days. Researchers at the University of Guelph in Canada found that the lizards use a combination of stem cells and proteins to do that.

They found that geckos have stem cells in their tail called radial glias. Normally these cells are dormant but that changes when the lizard loses its tail. As Matthew Vickaryous, lead author of the study, said in a news release:

“But when the tail comes off everything temporarily changes. The cells make different proteins and begin proliferating more in response to the injury. Ultimately, they make a brand new spinal cord. Once the injury is healed and the spinal cord is restored, the cells return to a resting state.”

Vickaryous hopes that understanding how the gecko can repair what is essentially an injury to its spinal cord, we’ll be better able to develop ways to help people with the same kind of injury.

The study is published in the Journal of Comparative Neurology.

Zika virus uses Trojan Horse strategy to infect developing brain
In April 2015, the World Health Organization declared that infection by Zika virus and its connection to severe birth defects was an international public health emergency. The main concern has been the virus’ link to microcephaly, a condition in which abnormal brain development causes a smaller than normal head size at birth. Microcephaly leads to number of problems in these infants including developmental delays, seizures, hearing loss and difficulty swallowing.

A false color micrograph shows microglia cells (green) infected by the Zika virus (blue). Image Muotri lab/UCSD

Since that time, researchers have been racing to better understand how Zika infection affects brain development with the hope of finding treatment strategies. Now, a CIRM-funded study in Human Molecular Genetics reports important new insights about how Zika virus may be transmitted from infected pregnant women to their unborn babies.

The UCSD researchers behind the study chose to focus on microglia cells. In a press release, team leader Alysson Muotri explained their rationale for targeting these cells:

“During embryogenesis — the early stages of prenatal development — cells called microglia form in the yolk sac and then disperse throughout the central nervous system (CNS) of the developing child. Considering the timing of [Zika] transmission, we hypothesized that microglia might be serving as a Trojan horse to transport the virus during invasion of the CNS.”

In the developing brain, microglia continually travel throughout the brain and clear away dead or infected cells. Smuggling itself aboard microglia would give Zika a devious way to slip through the body’s defenses and infect other brain cells. And that’s exactly what Dr. Muotri’s team found.

Using human induced pluripotent stem cells (iPSCs), they generated brain stem cells – the kind found in the developing brain – and in lab dish infected them with Zika virus. When iPSC-derived microglia were added to the infected neural stem cells, the microglia gobbled them up and destroyed them, just as they would do in the brain. But when those microglia were placed next to uninfected brain stem cells, the Zika virus was easily transmitted to those cells. Muotri summed up the results this way:

“Our findings show that the Zika virus can infect these early microglia, sneaking into the brain where they transmit the virus to other brain cells, resulting in the devastating neurological damage we see in some newborns.”

The team went on to show that an FDA-approved drug to treat hepatitis – a liver disease often caused by viral infection – was effective at decreasing the infection of brain stem cells by Zika-carrying microglia. Since these studies were done in petri dishes, more research will be required to confirm that the microglia are a true drug target for stopping the devastating impact of Zika on newborns.

Caught our eye: new Americans 4 Cures video, better mini-brains reveal Zika insights and iPSC recipes go head-to-head

How stem cell research gives patients hope (Karen Ring).
You can learn about the latest stem cell research for a given disease in seconds with a quick google search. You’ll find countless publications, news releases and blogs detailing the latest advancements that are bringing scientists and clinicians closer to understanding why diseases happen and how to treat or cure them.

But one thing these forms of communications lack is the personal aspect. A typical science article explains the research behind the study at the beginning and ends with a concluding statement usually saying how the research could one day lead to a treatment for X disease. It’s interesting, but not always the most inspirational way to learn about science when the formula doesn’t change.

However, I’ve started to notice that more and more, institutes and organizations are creating videos that feature the scientists/doctors that are developing these treatments AND the patients that the treatments could one day help. This is an excellent way to communicate with the public! When you watch and listen to a patient talk about their struggles with their disease and how there aren’t effective treatments at the moment, it becomes clear why funding and advancing research is important.

We have a great example of a patient-focused stem cell video to share with you today thanks to our friends at Americans for Cures, a non-profit organization that advocates for stem cell research. They posted a new video this week in honor of Stem Cell Awareness Day featuring patients and patient advocates responding to the question, “What does stem cell research give you hope for?”. Many of these patients and advocates are CIRM Stem Cell Champions that we’ve featured on our website, blog, and YouTube channel.

Americans for Cures is encouraging viewers to take their own stab at answering this important question by sharing a short message (on their website) or recording a video that they will share with the stem cell community. We hope that you are up for the challenge!

Mini-brains help uncover some of Zika’s secrets (Kevin McCormack).
One of the hardest things about trying to understand how a virus like Zika can damage the brain is that it’s hard to see what’s going on inside a living brain. That’s not surprising. It’s not considered polite to do an autopsy of someone’s brain while they are still using it.

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Microscopic image of a mini brain organoid, showing layered neural tissue and different groups of neural stem cells (in blue, red and magenta) giving rise to neurons (green). Image: Novitch laboratory/UCLA

But now researchers at UCLA have come up with a way to mimic human brains, and that is enabling them to better understand how Zika inflicts damage on a developing fetus.

For years researchers have been using stem cells to help create “mini brain organoids”, essentially clusters of some of the cells found in the brain. They were helpful in studying some aspects of brain behavior but limited because they were very small and didn’t reflect the layered complexity of the brain.

In a study, published in the journal Cell Reports, UCLA researchers showed how they developed a new method of creating mini-brain organoids that better reflected a real brain. For example, the organoids had many of the cells found in the human cortex, the part of the brain that controls thought, speech and decision making. They also found that the different cells could communicate with each other, the way they do in a real brain.

They used these organoids to see how the Zika virus attacks the brain, damaging cells during the earliest stages of brain development.

In a news release, Momoko Watanabe, the study’s first author, says these new organoids can open up a whole new way of looking at the brain:

“While our organoids are in no way close to being fully functional human brains, they mimic the human brain structure much more consistently than other models. Other scientists can use our methods to improve brain research because the data will be more accurate and consistent from experiment to experiment and more comparable to the real human brain.”

iPSC recipes go head-to-head: which one is best?
In the ten years since the induced pluripotent stem cell (iPSC) technique was first reported, many different protocols, or recipes, for reprogramming adult cells, like skin, into iPSCs have been developed. These variations bring up the question of which reprogramming recipe is best. This question isn’t the easiest to answer given the many variables that one needs to test. Due to the cost and complexity of the methods, comparisons of iPSCs generated in different labs are often performed. But one analysis found significant lab-to-lab variability which can really muck up the ability to make a fair comparison.

A Stanford University research team, led by Dr. Joseph Wu, sought to eliminate these confounding variables so that any differences found could be attributed specifically to the recipe. So, they tested six different reprogramming methods in the same lab, using cells from the same female donor. And in turn, these cells were compared to a female source of embryonic stem cells, the gold standard of pluripotent stem cells. They reported their findings this week in Nature Biomedical Engineering.

Previous studies had hinted that the reprogramming protocol could affect the ability to fully specialize iPSCs into a particular cell type. But based on their comparisons, the protocol chosen did not have a significant impact on how well iPSCs can be matured. Differences in gene activity are a key way that researchers do side-by-side comparisons of iPSCs and embryonic stem cells. And based on the results in this study, the reprogramming method itself can influence the differences. A gene activity comparison of all the iPSCs with the embryonic stem cells found the polycomb repressive complex – a set of genes that play an important role in embryonic development and are implicated in cancer – had the biggest difference.

In a “Behind the Paper” report to the journal, first author Jared Churko, says that based on these findings, their lab now mostly uses one reprogramming protocol – which uses the Sendai virus to deliver the reprogramming genes to the cells:

“The majority of our hiPSC lines are now generated using Sendai virus. This is due to the ease in generating hiPSCs using this method as well as the little to no chance of transgene integration [a case in which a reprogramming gene inserts into the cells’ DNA which could lead to cancerous growth].”

Still, he adds a caveat that the virus does tend to linger in the cells which suggests that:

“cell source or reprogramming method utilized, each hiPSC line still requires robust characterization prior to them being used for downstream experimentation or clinical use.”