“Brains” in a dish that can create electrical impulses

Brain organoids in a petri dish: photo courtesy UCSD

For several years, researchers have been able to take stem cells and use them to make three dimensional structures called organoids. These are a kind of mini organ that scientists can then use to study what happens in the real thing. For example, creating kidney organoids to see how kidney disease develops in patients.

Scientists can do the same with brain cells, creating clumps of cells that become a kind of miniature version of parts of the brain. These organoids can’t do any of the complex things our brains do – such as thinking – but they do serve as useful physical models for us to use in trying to develop a deeper understanding of the brain.

Now Alysson Muotri and his team at UC San Diego – in a study supported by two grants from CIRM – have taken the science one step further, developing brain organoids that allow us to measure the level of electrical activity they generate, and then compare it to the electrical activity seen in the developing brain of a fetus. That last sentence might cause some people to say “What?”, but this is actually really cool science that could help us gain a deeper understanding of how brains develop and come up with new ways to treat problems in the brain caused by faulty circuitry, such as autism or schizophrenia.

The team developed new, more effective methods of growing clusters of the different kinds of cells found in the brain. They then placed them on a multi-electrode array, a kind of muffin tray that could measure electrical impulses. As they fed the cells and increased the number of cells in the trays they were able to measure changes in the electrical impulses they gave off. The cells went from producing 3,000 spikes a minute to 300,000 spikes a minute. This is the first time this level of activity has been achieved in a cell-based laboratory model. But that’s not all.

When they further analyzed the activity of the organoids, they found there were some similarities to the activity seen in the brains of premature babies. For instance, both produced short bursts of activity, followed by a period of inactivity.

Alysson Muotri

In a news release Muotri says they were surprised by the finding:

“We couldn’t believe it at first — we thought our electrodes were malfunctioning. Because the data were so striking, I think many people were kind of skeptical about it, and understandably so.”

Muotri knows that this research – published in the journal Cell Stem Cell – raises ethical issues and he is quick to say that these organoids are nothing like a baby’s brain, that they differ in several critical ways. The organoids are tiny, not just in size but also in the numbers of cells involved. They also don’t have blood vessels to keep them alive or help them grow and they don’t have any ability to think.

“They are far from being functionally equivalent to a full cortex, even in a baby. In fact, we don’t yet have a way to even measure consciousness or sentience.”

What these organoids do have is the ability to help us look at the structure and activity of the brain in ways we never could before. In the past researchers depended on mice or other animals to test new ideas or therapies for human diseases or disorders. Because our brains are so different than animal brains those approaches have had limited results. Just think about how many treatments for Alzheimer’s looked promising in animal models but failed completely in people.

These new organoids allow us to explore how new therapies might work in the human brain, and hopefully increase our ability to develop more effective treatments for conditions as varied as epilepsy and autism.

Stanford study successful in transplant of mismatched stem cells, tissue in mice

Dr. Irv Weissman at Stanford University

A transplant can be a lifesaving procedure for many people across the United States. In fact, according to the Health Resources & Services Administration, 36,528 transplants were performed in 2018. However, as of January 2019, the number of men, women, and children on the national transplant waiting list is over 113,000, with 20 people dying each day waiting for a transplant and a new person being added to the list every 10 minutes.

Before considering a transplant, there needs to be an immunological match between the donated tissue and/or blood stem cells and the recipient. To put it simply, a “match” indicates that the donor’s cells will not be marked by the recipient’s immune cells as foreign and begin to attack it, a process known as graft-versus-host disease. Unfortunately, these matches can be challenging to find, particularly for some ethnic minorities. Often times, immunosuppression drugs are also needed in order to prevent the foreign cells from being attacked by the body’s immune system. Additionally, chemotherapy and radiation are often needed as well.

Fortunately, a CIRM-funded study at Stanford has shown some promising results towards addressing the issue of matching donor cells and recipient. Dr. Irv Weissman and his colleagues at Stanford have found a way to prepare mice for a transplant of blood stem cells, even when donor and recipient are an immunological mismatch. Their method involved using a combination of six specific antibodies and does not require ongoing immunosuppression.

The combination of antibodies did this by eliminating several types of immune cells in the animals’ bone marrow, which allowed blood stem cells to engraft and begin producing blood and immune cells without the need for continued immunosuppression. The blood stem cells used were haploidentical, which, to put it simply, is what naturally occurs between parent and child, or between about half of all siblings. 

Additional experiments also showed that the mice treated with the six antibodies could also accept completely mismatched purified blood stem cells, such as those that might be obtained from an embryonic stem cell line. 

The results established in this mouse model could one day lay the foundation necessary to utilize this approach in humans after conducting clinical trials. The idea would be that a patient that needs a transplanted organ could first undergo a safe, gentle transplant with blood stem cells derived in the laboratory from embryonic stem cells. The same embryonic stem cells could also then be used to generate an organ that would be fully accepted by the recipient without requiring the need for long-term treatment with drugs to suppress the immune system. 

In a news release, Dr. Weissman is quoted as saying,

“With support by the California Institute for Regenerative Medicine, we’ve been able to make important advances in human embryonic stem cell research. In the past, these stem cell transplants have required a complete match to avoid rejection and reduce the chance of graft-versus-host disease. But in a family with four siblings the odds of having a sibling who matches the patient this closely are only one in four. Now we’ve shown in mice that a ‘half match,’ which occurs between parents and children or in two of every four siblings, works without the need for radiation, chemotherapy or ongoing immunosuppression. This may open up the possibility of transplant for nearly everyone who needs it. Additionally, the immune tolerance we’re able to induce should in the future allow the co-transplantation of [blood] stem cells and tissues, such as insulin-producing cells or even organs generated from the same embryonic stem cell line.”

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

Blood-brain barrier chip created with stem cells expands potential for personalized medicine

An Organ-Chip used in the study to create a blood-brain barrier (BBB).

The brain is a complex part of the human body that allows for the formation of thoughts and consciousness. In many ways it is the essence of who we are as individuals. Because of its importance, our bodies have developed various layers of protection around this vital organ, one of which is called the blood-brain barrier (BBB).

The BBB is a thin border of various cell types around the brain that regulate what can enter the brain tissue through the bloodstream. Its primary purpose is to prevent toxins and other unwanted substances from entering the brain and damaging it. Unfortunately this barrier can also prevent helpful medications, designed to fix problems, from reaching the brain.

Several brain disorders, such as Amyotrophic Lateral Sclerosis (ALS – also known as Lou Gehrig’s disease), Parkinson’s Disease (PD), and Huntington’s Disease (HD) have been linked to defective BBBs that keep out critical biomolecules needed for healthy brain activity.

In a CIRM-funded study, a team at Cedars-Sinai Medical Center created a BBB through the use of stem cells and an Organ-Chip made from induced pluripotent stem cells (iPSCs). These are a specific type of stem cells that can turn into any type of cell in the body and can be generated from a person’s own cells. In this study, iPSCs were created from adult blood samples and used to make the neurons and other supporting cells that make up the BBB. These cells were then placed inside an Organ-Chip which recreates the environment that cells normally experience within the human body.

Inside the 3-D Organ-Chip, the cells were able to form a BBB that functions as it does in the body, with the ability to block entry of certain drugs. Most notably, when the BBB was generated from cell samples of patients with HD, the BBB malfunctioned in the same way that it does in patients with the disease.

These findings expand the potential for personalized medicine for various brain disorders linked to problems in the BBB. In a press release, Dr. Clive Svendsen, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute and senior author of the study, was quoted as saying,

“The study’s findings open a promising pathway for precision medicine. The possibility of using a patient-specific, multicellular model of a blood barrier on a chip represents a new standard for developing predictive, personalized medicine.”

The full results of the study were published in the scientific journal Cell Stem Cell.

Of Mice and Men, and Women Too; Stem cell stories you might have missed

Mice brains can teach us a lot

Last week’s news headlines were dominated by one big story, the use of a stem cell transplant to effectively cure a person of HIV. But there were other stories that, while not quite as striking, did also highlight how the field is advancing.

A new way to boost brain cells (in mice!)

It’s hard to fix something if you don’t really know what’s wrong in the first place. It would be like trying to determine why a car is not working just by looking at the hood and not looking inside at the engine. The human brain is far more complex than a car so trying to determine what’s going wrong is infinitely more challenging. But a new study could help give us a new option.

Researchers in Luxembourg and Germany have developed a new computer model for what’s happening inside the brain, identifying what cells are not operating properly, and fixing them.

Antonio del Sol, one of the lead authors of the study – published in the journal Cell – says their new model allows them to identify which stem cells are active and ready to divide, or dormant. 

“Our results constitute an important step towards the implementation of stem cell-based therapies, for instance for neurodegenerative diseases. We were able to show that, with computational models, it is possible to identify the essential features that are characteristic of a specific state of stem cells.”

The work, done in mice, identified a protein that helped keep brain stem cells inactive in older animals. By blocking this protein they were able to help “wake up” those stem cells so they could divide and proliferate and help regenerate the aging brain.

And if it works in mice it must work in people right? Well, that’s what they hope to see next.

Deeper understanding of fetal development

According to the Mayo Clinic between 10 and 20 percent of known pregnancies end in miscarriage (though they admit the real number may be even higher) and our lack of understanding of fetal development makes it hard to understand why. A new study reveals a previously unknown step in this development that could help provide some answers and, hopefully, lead to ways to prevent miscarriages.

Researchers at the Karolinska Institute in Sweden used genetic sequencing to follow the development stages of mice embryos. By sorting those different sequences into a kind of blueprint for what’s happening at every stage of development they were able to identify a previously unknown phase. It’s the time between when the embryo attaches to the uterus and when it begins to turn these embryonic stem cells into identifiable parts of the body.

Qiaolin Deng, Karolinska Institute

Lead researcher Qiaolin Deng says this finding provides vital new evidence.

“Being able to follow the differentiation process of every cell is the Holy Grail of developmental biology. Knowledge of the events and factors that govern the development of the early embryo is indispensable for understanding miscarriages and congenital disease. Around three in every 100 babies are born with fetal malformation caused by faulty cellular differentiation.”

The study is published in the journal Cell Reports.

Could a new drug discovery reduce damage from a heart attack?

Every 40 seconds someone in the US has a heart attack. For many it is fatal but even for those who survive it can lead to long-term damage to the heart that ultimately leads to heart failure. Now British researchers think they may have found a way to reduce that likelihood.

Using stem cells to create human heart muscle tissue in the lab, they identified a protein that is activated after a heart attack or when exposed to stress chemicals. They then identified a drug that can block that protein and, when tested in mice that had experienced a heart attack, they found it could reduce damage to the heart muscle by around 60 percent.

Prof Michael Schneider, the lead researcher on the study, published in Cell Stem Cell, said this could be a game changer.

“There are no existing therapies that directly address the problem of muscle cell death and this would be a revolution in the treatment of heart attacks. One reason why many heart drugs have failed in clinical trials may be that they have not been tested in human cells before the clinic. Using both human cells and animals allows us to be more confident about the molecules we take forward.”

Media shine a spotlight on dodgy stem cell clinics

A doctor collects fat from a patient’’s back as part of an experimental stem cell procedure in Beverly Hills, Calif. on Dec. 5, 2014. (Raquel Maria Dillon / Associated Press)

For several years now, we have been trying to raise awareness about the risks posed by clinics offering unproven or unapproved stem cell therapies. At times it felt as if we were yelling into the wind, that few people were listening. But that’s slowly changing. A growing number of TV stations and newspapers are picking up the message and warning their readers and viewers. It’s a warning that is getting national exposure.

Why are we concerned about these clinics? Well, they claim their therapies, which usually involve the patient’s own fat or blood cells, can cure everything from arthritis to Alzheimer’s. However, they offer no scientific proof, have no studies to back up their claims and charge patients thousands, sometimes tens of thousands of dollars.

In the LA Times, for example, reporter Usha Lee McFarling, wrote an article headline “California has gone crazy for sketchy stem cell treatments”. In it she writes about the claims made by these clinics and the dangers they pose:

“If it sounds too good to be true, it is. There is no good scientific evidence the pricey treatments work, and there is growing evidence that some are dangerous, causing blindness, tumors and paralysis. Medical associations, the federal government and even Consumer Reports have all issued stern warnings to patients about the clinics.”

In Denver, the ABC TV station recently did an in-depth interview with a local doctor who is trying to get Colorado state legislators to take legal action against stem cell clinics making these kinds of unsupported claims.

Chris Centeno of the Centeno-Schultz Clinic, who’s specialized in regenerative medicine and research for more than a decade, said too many people are simply being scammed.

“It’s really out of control,” he told the station.

ABC7 did a series of reports last year on the problem and that may be prompting this push for a law warning consumers about the dangers posed by these unregulated treatments which are advertised heavily online, on TV and in print.

In California there is already one law on the books attempting to warn consumers about these clinics. CIRM worked with State Senator Ed Hernandez to get that passed (you can read about that here) and we are continuing to support even stronger measures.

And the NBC TV station in San Diego recently reported on the rise of stem cell clinics around the US, a story that was picked up by the networks and run on the NBC Today Show.

One of the critical elements in helping raise awareness about the issue has been the work done by Paul Knoepfler and Leigh Turner in identifying how many of these clinics there are around the US. Their report, published in the journal Cell Stem Cell, was the first to show how big the problem is. It attracted national attention and triggered many of the reports that followed.

It is clear momentum is building and we hope to build on that even further. Obviously, the best solution would be to have the Food and Drug Administration (FDA) crack down on these clinics, and in some cases they have. But the FDA lacks the manpower to tackle all of them.

That’s where the role of the media is so important. By doing stories like these and raising awareness about the risks these clinics pose they can hopefully help many patients avoid treatments that will do little except make a dent in their pocket.

Sequencing data helps us understand the genes involved in heart cell development

skin cells to beating heart

Human heart cells generated in the laboratory. Image courtesy of Nathan Palapant at the University of Queensland

Heart disease is the leading cause of death for both men and women in the United States and is estimated to be responsible for 31% of all deaths globally. This disease encompasses a wide variety of conditions that all effect how well your heart is able to pump blood to the rest of your body. One of the reasons that heart disease is so devastating is because, unlike many other organs in our bodies, heart tissue is not able to repair itself once it is damaged. Now scientists at the Institute for Molecular Bioscience at the University of Queensland and the Garvan Institute for Medical Research in Australia have conducted a tour de force study to exquisitely understand the genes involved in heart development.

The findings of the study are published in the journal Cell Stem Cell. in a press release, Dr. Nathan Palapant, one of the the lead authors, says this type of research could pay dividends for heart disease treatment because:

“We think the answers to heart repair almost certainly lie in understanding heart development. If we can get to grips with the complex choreography of how the heart builds itself in the first place, we’re well placed to find new approaches to helping it rebuild after damage.”

To determine which genes are involved in heart cell development, the investigators use a method called single cell RNA sequencing. This technique allowed them to measure how 17,000 genes (almost every gene that is active in the heart) were being turned on and off during various stages of heart cell development in 40,000 human pluripotent stem cells (stem cells that are capable of becoming any other cell type) experimentally induced to turn into heart cells.  This data set, the first of its kind, is a critical new resource for all scientists studying heart development and disease.

Interestingly, this study also addressed a commonly present, but rarely discussed issue with scientific studies: how applicable are results generated in vitro (in the lab) rather than the body, in the context of human health and disease? It is well known that heart cells generated in the lab do not have the exact same characteristics as mature heart cells found in our bodies, but the extent and precise nature of those discrepancies is not well understood. These scientists find that a gene called HOPX, which is one of earliest markers of heart cell development, is not always expressed when it should be during in vitro cardiac cell development, which, in turn, affects expression of other genes that are downstream of HOPX later on in development. Therefore, these scientists suggest that mis-expression of HOPX  might be one reason why in vitro heart cells express different genes and are distinct from heart cells in humans.

The scientists also learned that HOPX is responsible for controlling whether the developing heart cell moves past the “immature” dividing phase to the mature phase where cells grow bigger, but do not divide. This finding shows that this data set is powerful both for determining differences between laboratory grown cells versus mature human cells, but also provides critical biological information about heart cell development.

Joseph Powell, another lead author of this research, further explains how this work contributes to the important fundamentals of heart cell development:

“Each cell goes through its own series of complex, nuanced changes. They are all different, and changes in one cell affect the activity of other cells. By tracking those changes across the different stages of development, we can learn a huge amount about how different sub-types of heart cells are controlled, and how they work together to build the heart.”

Support cells have different roles in blood stem cell maintenance before and after stress

How-Stem-Cells-Act-When-Stressed-Versus-When-At-Rest

Expression of pleiotrophin (green) in bone marrow blood vessels (red) and stromal cells (white) in normal mice (left), and in mice 24 hours after irradiation (right). UCLA Broad Stem Cell Research Center/Cell Stem Cell

A new study published in the journal Cell Stem Cell, reveals how different types of cells in the bone marrow are responsible for supporting blood stem cell maintenance before and after injury.

It was already well known in the field that two different cell types, namely endothelial cells (which line blood vessels) and stromal cells (which make up connective tissue, or tissue that provides structural support for any organ), are responsible for maintaining the population of blood stem cells in the bone marrow. However, how these cells and the molecules they secrete impact blood stem cell development and maintenance is not well understood.

Hematopoietic stem cells are responsible for generating the multiple different types of cells found in blood, from our oxygen carrying red blood cells to the many different types of white blood cells that make up our immune system.

Dr. John Chute’s group at UCLA had previously discovered that a molecule called pleiotrophin, or PTN, is important for promoting self-renewal of the blood stem cell population. They did not, however, understand which cells secrete this molecule and when.

To answer this question, the scientists developed mouse models that did not produce PTN in different types of bone marrow cells, such as endothelial cells and stromal cells. Surprisingly, they saw that the inability of stromal cells to produce PTN decreased the blood stem cell population, but deletion of PTN in endothelial cells did not affect the blood stem cell niche.

Even more interestingly, the researchers found that in animals that were subjected to an environmental stressor, in this case, radiation, the result was reversed: endothelial cell PTN was necessary for blood stem cell renewal, whereas stromal cell PTN was not. While an important part of the knowledge base for blood stem cell biology, the reason for this switch in PTN secretion at times of homeostasis and disease is still unknown.

As Dr. Chute states in a press release, this result could have important implications for cancer treatments such as radiation:

“It may be possible to administer modified, recombinant versions of pleiotrophin to patients to accelerate blood cell regeneration. This strategy also may apply to patients undergoing bone marrow transplants.”

Another important consideration to take away from this work is that animal models developed in the laboratory should take into account the possibility that blood stem cell maintenance and regeneration is distinctly controlled under healthy and disease state. In other words, cellular function in one state is not always indicative of its role in another state.

This work was partially funded by a CIRM Leadership Award.

 

 

Stem Cell Roundup: Backup cells to repair damaged lungs; your unique bowels; and California Cures, 71 ways CIRM is changing the face of medicine

It’s good to have a backup plan

3D illustration of Lungs, medical concept.

Our lungs are amazing things. They take in the air we breathe and move it into our blood so that oxygen can be carried to every part of our body. They’re also surprisingly large. If you were to spread out a lung – and I have no idea why you would want to do that – it would be almost as large as a tennis court.

But lungs are also quite vulnerable organs, relying on a thin layer of epithelial cells to protect them from harmful materials in the air. If those materials damage the lungs our body calls in local stem cells to repair the injury.

Now researchers at the University of Iowa have identified a new group of stem cells, called glandular myoepithelial cells (MECs), that also appear to play an important role in repairing injuries in the lungs.

These MECs seem to be a kind of “reserve” stem cell, waiting around until they are needed and then able to spring into action and develop into new replacement cells in the lungs.

In a news release study author Preston Anderson, said these cells could help develop new approaches to lung regeneration:

“We demonstrated that MECs can self-renew and differentiate into seven distinct cell types in the airway. No other cell type in the lung has been identified with this much stem cell plasticity.”

The study is published in Cell Stem Cell.

Your bowels are unique

About_Bowel_Cancer_What-is-Bowel-Cancer_370newfinal

Not to worry, that’s a plastic model of  a bowel

If you are eating as you read this, you should either put your food down or skip this item for now. A new study on bowel cancer says that every tumor is unique and every cell within that tumor is also genetically unique.

Researchers in the UK and Netherlands took samples of normal bowel tissue and cancerous bowel tissue from three people with colorectal cancer. They then grew these in the labs and turned them into mini 3D organoids, so they could study them in greater detail.

In the study, published in the journal Nature, the researchers say they found that tumor cells, not surprisingly, had many more mutations than normal cells, and that not only was each bowel cancer genetically different from each other, but that each cell they studied within that cancer was also different.

In a news release, Prof Sir Mike Stratton, joint corresponding author on the paper from the Wellcome Sanger Institute, said:

“This study gives us fundamental knowledge on the way cancers arise. By studying the patterns of mutations from individual healthy and tumour cells, we can learn what mutational processes have occurred, and then look to see what has caused them. Extending our knowledge on the origin of these processes could help us discover new risk factors to reduce the incidence of cancer and could also put us in a better position to create drugs to target cancer-specific mutational processes directly.”

California Cures: a great title for a great book about CIRM

reed, thomas cirm photo (2)

CIRM Board Chair Jonathan Thomas (L) and Don Reed

One of the first people I met when I started working at CIRM was Don Reed. He impressed me then with his indefatigable enthusiasm, energy and positive outlook on life. Six years later he is still impressing me.

Don has just completed his second book on stem cell research charting the work of CIRM. It’s called “California Cures: How the California Stem Cell Research Program is Fighting Your Incurable Disease”. It’s a terrific read combining stories about stem cell research with true tales about Al Jolson, Enrico Caruso and how a dolphin named Ernestine burst Don’s ear drum.

On his website, Stem Cell Battles, Don describes CIRM as a “scrappy little stage agency” – I love that – and says:

“No one can predict the pace of science, nor say when cures will come; but California is bringing the fight. Above all, “California Cures” is a call for action. Washington may argue about the expense of health care (and who will get it), but California works to bring down the mountain of medical debt: stem cell therapies to ease suffering and save lives. We have the momentum. We dare not stop short. Chronic disease threatens everyone — we are fighting for your family, and mine!”

 

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 stories that caught our eye: How Zika may impact adult brains; Move over CRISPR there’s a new kid in town; How our bodies store fat

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

zika

Zika mosquito

Zika virus could impact adult brains

It’s not just a baby’s developing brain that is vulnerable to the Zika virus, adult brains may be too. A new study shows that some stem cells that help repair damage in the adult brain can be impacted by Zika. This is the first time we’ve had any indication this could be a problem in a fully developed brain.

The study, in the journal Cell Stem Cell, looked at neural progenitors, a  stem cell that plays an important role in helping replace or repair damaged neurons, or nerve cells, in the brain. The researchers exposed the cells to the Zika virus and found that it infected the cells, causing some of the cells to die, and also limited the ability of the cells to proliferate.

In an interview in Healthday, Sujan Shresta, a researcher at the La Jolla Institute for Allergy and Immunology and one of the lead authors of the study, says although their work was done in adult mice, it may have implications for people:

“Zika can clearly enter the brains of adults and can wreak havoc. But it’s a complex disease, it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle and now we know what to look for.”

Move over CRISPR, there’s a new gene-editing tool in town

jlo

Jennifer Lopez: Photo courtesy MTV

For much of the last year the hottest topic in stem cell and gene editing research has been CRISPR and the ease with which it can be used to edit genes. It’s so hot that apparently it’s the title of an upcoming TV show starring Jeniffer Lopez.

But hold on J-Lo, a new study in Nature Communications says by the time the show is on the air it may be old hat. Researchers at Carnegie Mellon and Yale University have developed a new gene-editing system, one they claim is easier to use and more accurate than CRISPR. And to prove it, they say they have successfully cured a genetic blood disorder in mice, using a simple IV approach.

Tools like CRISPR use enzymes to cut open sections of DNA to edit a specific gene. It’s like using a pair of scissors to cut a piece of string that has a big knot in the middle; you cut out the knot then join the ends of the string together. The problem with CRISPR is that the enzymes it uses are quite large and hard to use in a living animal – let alone a human – so they have to remove the target cells from the body and do the editing in the lab. Another problem is that CRISPR sometimes cuts sections of DNA that the researchers don’t want cut and could lead to dangerous side effects.

Greater precision

The Carnegie Mellon/Yale team say their new method avoids both problems. They use nanoparticles that contain molecules made from peptide nucleic acid (PNA), a kind of artificial form of DNA. This PNA is engineered to be able to cut open DNA and bind to a specific target without cutting anything else.

The team used this approach to target the mutated gene in beta thalassemia, a blood disorder that can be fatal if left untreated. The therapy binds to the malfunctioning gene, enabling the body’s own DNA repair system to correct the problem.

In a news story in Science Daily Danith Ly, one of the lead authors on the study, says even though the technique was successful in editing the target genes just 7 percent of the time, that is way more than the 0.1 percent rate most other gene editing tools achieve.

“The effect may only be 7 percent, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

Hormone that controls if and when fat cells mature

Obesity is one of the fastest growing public health problems in the US and globally. Understanding the mechanisms behind how that happens could be key to finding ways to address it. Now researchers at Stanford University think they may have uncovered an important part of the answer.

Their findings, reported in Science Signaling, show that mature fat cells produce a hormone called Adamts1 which acts like a switch for surrounding stem cells, determining if they change into fat-storing cells.   People who eat a high-fat diet experience a change in their Adamst1 production, and that triggers the nearby stem cells to specialize and start storing fat.

There are still a lot of questions to be answered about Adamst1, including whether it acts alone or in conjunction with other as yet unknown hormones. But in an article in Health Canal, Brian Feldman, the senior author of the study, says they can now start looking at potential use of Adamst1 to fight obesity.

“That won’t be a simple answer. If you block fat formation, extra calories have to go somewhere in the body, and sending them somewhere else outside fat cells could be more detrimental to metabolism. We know from other researchers’ work that liver and muscle are both bad places to store fat, for example. We do think there are going to be opportunities for new treatments based on our discoveries, but not by simply blocking fat formation alone.”