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.”

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.

CIRM-Funded Clinical Trials Targeting Brain and Eye Disorders

This blog is part of our Month of CIRM series, which features our Agency’s progress towards achieving our mission to accelerate stem cell treatments to patients with unmet medical needs.

 This week, we’re highlighting CIRM-funded clinical trials to address the growing interest in our rapidly expanding clinical portfolio. Our Agency has funded a total of 40 trials since its inception. 23 of these trials were funded after the launch of our Strategic Plan in 2016, bringing us close to the half way point of our goal to fund 50 new clinical trials by 2020.

Today we are featuring CIRM-funded trials in our neurological and eye disorders portfolio.  CIRM has funded a total of nine trials targeting these disease areas, and seven of these trials are currently active. Check out the infographic below for a list of our currently active trials.

For more details about all CIRM-funded clinical trials, visit our clinical trials page and read our clinical trials brochure which provides brief overviews of each trial.

Using stem cells to fix bad behavior in the brain

 

finkbeiner-skibinski-16x9-13

Gladstone Institutes Steven Finkbeiner and Gaia Skibinski: Photo courtesy Chris Goodfellow, Gladstone Institutes

Diseases of the brain have many different names, from Alzheimer’s and Parkinson’s to ALS and Huntington’s, but they often have similar causes. Researchers at the Gladstone Institutes in San Francisco are using that knowledge to try and find an approach that might be effective against all of these diseases. In a new CIRM-funded study, they have identified one protein that could help do just that.

Many neurodegenerative diseases are caused by faulty proteins, which start to pile up and cause damage to neurons, the brain cells that are responsible for processing and transmitting information. Ultimately, the misbehaving proteins cause those cells to die.

The researchers at the Gladstone found a way to counter this destructive process by using a protein called Nrf2. They used neurons from humans (made from induced pluripotent stem cells – iPSCs – hence the stem cell connection here) and rats. They then tested these cells in neurons that were engineered to have two different kinds of mutations found in  Parkinson’s disease (PD) plus the Nrf2 protein.

Using a unique microscope they designed especially for this study, they were able to track those transplanted neurons and monitor what happened to them over the course of a week.

The neurons that expressed Nrf2 were able to render one of those PD-causing proteins harmless, and remove the other two mutant proteins from the brain cells.

In a news release to accompany the study in The Proceedings of the National Academy of Sciences, first author Gaia Skibinski, said Nrf2 acts like a house-cleaner brought in to tidy up a mess:

“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now. Over-expressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”

Steven Finkbeiner, the senior author on the study and a Gladstone professor, said this model doesn’t just hold out hope for treating Parkinson’s disease but for treating a number of other neurodegenerative problems:

“I am very enthusiastic about this strategy for treating neurodegenerative diseases. We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”

The next step is to use this deeper understanding to identify other proteins that interact with Nrf2, and potentially find ways to harness that knowledge for new therapies for neurodegenerative disorders.

An inside look reveals the adult brain prunes its own branches

Did you know that when you’re born, your brain contains around 100 billion nerve cells? This is impressive considering that these nerve cells, also called neurons, are already connected to each other through an intricate, complex neural network that is essential for brain function.

Here’s how the brain does it. During development, neural stem cells produce neurons that navigate their way through the brain. Once at their destination, neurons set up shop and send out long extensions called axons and branched extensions called dendrites that allow them to form what are called synaptic connections through which they can communicate through electrical and chemical signals.

Studies of early brain development revealed that neurons in the developing brain go on overdrive and make more synaptic connections than they need. Between birth and early adulthood, the brain carefully prunes away weak or unnecessary connections, and by your mid-twenties, your brain has eliminated almost half of the synaptic connections you started out with as a baby.

This synaptic pruning process allows the brain to fine-tune its neural network and strengthen the connections between neurons that are important for brain function. It’s similar to how a gardener prunes away excess branches on fruit trees so that the resulting branches can produce healthier and better tasting fruit.

The brain can make new neurons

It was thought that by adulthood, this process of pruning excess connections between neurons was over. However, a new study from the Salk Institute offers visual proof that synaptic pruning occurs during adulthood similarly to how it does during development. The work was published today in the journal Nature Neuroscience, and it was funded in part by CIRM.

Rusty Gage, Salk Institute.

Rusty Gage, Salk Institute.

The study was led by senior author and Salk Professor Rusty Gage. Gage is well known for his earlier work on adult neurogenesis. In the late 90’s, he discovered that the adult brain can in fact make new neurons, a notion that overturned the central dogma that the brain doesn’t contain stem cells and that we’re born with all the neurons we will ever have.

There are two main areas of the adult brain that harbor neural stem cells that can generate new neurons. One area is called the dentate gyrus, which is located in the memory forming area of the brain called the hippocampus. Gage and his team were curious to know whether the new neurons generated from stem cells in the dentate gyrus also experienced the same synaptic overgrowth and pruning that the neurons in the developing brain did.

Pruning the Adult Brain

They developed a special microscope technique that allowed them to visually image the development of new neurons from stem cells in the dentate gyrus of the mouse brain. Every day, they would image the growing neurons and monitor how many dendritic branches they sent out.

Newly generated neurons (green) send out branched dendritic extensions to make connections with other neurons. (Image credit: Salk Institute)

Newly generated neurons (green) send out branched dendritic extensions to make connections with other neurons. (Image credit: Salk Institute)

After observing the neurons for a few weeks, they were amazed to discover that these new neurons behaved similarly to neurons in the developing brain. They sent out dozens of dendritic branches and formed synaptic connections with other neurons, some of which were eventually pruned away over time.

This phenomenon was observed more readily when they made the mice exercise, which stimulated the stem cells in the dentate gyrus to divide and produce more neurons. These exercise-induced neurons robustly sent out dendritic branches only to have them pruned back later.

First author on the paper, Tiago Gonçalves commented on their observations:

“What was really surprising was that the cells that initially grew faster and became bigger were pruned back so that, in the end, they resembled all the other cells.”

Rusty Gage was also surprised by their findings but explained that developing neurons, no matter if they are in the developing or adult brain, have evolved this process in order to establish the best connections.

“We were surprised by the extent of the pruning we saw. The results suggest that there is significant biological pressure to maintain or retain the dendrite tree of these neurons.”

A diagram showing how the adult brain prunes back the dendritic branches of newly developing neurons over time. (Image credit: Salk Institute).

A diagram showing how the adult brain prunes back the dendritic branches of newly developing neurons over time. (Image credit: Salk Institute).

Potential new insights into brain disorders

This study is important because it increases our understanding of how neurons develop in the adult brain. Such knowledge can help scientists gain a better understanding of what goes wrong in brain disorders such as autism, schizophrenia, and epilepsy, where defects in how neurons form synaptic connections or how these connections are pruned are to blame.

Gonçalves also mentioned that this study raises another important question related to the regenerative medicine applications of stem cells for neurological disease.

“This also has big repercussions for regenerative medicine. Could we replace cells in this area of the brain with new stem cells and would they develop in the same way? We don’t know yet.”


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Unlocking the brain’s secrets: scientists find over 100 unique mutations in brain cells

Your brain is made up of approximately 100 billion neurons. These are the cells that process information and pass along electrical and chemical signals to their other neuron buddies throughout the body to coordinate thoughts, movement, and many other functions. It’s no small task to create the intricate neuronal network that is the backbone of the central nervous system. If any of these neurons or a group of neurons acquire genetic mutations that alter their function, a lot can go wrong.

The genetic makeup of neurons is particularly interesting because it appears that each neuron has its own unique genome. That means 100 billion different genomes in a single cell type in the brain. Scientists suggest that this “individuality” could explain why monozygotic, or identical, twins have different personalities and susceptibilities to neurological disorders or mental illnesses and why humans develop brain diseases or cancer over time.

To understand what a genome of a cell looks like, you need to sequence its genetic material, or the DNA, that’s housed in a cell’s nucleus. Sequencing the genome of an individual cell is hard to do accurately with our current technology, so scientists have developed clever alternatives to get a front-row view into the workings of neuronal genomes.

Cloning mouse neurons reveals 100+ unique genetic mutations

One such method was published recently in the journal Neuron by a CIRM-funded team from The Scripps Research Institute (TSRI). Led by senior author and Associate Professor at TSRI, Kristen Baldwin, the team took on the challenge of cloning individual mouse neurons to unlock the secrets of neuronal genomes. (For those who aren’t familiar with the term, cloning is a process that produces new cells or organisms that harbor identical genetic information from the originating cell.)

What they found from their cloning experiment was surprising: each neuron they sequenced had an average of more than 100 unique genetic mutations, and these mutations tended to appear in genes that were heavily used by neurons, something that is uncommon in cell types of other organs that tend to protect their frequently used genes. Their findings could help unravel the mystery behind some of the causes for diseases like Alzheimer’s and autism.

In a TSRI news release, Kristen Baldwin explained:

Kristen Baldwin

Kristen Baldwin

“Neuronal genomes have remained a mystery for a long time. The findings in this study and the extensive validation of genome sequencing-based mutation discovery that this method permits, open the door to additional studies of brain mutations in aging and disease, which may help us understand or treat cognitive decline in aging, neurodegeneration and neurodevelopmental diseases such as autism.”

Making mice with neuronal genomes

To clone individual neurons, the team took the nucleus of a single neuron and transplanted it into a mouse egg cell that lacked its own nucleus. The egg developed and matured all while copying and passing on the genetic information of the original mouse neuron. The team generated cloned embryonic stem cell lines from these eggs and were able to expand the stem cell lines to generate millions of stem cells that contained the same genetic material.

TSRI Research Assistant Alberto Rodriguez uses a tiny straw-like micropipette to pick up red fluorescent neurons and transfer their genomes into an egg.

TSRI scientists extract the nuclei of neurons and transfer their genomes into an egg. (Image courtesy of TSRI)

They made several different cloned stem cell lines representing different neuronal genomes and sequenced these lines to identify unique genetic mutations. They also were able to generate cloned stem cell lines from the neurons of older mice, and thus were able to track the accumulation of genetic mutations over time. Even more impressive, they made living mice that contained the cloned genomes of individual neurons in all of their cells, proving that neuronal genomes are compatible with development.

The team did report that not all neurons could be developed into cloned stem cell lines for reasons that they couldn’t fully explain, but they decided to focus on studying the cloned stem cell lines that were successful.

What does this mean for humans?

Baldwin explained that what was most surprising about their study was “that every neuron we looked at was unique – carrying more than 100 DNA changes or mutations that were not present in other cells.”

The next steps for their research are to explore why this diversity among neuronal genomes exists and how this could contribute to neurological disease in humans.

Co-first authors Jennifer Hazen and Gregory Faust.

Co-first authors Jennifer Hazen and Gregory Faust.

Co-first author Jennifer Hazen explains, “We need to know more about mutations in the brain and how they might impact cell function.”

Also mentioned in the news release, the team plans “to study neuronal genomes of very old mice and those with neurological diseases. They hope this work will lead to new insights and therapeutic strategies for treating brain aging and neurologic diseases caused by neuronal mutations.”


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