“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.

A future scientist’s journey

All this week we have been highlighting blogs from our SPARK (Summer Program to Accelerate Regenerative medicine Knowledge) students. SPARK gives high school students a chance to spend their summer working in a world class stem cell research facility here in California. In return they write about their experiences and what they learned.

The standard for blogs this year was higher than ever, so choosing a winner was particularly tough. In the end we chose Abigail Mora, who interned at UC San Francisco. We felt the obstacles she overcame in getting to this point made her story all the more remarkable and engaging.

Abigail Mora

When I was 15, my mother got sick and went to several doctors. Eventually, she found out that she was pregnant with a 3-month-old baby. A month after, my mom fell from the stairs, which were not high but still dangerous. Luckily, everything seemed to be okay with the baby. In the last week of her six-month pregnancy, she went in the clinic for a regular check-up but she ended up giving birth to my brother, who was born prematurely. She stayed in the clinic for a month and my brother also had to stay so that his lungs could develop properly.

When he came home, I was so happy. I spent a lot of time with him and was like his second mom. After an initial period of hard time, he grew into a healthy kid. Then I moved to San Francisco with my aunt, leaving my parents and siblings in Mexico so that I could become a better English speaker and learn more about science. My experience with my brother motivated me to learn more about the condition of premature babies, since there are many premature babies who are not as fortunate. I want to study neurodevelopment in premature kids, and how it may go wrong.

I was so happy when I got into the SEP High School Program, which my chemistry teacher introduced me to, and I found the research of Eric Huang’s lab at UCSF about premature babies and stem cell development in the brain super interesting. I met Lakisha and Jean, and they introduced me to the lab and helped me walk through the training process.

My internship experience was outstanding: I enjoyed doing research and how my mentor Jiapei helped me learn new things about the brain. I learned that there are many different cell types in the brain, like microglia, progenitor cells, and intermediate progenitors.

As all things in life can be challenging, I was able to persevere with my mentor’s help. For example, when I first learned how to cut mouse brains using a cryostat, I found it hard to pick up the tissue onto slides. After practicing many times, I became more familiar with the technique and my slices got better. Another time, I was doing immunostaining and all the slices fell from the slide because we didn’t bake the slides long enough. I was sad, but we learned from our mistakes and there are a lot of trials and errors in science.

I’ve also learned that in science, since we are studying the unknown, there is not a right or wrong answer. We use our best judgement to draw conclusions from what we observe, and we repeat the experiment if it’s not working.

The most challenging part of this internship was learning and understanding all the new words in neuroscience. Sometimes, I got confused with the abbreviations of these words. I hope in the future I can explain as well as my mentor Jiapei explained to me.

My parents are away from me but they support me, and they think that this internship will open doors to better opportunities and help me grow as a person.

I want to become a researcher because I want to help lowering the risk of neurodevelopmental disorders in premature babies. Many of these disorders, such as autism or schizophrenia, don’t have cures. These are some of the hardest diseases to cure because people aren’t informed about them and not enough research has been done. Hopefully, one day I can work on developing a cure for these disorders.

CIRM’s Stephen Lin, PhD, who heads the SPARK program and Abigail after her blog won first prize

Advancing stem cell research in many ways

Speakers at the Alpha Stem Cell Clinics Network Symposium: Photo by Marco Sanchez

From Day One CIRM’s goal has been to advance stem cell research in California. We don’t do that just by funding the most promising research -though the 51 clinical trials we have funded to date clearly shows we do that rather well – but also by trying to bring the best minds in the field together to overcome problems.

Over the years we have held conferences, workshops and symposiums on everything from Parkinson’s disease, cerebral palsy and tissue engineering. Each one attracted the key players and stakeholders in the field, brainstorming ideas to get past obstacles and to explore new ways of developing therapies. It’s an attempt to get scientists, who would normally be rivals or competitors, to collaborate and partner together in finding the best way forward.

It’s not easy to do, and the results are not always obvious right away, but it is essential if we hope to live up to our mission of accelerating stem cell therapies to patients with unmet medical needs.

For example. This past week we helped organize two big events and were participants in another.

The first event we pulled together, in partnership with Cedars-Sinai Medical Center, was a workshop called “Brainstorm Neurodegeneration”. It brought together leaders in stem cell research, genomics, big data, patient advocacy and the Food and Drug Administration (FDA) to tackle some of the issues that have hampered progress in finding treatments for things like Parkinson’s, Alzheimer’s, ALS and Huntington’s disease.

We rather ambitiously subtitled the workshop “a cutting-edge meeting to disrupt the field” and while the two days of discussions didn’t resolve all the problems facing us it did produce some fascinating ideas and some tantalizing glimpses at ways to advance the field.

Alpha Stem Cell Clinics Network Symposium: Photo by Marco Sanchez

Two days later we partnered with UC San Francisco to host the Fourth Annual CIRM Alpha Stem Cell Clinics Network Symposium. This brought together the scientists who develop therapies, the doctors and nurses who deliver them, and the patients who are in need of them. The theme was “The Past, Present & Future of Regenerative Medicine” and included both a look at the initial discoveries in gene therapy that led us to where we are now as well as a look to the future when cellular therapies, we believe, will become a routine option for patients. 

Bringing these different groups together is important for us. We feel each has a key role to play in moving these projects and out of the lab and into clinical trials and that it is only by working together that they can succeed in producing the treatments and cures patients so desperately need.

Cierra Jackson: Photo by Marco Sanchez

As always it was the patients who surprised us. One, Cierra Danielle Jackson, talked about what it was like to be cured of her sickle cell disease. I think it’s fair to say that most in the audience expected Cierra to talk about her delight at no longer having the crippling and life-threatening condition. And she did. But she also talked about how hard it was adjusting to this new reality.

Cierra said sickle cell disease had been a part of her life for all her life, it shaped her daily life and her relationships with her family and many others. So, to suddenly have that no longer be a part of her caused a kind of identity crisis. Who was she now that she was no longer someone with sickle cell disease?

She talked about how people with most diseases were normal before they got sick, and will be normal after they are cured. But for people with sickle cell, being sick is all they have known. That was their normal. And now they have to adjust to a new normal.

It was a powerful reminder to everyone that in developing new treatments we have to consider the whole person, their psychological and emotional sides as well as the physical.

CIRM’s Dr. Maria Millan (right) at a panel presentation at the Stanford Drug Discovery Symposium. Panel from left to right are: James Doroshow, NCI; Sandy Weill, former CEO Citigroup; Allan Jones, CEO Allen Institute

And so on to the third event we were part of, the Stanford Drug Discovery Symposium. This was a high level, invitation-only scientific meeting that included some heavy hitters – such as Nobel Prize winners Paul Berg and  Randy Schekman, former FDA Commissioner Robert Califf. Over the course of two days they examined the role that philanthropy plays in advancing research, the increasingly important role of immunotherapy in battling diseases like cancer and how tools such as artificial intelligence and big data are shaping the future.

CIRM’s President and CEO, Dr. Maria Millan, was one of those invited to speak and she talked about how California’s investment in stem cell research is delivering Something Better than Hope – which by a happy coincidence is the title of our 2018 Annual Report. She highlighted some of the 51 clinical trials we have funded, and the lives that have been changed and saved by this research.

The presentations at these conferences and workshops are important, but so too are the conversations that happen outside the auditorium, over lunch or at coffee. Many great collaborations have happened when scientists get a chance to share ideas, or when researchers talk to patients about their ideas for a successful clinical trial.

It’s amazing what happens when you bring people together who might otherwise never have met. The ideas they come up with can change the world.

Organoids revolutionize approach to studying a variety of diseases

Organoids

There are limitations to studying cells under a microscope. To understand some of the more complex processes, it is critical to see how these cells behave in an environment that is similar to conditions in the body. The production of organoids has revolutionized this approach.

Organoids are three-dimensional structures derived from stem cells that have similar characteristics of an actual organ. There have been several studies recently published that have used this approach to understand a wide scope of different areas.

In one such instance, researchers at The University of Cambridge were able to grow a “mini-brain” from human stem cells. To demonstrate that this organoid had functional capabilities similar to that of an actual brain, the researchers hooked it up to a mouse spinal cord and surrounding muscle. What they found was remarkable– the “mini-brain” sent electrial signals to the spinal cord that made the surrounding muscles twitch. This model could pave the way for studying neurodegenerative diseases such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS).

Spinal muscular atrophy

Speaking of SMA, researchers in Singapore have used organoids to come up with some findings that might be able to help people battling the condition.

SMA is a neurodegenerative disease caused by a protein deficiency that results in nerve degeneration, paralysis and even premature death. The fact that it mainly affects children makes it even worse. Not much is known how SMA develops and even less how to treat or prevent it.

That’s where the research from the A*STAR’s Institute of Molecular and Cell Biology (IMCB) comes in. Using the iPSC method they turned tissue samples from healthy people and people with SMA into spinal organoids.

They then compared the way the cells developed in the organoids and found that the motor nerve cells from healthy people were fully formed by day 35. However, the cells from people with SMA started to degenerate before they got to that point.

They also found that the protein problem that causes SMA to develop did so by causing the motor nerve cells to divide, something they don’t normally do. So, by blocking the mechanism that caused the cells to divide they were able to prevent the cells from dying.

In an article in Science and Technology Research News lead researcher Shi-Yan Ng said this approach could help unlock clues to other diseases such as ALS.

“We are one of the first labs to report the formation of spinal organoids. Our study presents a new method for culturing human spinal-cord-like tissues that could be crucial for future research.”

Just yesterday the CIRM Board awarded almost $4 million to Ankasa Regenerative Therapeutics to try and develop a treatment for another debilitating back problem called degenerative spondylolisthesis.

And finally, organoid modeling was used to better understand and study an infectious disease. Scientists from the Max Planck Institute for Infection Biology in Berlin created fallopian tube organoids from normal human cells. Fallopian tubes are the pair of tubes found inside women along which the eggs travel from the ovaries to the uterus. The scientists observed the effects of chronic infections of Chlamydia, a sexually transmittable infection. It was discovered that chronic infections lead to permanent changes at the DNA level as the cells age. These changes to DNA are permanent even after the infection is cleared, and could be indicative of the increased risk of cervical cancer observed in women with Chlamydia or those that have contracted it in the past.

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.

Research Transforming Mature Neurons into Dopamine Factories could Help Fight Brain Diseases

dopaminergic neurons-1

Researchers accidentally converted mature neurons into dopaminergic cells (in green) without first reverting them to a stem-cell state. (Lei-Lei Wang/UT Southwestern)

A team of researchers at the University of Texas Southwestern Medical Center made a startling discovery that could improve patient outcomes for neurological diseases.

And they did it completely by accident.

Scientists have long believed that turning one type of mature cell into another is impossible without first reverting the original cell back into a stem cell. So, the group set out to make dopamine-producing neurons (the kind of cell destroyed in Parkinson’s disease) out of glial cells (support cells in the brain and spinal cord) in live mouse brains. But according to results published in the journal Stem Cell Reports, they instead turned the mature neurons into dopaminergic neuron-like cells. They believe their inadvertent discovery could be used to treat diseases of the brain and spinal cord.

Dopaminergic neurons in the brain produce dopamine, which is important for controlling voluntary movement and the motivation-reward system that drives behavior. The loss of these cells has been linked to disorders like Parkinson’s disease, and scientists are on the hunt for new methods of replenishing these vital neurons.

Glial cells, which surround neurons and provide protective support, can regenerate and multiply easily, thus making them better candidates as potential neuron replacement therapies. That’s why Zhang and his team targeted them in the first place.

They injected a mixture of cell reprogramming promoters into a part of a mouse’s brain called the striatum.

To the team’s dismay, the glia remained unchanged; instead, so-called GABAergic medium spiny neurons that are plentiful within the striatum—and key in controlling movements—had transformed into cells that behaved like dopaminergic neurons. These new cells displayed rhythmic activity and formed network connections, much like dopaminergic cells do. Most importantly, the team found that the new cells came into being without passing through a stem cell-like transition phase.

“To our knowledge, changing the phenotype of resident, already-mature neurons has never been accomplished before,” said Zhang in a statement. “This could mean that no cell type is fixed even for a functional, mature neuron.”

Zhang believes UT Southwestern’s new discovery should be further investigated for the treatment of Parkinson’s and related disorders. “Such knowledge may one day be applied to devise therapeutic strategies for treating neurological diseases through reprogramming the phenotype of local neurons,” the team wrote in the study.

 

 

Stem cell stories that caught our eye: CIRM-funded scientist wins prestigious prize and a tooth trifecta

CIRM-grantee wins prestigious research award

Do we know how to pick ‘em or what? For a number of years now we have been funding the work of Stanford’s Dr. Marius Wernig, who is doing groundbreaking work in helping advance stem cell research. Just how groundbreaking was emphasized this week when he was named as the winner of the 2018 Ogawa-Yamanaka Stem Cell Prize.

WernigMarius_Stanford

Marius Wernig, MD, PhD. [Photo: Stanford University]

The prestigious award, from San Francisco’s Gladstone Institutes, honors Wernig for his innovative work in developing a faster, more direct method of turning ordinary cells into, for example, brain cells, and for his work advancing the development of disease models for diseases of the brain and skin disorders.

Dr. Deepak Srivastava, the President of Gladstone, announced the award in a news release:

“Dr. Wernig is a leader in his field with extraordinary accomplishments in stem cell reprogramming. His team was the first to develop neuronal cells reprogrammed directly from skin cells. He is now investigating therapeutic gene targeting and cell transplantation–based strategies for diseases with mutations in a single gene.”

Wernig was understandably delighted at the news:

“It is a great honor to receive this esteemed prize. My lab’s goal is to discover novel biology using reprogrammed cells that aids in the development of effective treatments.”

Wernig will be presented with the award, and a check for $150,000, at a ceremony on Oct. 15 at the Gladstone Institutes in San Francisco.

A stem cell trifecta for teeth research

It was a tooth trifecta among stem cell scientists this week. At Tufts University School of Medicine, researchers made an important advance in the development of bioengineered teeth. The current standard for tooth replacement is a dental implant. This screw-shaped device acts as an artificial tooth root that’s inserted into the jawbone. Implants have been used for 30 years and though successful they can lead to implant failure since they lack many of the properties of natural teeth. By implanting postnatal dental cells along with a gel material into mice, the team demonstrated, in a Journal of Dental Research report, the development of natural tooth buds. As explained in Dentistry Today, these teeth “include features resembling natural tooth buds such as the dental epithelial stem cell niche, enamel knot signaling centers, transient amplifying cells, and mineralized dental tissue formation.”

Another challenge with the development of a bioengineered tooth replacement is reestablishing nerve connections within the tooth, which plays a critical role in its function and protection but doesn’t occur spontaneously after an injury. A research team across the “Pond” at the French National Institute of Health and Medical Research, showed that bone marrow-derived mesenchymal stem cells in the presence of a nerve fiber can help the nerve cells make connections with bioengineered teeth. The study was also published in the Journal of Dental Research.

And finally, a research report about stem cells and the dreaded root canal. When the living soft tissue, or dental pulp, of a tooth becomes infected, the primary course of action is the removal of that tissue via a root canal. The big downside to this procedure is that it leaves the patient with a dead tooth which can be susceptible to future infections. To combat this side effect, researchers at the New Jersey Institute of Technology report the development of a potential remedy: a gel containing a fragment of a protein that stimulates the growth of new blood vessels as well as a fragment of a protein that spurs dental stem cells to divide and grow. Though this technology is still at an early stage, it promises to help keep teeth alive and healthy after root canal. The study was presented this week at the National Meeting of the American Chemical Society.

Here’s an animated video that helps explain the research:

Friday Stem Cell Round: Ask the Expert Facebook Live, Old Brain Cells Reveal Insights and Synthetic Development

Stem Cell Photo of the Week: We’re Live on Facebook Live!

Our stem cell photo of the week is a screenshot from yesterday’s Facebook Live event: “Ask the Expert: Stem Cells and Stroke”. It was our first foray into Facebook Live and, dare I say, it was a success with over 150 comments and 4,500 views during the live broadcast.

FacebookLive_AskExperts_Stroke_IMG_1656

Screen shot of yesterday’s Facebook Live event. Panelists included (from top left going clockwise): Sonia Coontz, Kevin McCormack, Gary Steinberg, MD, PhD and Lila Collins, PhD.

Our panel included Dr. Gary Steinberg, MD, PhD, the Chair of Neurosurgery at Stanford University, who talked about promising clinical trial results testing a stem cell-based treatment for stroke. Lila Collins, PhD, a Senior Science Officer here at CIRM, provided a big picture overview of the latest progress in stem cell therapies for stroke. Sonia Coontz, a patient of Dr. Steinberg’s, also joined the live broadcast. She suffered a devastating stroke several years ago and made a remarkable recovery after getting a stem cell therapy. She had an amazing story to tell. And Kevin McCormack, CIRM’s Senior Director of Public Communications, moderated the discussion.

Did you miss the Facebook Live event? Not to worry. You can watch it on-demand on our Facebook Page.

What other disease areas would you like us to discuss? We plan to have these Ask the Expert shows on a regular basis so let us know by commenting here or emailing us at info@cirm.ca.gov!

Brain cells’ energy “factories” may be to blame for age-related disease

Salk Institute researchers published results this week that shed new light on why the brains of older individuals may be more prone to neurodegenerative diseases like Parkinson’s and Alzheimer’s. To make this discovery, the team applied a technique they devised back in 2015 which directly converts skin cells into brain cells, aka neurons. The method skips the typical intermediate step of reprogramming the skin cells into induced pluripotent stem cells (iPSCs).

They collected skin samples from people ranging in age from 0 to 89 and generated neurons from each. With these cells in hand, the researchers then examined how increased age affects the neurons’ mitochondria, the structures responsible for producing a cell’s energy needs. Previous studies have shown a connection between faulty mitochondria and age-related disease.

While the age of the skin cells had no bearing on the health of the mitochondria, it was a different story once they were converted into neurons. The mitochondria in neurons derived from older individuals clearly showed signs of deterioration and produced less energy.

Aged-mitochondria-green-in-old-neurons-gray-appear-mostly-as-small-punctate-dots-rather-than-a-large-interconnected-network-300x301

Aged mitochondria (green) in old neurons (gray) appear mostly as small punctate dots rather than a large interconnected network. Credit: Salk Institute.

The researchers think this stark difference in the impact of age on skin cells vs. neurons may occur because neurons have higher energy needs. So, the effects of old age on mitochondria only become apparent in the neurons. In a press release, Salk scientist Jerome Mertens explained the result using a great analogy:

“If you have an old car with a bad engine that sits in your garage every day, it doesn’t matter. But if you’re commuting with that car, the engine becomes a big problem.”

The team is now eager to use this method to examine mitochondrial function in neurons derived from Alzheimer’s and Parkinson’s patient skin samples and compared them with skin-derived neurons from similarly-aged, healthy individuals.

The study, funded in part by CIRM, was published in Cell Reports.

“Synthetically” Programming embryo development

One of the most intriguing, most fundamental questions in biology is how an embryo, basically a non-descript ball of cells, turns into a complex animal with eyes, a brain, a heart, etc. A deep understanding of this process will help researchers who aim to rebuild damaged or diseased organs for patients in need.

3-layer_1.16.9

Researchers programmed cells to self-assemble into complex structures such as this one with three differently colored layers. Credit: Wendell Lim/UCSF

A fascinating report published this week describes a system that allows researchers to program cells to self-organize into three-dimensional structures that mimic those seen during early development. The study applied a customizable, synthetic signaling molecule called synNotch developed in the Wendell Lim’s UCSF lab by co-author Kole Roybal, PhD, now an assistant professor of microbiology and immunology at UCSF, and Leonardo Morsut, PhD, now an assistant professor of stem cell biology and regenerative medicine at the University of Southern California.

A UCSF press release by Nick Weiler describes how synNotch was used:

“The researchers engineered cells to respond to specific signals from neighboring cells by producing Velcro-like adhesion molecules called cadherins as well as fluorescent marker proteins. Remarkably, just a few simple forms of collective cell communication were sufficient to cause ensembles of cells to change color and self-organize into multi-layered structures akin to simple organisms or developing tissues.”

Senior author Wendell Lim also explained how this system could overcome the challenges facing those aiming to build organs via 3D bioprinting technologies:

“People talk about 3D-printing organs, but that is really quite different from how biology builds tissues. Imagine if you had to build a human by meticulously placing every cell just where it needs to be and gluing it in place. It’s equally hard to imagine how you would print a complete organ, then make sure it was hooked up properly to the bloodstream and the rest of the body. The beauty of self-organizing systems is that they are autonomous and compactly encoded. You put in one or a few cells, and they grow and organize, taking care of the microscopic details themselves.”

Study was published in Science.

Stem Cell Roundup: better model of schizophrenia, fasting boosts stem cells, and why does our hair gray.

Stem cell photo of the week:
Recreating brain cell interactions for studying schizophrenia

169585_web

Salk researchers used stem cells to derive CA3 pyramidal neurons (green), including a rare subtype of the cells (red). Image: Salk Institute

Our pick for the stem cell image of the week is from the laboratory of Rusty Gage at the Salk Institute. The team generated multiple types of nerve cells from stem cells to more closely represent the interactions that occur in the brain. They’re using this system to show how the communication between these nerve cells becomes faulty in people with schizophrenia. A Salk Institute press release provides more details about their study which was published in Cell Stem Cell.

Regenerative power of intestinal stem cells maintained via fasting
For many decades, researchers have known that restricting food intake in mice can extend life span. Why it happens hasn’t been well understood. This week, a team at MIT uncovered a possible explanation: fasting increases the regenerative power of stem cells.

May3_2018_MIT_StemCellDiet2247912117

Intestinal stem cells from mice that fasted for 24 hours, at right, produced much more substantial intestinal organoids than stem cells from mice that did not fast, at left.
Image: Maria Mihaylova and Chia-Wei Cheng, MIT

The report, published in Cell Stem Cell, focused on the well-studied intestinal stem cell, which renews the intestinal lining every five days. As we age, the intestinal stem cell’s regenerative abilities wane and damage to the intestinal lining takes longer to repair.

Mice were fasted for 24 hours and then their intestinal stem cells were retrieved and grown into mini-intestine organoids in petri dishes. According to Maria Mihaylova, PhD, one of the lead authors, the results of the experiment were very clear:

“It was very obvious that fasting had this really immense effect on the ability of intestinal crypts to form more organoids, which is stem-cell-driven,” Mihaylova said in a press release. “This was something that we saw in both the young mice and the aged mice, and we really wanted to understand the molecular mechanisms driving this.”

Mihaylova and the team went on to show that fasting caused the stem cells to burn fat instead of carbohydrates for their energy needs. Inhibiting the gene pathways that flip this metabolic switch also blocks the regenerative capacity of fasting. On the other hand, molecules that boost the gene pathways mimic the effects of fasting without changing food intake. This intriguing finding could potentially have clinical applications for cancer patients who suffer intestinal injury from the toxic effects of chemotherapy drugs but who certainly aren’t in a condition to fast.

Premature graying, our immune system and stem cells: a surprising link. (Kevin McCormack)
As someone whose hair went gray at a relatively young age – well, it seemed young to me! – this next story naturally caught my eye. It highlights how our immune systems may play a key role in determining our hair color and, in particular, when that hair turns gray.

Our bodies are constantly shedding hairs and replacing them with new ones. Normally stem cells called melanocytes help ensure the new hairs have your original color, be it black, blonde, brunette or red.

Researchers at the National Institutes of Health and the University of Alabama, Birmingham, found that when the body is attacked by a virus, our immune system kicks in and respond by producing interferon to fight off the infection. However, when a protein called MITF, that is involved in regulating how cells use interferon, fails to work properly it can also affect melanocytes causing them to lose their pigmentation. Without that pigmentation the new hairs are gray.

The study, which appears in the journal PLOS Biology, is too late to help me and my gray hair – particularly as it was done in mice – but it could pave the way for further research that identifies how genes that control pigment in our hair and skin also control our immune system.

Building a better brain organoid

One of the reasons why it’s so hard to develop treatments for problems in the brain – things like Alzheimer’s, autism and schizophrenia – is that you can’t do an autopsy of a living brain to see what’s going wrong. People tend to object. To get around that, scientists have used stem cells to create models of what’s happening inside the brain. They’re good, but they have their limitations. Now a team at the Salk Institute for Biological Studies has found a way to create a better brain model, and hopefully a faster route to developing new treatments.

For a few years now, scientists have been able to take skin cells from patients with neurodegenerative disorders and turn them into neurons, the kind of brain cell affected by these different diseases. They grow these cells in the lab and turn them into clusters of cells, so-called brain “organoids”, to help us better understand what’s happening inside the brain and even allow us to test medications on them to see if those treatments can help ease some symptoms.

Human-organoid-tissue-green-grafted-into-mouse-tissue.-Neurons-are-labeled-with-red-dye.

Human organoid tissue (green) grafted into mouse tissue. Neurons are labeled with red. Credit: Salk Institute

But those models don’t really capture the complexity of our brains – how could they – and so only offer a glimpse into what’s happening inside our skulls.

Now the team at Salk have developed a way of transplanting these organoids into mouse brains, giving them access to oxygen and nutrients that can help them not only survive longer but also display more of the characteristics found in the human brain.

In a news release, CIRM Grantee and professor at Salk’s Laboratory of Genetics, Rusty Gage said this new approach gives researchers a powerful new tool:

“This work brings us one step closer to a more faithful, functional representation of the human brain and could help us design better therapies for neurological and psychiatric diseases.”

The transplanted human brain organoids showed plenty of signs that they were becoming engrafted in the mouse brain:

  • They had blood vessels form in them and blood flowing through them
  • They formed neurons
  • They formed other brain support cells called astrocytes

They also used a series of imaging techniques to confirm that the neurons in the organoid were not just connecting but also sending signals, in essence, communicating with each other.

Abed AlFattah Mansour, a Salk research associate and the paper’s first author, says this is a big accomplishment.

“We saw infiltration of blood vessels into the organoid and supplying it with blood, which was exciting because it’s perhaps the ticket for organoids’ long-term survival. This indicates that the increased blood supply not only helped the organoid to stay healthy longer, but also enabled it to achieve a level of neurological complexity that will help us better understand brain disease.”

A better understanding of what’s going wrong is a key step in being able to develop new treatments to fix the problem.

The study is published in the journal Nature Biotechnology.

CIRM has a double reason to celebrate this work. Not only is the team leader, Rusty Gage, a CIRM grantee but one of the Salk team, Sarah Fernandes, is a former intern in the CIRM Bridges to Stem Cell Research program.

Gage-Natbiotech-press-release

From left: Sarah Fernandes, Daphne Quang, Stephen Johnston, Sarah Parylak, Rusty Gage, Abed AlFattah Mansour, Hao Li Credit: Salk Institute