Stem Cell Roundup: hESCs turn 20, tracking cancer stem cells, new ALS gene ID’d

Stem Cell Image of the Week

Picture1This week’s stunning stem cell image is brought to you by researchers in the Brivanlou Lab at Rockefeller University. What looks like the center of a sunflower is actual a ball of neural rosettes derived from human embryonic stem cells (ESCs). Neural rosettes are structures that contain neural stem and progenitor cells that can further specialize into mature brain cells like the stringy, blue-colored neurons in this photo.

This photo was part of a Nature News Feature highlighting how 20 years ago, human ESCs sparked a revolution in research that’s led to the development of ESC-based therapies that are now entering the clinic. It’s a great read, especially for those of you who aren’t familiar with the history of ESC research.

Increase in cancer stem cells tracked during one patient’s treatment
Cancer stem cells are nasty little things. They have the ability to evade surgery, chemotherapy and radiation and cause a cancer to return and spread through the body. Now a new study says they are also clever little things, learning how to mutate and evolve to be even better at evading treatment.

Researchers at the Colorado Cancer Center did three biopsies of tumors taken from a patient who underwent three surgeries for salivary gland cancer. They found that the number of cancer stem cells increased with each surgery. For example, in the first surgery the tumor contained 0.2 percent cancer stem cells. By the third surgery the number of cancer stem cells had risen to 4.5 percent.

Even scarier, the tumor in the third surgery had 50 percent more cancer-driving mutations meaning it was better able to resist attempts to kill it.

In a news release, Dr. Daniel Bowles, the lead investigator, said the tumor seemed to learn and become ever more aggressive:

Bowles headshot

Daniel Bowles

“People talk about molecular evolution of cancer and we were able to show it in this patient. With these three samples, we could see across time how the tumor developed resistance to treatment.”


The study is published in the journal Clinical Cancer Research.

New gene associated with ALS identified.
This week, researchers at UMass Medical School and the National Institute on Aging reported the identification of a new gene implicated in the development of amyotrophic lateral sclerosis (ALS). Also known as Lou Gehrig’s disease, ALS is a horrific neurodegenerative disorder that degrades the connection between nerve signals and the muscles. Sufferers are robbed of their ability to move and, ultimately, even to breathe. Life expectancy is just 3 to 5 years after diagnosis.

To identify the gene, called KIF5A, the team carried out the largest genetics effort in ALS research with support from the ALS Association, creators of the Ice Bucket Challenge that raised a $115 million for research. The study compared the genomes between a group of nearly 22,000 people with ALS versus a group of over 80,000 healthy controls. Two independent genetic analyses identified differences in the expression of the KIF5A gene between the two groups.


Cartoon representing the role that KIF5A plays in neurons. (Image: UMass Medical School)

KIF5A is active in neurons where it plays a key role in transporting cell components across the cell’s axon, the long, narrow portion of the cell that allows neurons to send long-range signals to other cells. It carries out this transport by tethering cell components on the axon’s cytoskeleton, a structural protein matrix within the cells. Several mutations in KIF5A were found in the ALS group which corroborates previous studies showing that mutations in other cytoskeleton genes are associated with ALS.

One next step for the researchers is to further examine the KIF5A mutations using patient-derived induced pluripotent stem cells.

The study was published in Neuron and picked up by Eureka Alert!

Stem Cell Roundup: Improving muscle function in muscular dystrophy; Building a better brain; Boosting efficiency in making iPSC’s

Here are the stem cell stories that caught our eye this week.

Photos of the week

TGIF! We’re so excited that the weekend is here that we are sharing not one but TWO amazing stem cell photos of the week.

RMI IntestinalChip

Image caption: Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. (Photo credit: Cedars-Sinai Board of Governors Regenerative Medicine Institute)

Photo #1 is borrowed from a blog we wrote earlier this week about a new stem cell-based path to personalized medicine. Scientists at Cedars-Sinai are collaborating with a company called Emulate to create intestines-on-a-chip using human stem cells. Their goal is to create 3D-organoids that represent the human gut, grow them on chips, and use these gut-chips to screen for precision medicines that could help patients with intestinal diseases. You can read more about this gut-tastic research here.

Young mouse heart 800x533

Image caption: UCLA scientists used four different fluorescent-colored proteins to determine the origin of cardiomyocytes in mice. (Image credit: UCLA Broad Stem Cell Research Center/Nature Communications)

Photo #2 is another beautiful fluorescent image, this time of a cross-section of a mouse heart. CIRM-funded scientists from UCLA Broad Stem Cell Research Center are tracking the fate of stem cells in the developing mouse heart in hopes of finding new insights that could lead to stem cell-based therapies for heart attack victims. Their research was published this week in the journal Nature Communications and you can read more about it in a UCLA news release.

Stem cell injection improves muscle function in muscular dystrophy mice

Another study by CIRM-funded Cedars-Sinai scientists came out this week in Stem Cell Reports. They discovered that they could improve muscle function in mice with muscular dystrophy by injecting cardiac progenitor cells into their hearts. The injected cells not only improved heart function in these mice, but also improved muscle function throughout their bodies. The effects were due to the release of microscopic vesicles called exosomes by the injected cells. These cells are currently being used in a CIRM-funded clinical trial by Capricor therapeutics for patients with Duchenne muscular dystrophy.

How to build a better brain (blob)

For years stem cell researchers have been looking for ways to create “mini brains”, to better understand how our own brains work and develop new ways to repair damage. So far, the best they have done is to create blobs, clusters of cells that resemble some parts of the brain. But now researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have come up with a new method they think can advance the field.

Their approach is explained in a fascinating article in the journal Science News, where lead researcher Bennet Novitch says finding the right method is like being a chef:

“It’s like making a cake: You have many different ways in which you can do it. There are all sorts of little tricks that people have come up with to overcome some of the common challenges.”

Brain cake. Yum.

A more efficient way to make iPS cells


Shinya Yamanaka. (Image source: Ko Sasaki, New York Times)

In 2006 Shinya Yamanaka discovered a way to take ordinary adult cells and reprogram them into embryonic-like stem cells that have the ability to turn into any other cell in the body. He called these cells induced pluripotent stem cells or iPSC’s. Since then researchers have been using these iPSC’s to try and develop new treatments for deadly diseases.

There’s been a big problem, however. Making these cells is really tricky and current methods are really inefficient. Out of a batch of, say, 1,000 cells sometimes only one or two are turned into iPSCs. Obviously, this slows down the pace of research.

Now researchers in Colorado have found a way they say dramatically improves on that. The team says it has to do with controlling the precise levels of reprogramming factors and microRNA and…. Well, you can read how they did it in a news release on Eurekalert.




Stem cell-based gut-on-a-chip: a new path to personalized medicine

“Personalized medicine” is a trendy phrase these days, frequently used in TV ads for hospitals, newspaper articles about medicine’s future and even here in the Stem Cellar. The basic gist is that by analyzing a patient’s unique biology, a physician can use disease treatments that are most likely to work in that individual.


Emulate’s Organ-on-a-Chip device.
Image: Emulate, Inc.

This concept is pretty straight-forward but it’s not always clear to me how it would play out as a routine clinical service for patients. A recent publication in Cellular and Molecular Gastroenterology and Hepatology by scientists at Cedars-Sinai and Emulate, Inc. paints a clearer picture. The report describes a device, Emulate’s Intestine-Chip, that aims to personalize drug treatments for people suffering from gastrointestinal diseases like inflammatory bowel disease and Chrohn’s disease.

Intestine-Chip combines the cutting-edge technologies of induced pluripotent stem cells (iPSCs) and microfluidic engineering. For the iPSC part of the equation, skin or blood samples are collected from a patient and reprogrammed into stem cells that can mature into almost any cell type in the body. Grown under the right conditions in a lab dish, the iPSCs self-organize into 3D intestinal organoids, structures made up of a few thousand cells with many of the hallmarks of a bona fide intestine.


Miniature versions of a human intestinal lining, known as organoids, derived from induced pluripotent stem cells (iPSCs).
Image: Cedars-Sinai Board of Governors Regenerative Medicine Institute

These iPSC-derived organoids have been described in previous studies and represent a breakthrough for studying human intestinal diseases. Yet, they vary a lot in shape and size, making it difficult to capture consistent results. And because the intestinal organoids form into hollow tubes, it’s a challenge to get drugs inside the organoid, a necessary step to systematically test the effects of various drugs on the intestine.

The Intestine-Chip remedies these drawbacks. About the size of a double A battery, the Chip is made up of specialized plastic engineered with tiny tunnels, or micro-channels. The research team placed the iPSC-derived intestinal organoid cells into the micro-channels and showed that passing fluids with a defined set of ingredients through the device can prod the cells to mimic the human intestine.

RMI IntestinalChip

Cells of a human intestinal lining, after being placed in an Intestine-Chip, form intestinal folds as they do in the human body. Image: Cedars-Sinai Board of Governors Regenerative Medicine Institute

The Intestine-Chip not only looks like a human intestine but acts like one too. A protein known to be at high levels in inflammatory bowel disease was passed through the microchannel and the impact on the intestinal cells matched what is seen in patients. Clive Svendsen, Ph.D., a co-author on the study and director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute, explained the exciting applications that the Intestine-Chip opens up for patients:


Clive Svendsen

“This pairing of biology and engineering allows us to re-create an intestinal lining that matches that of a patient with a specific intestinal disease—without performing invasive surgery to obtain a tissue sample,” he said in a press release. “We can produce an unlimited number of copies of this tissue and use them to evaluate potential therapies. This is an important advance in personalized medicine.”

Emulate’s sights are not just set on the human intestine but for the many other organs affected by disease. And because disease rarely impacts only one organ, a series of Organs-on-Chips for a particular patient could be examined together. Geraldine A. Hamilton, Ph.D., president and chief scientific officer of Emulate, Inc. summed up this point in a companion press release:


Geraldine Hamilton

“By creating a personalized Patient-on-a-Chip, we can really begin to understand how diseases, medicines, chemicals and foods affect an individual’s health.”



Stem Cell Roundup: Lab-grown meat, stem cell vaccines for cancer and a free kidney atlas for all

Here are the stem cell stories that caught our eye this week.

Cool Stem Cell Photo: Kidneys in the spotlight

At an early stage, a nephron forming in the human kidney generates an S-shaped structure. Green cells will generate the kidneys’ filtering device, and blue and red cells are responsible for distinct nephron activities. (Image/Stacy Moroz and Tracy Tran, Andrew McMahon Lab, USC Stem Cell)

I had to take a second look at this picture when I first saw it. I honestly thought it was someone’s scientific interpretation of Vincent van Gogh’s Starry Night. What this picture actually represents is a nephron. Your kidney has over a million nephrons packed inside it. These tiny structures filter our blood and remove waste products by producing urine.

Scientists at USC Stem Cell are studying kidney development in animals and humans in hopes of gaining new insights that could lead to improved stem cell-based technologies that more accurately model human kidneys (by coincidence, we blogged about another human kidney study on Tuesday). Yesterday, these scientists published a series of articles in the Journal of American Society of Nephrology that outlines a new, open-source kidney atlas they created. The atlas contains a catalog of high resolution images of different structures representing the developing human kidney.

CIRM-funded researcher Andrew McMahon summed it up nicely in a USC news release:

“Our research bridges a critical gap between animal models and human applications. The data we collected and analyzed creates a knowledge-base that will accelerate stem cell-based technologies to produce mini-kidneys that accurately represent human kidneys for biomedical screening and replacement therapies.”

And here’s a cool video of a developing kidney kindly provided by the authors of this study.

Video Caption: Kidney development begins with a population of “progenitor cells” (green), which are similar to stem cells. Some progenitor cells (red) stream out and aggregate into a ball, the renal vesicle (gold). As each renal vesicle grows, it radically morphs into a series of shapes — can you spot the two S-shaped bodies (green-orange-pink structures)? – and finally forms a nephron. Each human kidney contains one million mature nephrons, which form an expansive tubular network (white) that filters the blood, ensuring a constant environment for all of our body’s functions. (Video courtesy of Nils Lindstorm, Andy McMahon, Seth Ruffins and the Microscopy Core Facility at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at the Keck School of Medicine of USC)

Lab-grown hamburgers coming to a McDonald’s near you…

“Lab-grown meat is coming, whether you like it or not” sure makes a splashy headline! This week, Wired magazine featured two Bay Area startup companies, Just For All and Finless Foods, dedicated to making meat-in-a-dish in hopes of one day reducing our dependence on livestock. The methods behind their products aren’t exactly known. Just For All is engineering “clean meat” from cells. On the menu currently are cultured chorizo, nuggets, and foie gras. I bet you already guessed what Finless Foods specialty is. The company is isolating stem-like muscle progenitor cells from fish meat in hopes of identifying a cell that will robustly create the cell types found in fish meat.

Just’s tacos made with lab-grown chorizo. (Wired)

I find the Wired article particularly interesting because of the questions and issues Wired author Matt Simon raises. Are clean meat companies really more environmentally sustainable than raising livestock? Currently, there isn’t enough data to prove this is the case, he argues. And what about the feasibility of convincing populations that depend on raising livestock for a living to go “clean”? And what about flavor and texture? Will people be willing to eat a hamburger that doesn’t taste and ooze in just the right way?

As clean meat technologies continue to advance and become more affordable, I’ll be interested to see what impact they will have on our eating habits in the future.

Induced pluripotent stem cells could be the next cancer vaccine

Our last story is about a new Cell Stem Cell study that suggests induced pluripotent stem cells (iPSCs) could be developed into a vaccine against cancer. CIRM-funded scientist Joseph Wu and his team at Stanford University School of Medicine found that injecting iPSCs into mice that were transplanted with breast cancer cells reduced the formation of tumors.

The team dug deeper and discovered that iPSCs shared similarities with cancer cells with respect to the panel of genes they express and the types of proteins they carry on their cell surface. This wasn’t surprising to them as both cells represent an immature development stage. Because of these similarities, injecting iPSCs primed the mouse’s immune system to recognize and reject similar cells like cancer cells.

The team will next test their approach on human cancer cells in the lab. Joseph Wu commented on the potential future of iPSC-based vaccines for cancer in a Stanford news release:

“Although much research remains to be done, the concept itself is pretty simple. We would take your blood, make iPS cells and then inject the cells to prevent future cancers. I’m very excited about the future possibilities.”


A Tribute to Stem Cells on Valentine’s Day

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

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

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

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

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

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

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

What do you love most about your job at CIRM?

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

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

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

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

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

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

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

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

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

There was a young scientist at CIRM

Whose research made some people squirm

He took lots of cells

Fed them proteins and gels

Until they were grown to full-term

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


One stem cell to rule them all

Many paths to choose

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

Shape-shifting stem cell

Hero for those who suffer

Repairing lost hope

One year ago…

Stem Cell Roundup: New infertility tools, helping the 3 blind mice hear and cow ESCs

Cool Stem Cell Image of the Week


Human egg grown from immature cells in ovarian tissue. (credit: David Albertini)

This week’s Cool Stem Cell Image of the Week comes to us from the lab of reproductive biologist Evelyn Telfer at the University of Edinburgh. Telfer and her team successfully grew human eggs cells from immature ovarian tissue.

This technology could revolutionize the way doctors approach infertility. For instance, when girls and young women undergo chemotherapy for cancer, their eggs are often damaged. By preserving a small piece of ovarian tissue before the cancer treatments, this method could be used to generate eggs later in life for in vitro fertilization. Much more work is necessary to figure out if these eggs are healthy and safe to use to help infertile women.

The study was recently published in Molecular Human Reproduction and was picked up this Science writer Kelly Servick.

Forget 3 blind mice, iPS cells could help 3 deaf mice hear again (Kevin McCormack)
For years scientists have been trying to use stem cells to restore hearing to people who are deaf or hearing impaired. Now a group of researchers in Japan may have found a way.

The team used human iPS cells to create inner ear cells, the kind damaged in one of the most common forms of hereditary deafness. They then transplanted them into the inner ears of mice developing in the womb that are suffering from a congenital form of hearing loss. The cells appeared to engraft and produce a protein, Connexin 30, known to be critical in hearing development.

The research, published in the journal Scientific Reports, could be an important step towards developing a therapy for congenital hearing loss in people.

UC Davis team isolates cow embryonic stem cells for the first time


An early stage cow embryo. Inner cell mass (red) is source of embryonic stem cells. (Credit: Pablo Ross/UC Davis) 

Although human embryonic stem cells (ESCs) were isolated way back in ’98, researchers haven’t had similar luck with embryonic stem cells from cows. Until this week, that is.  A UC Davis team just published a report in PNAS showing that they not only can isolate cow ESCs but their method works almost 100% of the time.


Genetic engineering of these cow stem cells could have huge implications for the cattle industry. Senior author Pablo Ross mentioned in a press release how this breakthrough could help speed up the process of generating superior cows that produce more milk, release less methane and are more resistant to disease:

“In two and a half years, you could have a cow that would have taken you about 25 years to achieve. It will be like the cow of the future. It’s why we’re so excited about this.”

These cow ESCs may also lead to better models of human disease. Because of their small size, rat and mouse models are not always a good representation of how potential therapies or drugs will affect humans. Creating stem cell models from larger animals may provide a better representation.

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

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

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


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

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

A new therapeutic avenue for Parkinson’s diseaseBuck Institute

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

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

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

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

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


Crystal Zhao

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

Researchers Create First Stem Cells Using CRISPR Genome ActivationThe Gladstone Institutes

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


Modeling the Human Brain in 3D

(Image from Pasca Lab, Stanford University)

Can you guess what the tiny white balls are in this photo? I’ll give you a hint, they represent the organ that you’re using right now to answer my question.

These are 3D brain organoids generated from human pluripotent stem cells growing in a culture dish. You can think of them as miniature models of the human brain, containing many of the brain’s various cell types, structures, and regions.

Scientists are using brain organoids to study the development of the human nervous system and also to model neurological diseases and psychiatric disorders. These structures allow scientists to dissect the inner workings of the brain – something they can’t do with living patients.


Dr. Sergiu Pasca is a professor at Stanford University who is using 3D cultures to understand human brain development. Pasca and his lab have previously published methods to make different types of brain organoids from induced pluripotent stem cells (iPSCs) that recapitulate human brain developmental events in a dish.

Sergiu Pasca, Stanford University (Image credit: Steve Fisch)

My colleague, Todd Dubnicoff, blogged about Pasca’s research last year:

“Using brain tissue grown from patient-derived iPSCs, Dr. Sergiu Pasca and his team recreated the types of nerve cell circuits that form during the late stages of pregnancy in the fetal cerebral cortex, the outer layer of the brain that is responsible for functions including memory, language and emotion. With this system, they observed irregularities in the assembly of brain circuitry that provide new insights into the cellular and molecular causes of neuropsychiatric disorders like autism.”

Pasca generated brain organoids from the iPSCs of patients with a genetic disease called Timothy Syndrome – a condition that causes heart problems and some symptoms of autism spectrum disorder in children. By comparing the nerve cell circuits in patient versus healthy brain organoids, he observed a disruption in the migration of nerve cells in the organoids derived from Timothy Syndrome iPSCs.

“We’ve never been able to recapitulate these human-brain developmental events in a dish before,” said Pasca in a press release, “the process happens in the second half of pregnancy, so viewing it live is challenging. Our method lets us see the entire movie, not just snapshots.”

The Rise of 3D Brain Cultures

Pasca’s lab is just one of many that are working with 3D brain culture technologies to study human development and disease. These technologies are rising in popularity amongst scientists because they make it possible to study human brain tissue in normal and abnormal conditions. Brain organoids have also appeared in the mainstream news as novel tools to study how epidemics like the Zika virus outbreak affect the developing fetal brain (more here and here).

While these advances are exciting and promising, the field is still in its early stages and the 3D organoid models are far from perfect at representing the complex biology of the human brain.

Pasca addresses the progress and the hurdles of 3D brain cultures in a review article titled “The rise of three-dimensional brain cultures” published this week in the journal Nature. The article, describes in detail how pluripotent stem cells can assemble into structures that represent different regions of the human brain allowing scientists to observe how cells interact within neural circuits and how these circuits are disrupted by disease.

The review goes on to compare different approaches for creating 3D brain cultures (see figure below) and their different applications. For instance, scientists are culturing organoids on microchips (brains-on-a-chip) to model the blood-brain barrier – the membrane structure that protects the brain from circulating pathogens in the blood but also makes drug delivery to brain very challenging. Brain organoids are also being used to screen for new drugs and to model complex diseases like Alzheimer’s.

Human pluripotent stem cells, adult stem cells or cancer cells  can be used to derive microfluidics-based organs-on-a-chip (top), undirected organoids (middle), and region-specific brain organoids or organ spheroids (bottom). These 3D cultures can be manipulated with CRISPR-Cas9 genome-editing technologies, transplanted into animals or used for drug screening. (Pasca, Nature)

Pasca ends the review by identifying the major hurdles facing 3D brain culture technologies. He argues that “3D cultures only approximate the appearance and architecture of neural tissue” and that the cells and structures within these organoids are not always predictable. These issues can be address over time by enforcing quality control in how these 3D cultures are made and by using new biomaterials that enable the expansion and maturation of these cultures.

Nonetheless, Pasca believes that 3D brain cultures combined with advancing technologies to study them have “the potential to give rise to novel features for studying human brain development and disease.”

He concludes the review with a cautiously optimistic outlook:

“This is an exciting new field and as with many technologies, it may follow a ‘hype’ cycle in which we overestimate its effects in the short run and underestimate its effects in the long run. A better understanding of the complexity of this platform, and bringing interdisciplinary approaches will accelerate our progress up a ‘slope of enlightenment’ and into the ‘plateau of productivity’.”

3D brain culture from the Pasca Lab, Stanford University

Related Links:

UCLA scientists on track to develop a stem cell replacement therapy for Duchenne Muscular Dystrophy

Muscle cells generated by April Pyle’s Lab at UCLA.

Last year, we wrote about a CIRM-funded team at UCLA that’s on a mission to develop a stem cell treatment for patients with Duchenne muscular dystrophy (DMD). Today, we bring you an exciting update on this research just in time for the holidays (Merry Christmas and Happy Hanukkah and Kwanza to our readers!).

DMD is a deadly muscle wasting disease that primarily affects young boys and young men. The UCLA team is trying to generate better methods for making skeletal muscle cells from pluripotent stem cells to regenerate the muscle tissue that is lost in patients with the condition. DMD is caused by genetic mutations in the dystrophin gene, which codes for a protein that is essential for skeletal muscle function. Without dystrophin protein, skeletal muscles become weak and waste away.

In their previous study, the UCLA team used CRISPR gene editing technology to remove dystrophin mutations in induced pluripotent stem cells (iPSCs) made from the skin cells of DMD patients. These corrected iPSCs were then matured into skeletal muscle cells that were transplanted into mice. The transplanted muscle cells successfully produced dystrophin protein – proving for the first time that DMD mutations can be corrected using human iPSCs.

A Step Forward

The team has advanced their research a step forward and published a method for making skeletal muscle cells, from DMD patient iPSCs, that look and function like real skeletal muscle tissue. Their findings, which were published today in the journal Nature Cell Biology, address a longstanding problem in the field: not being able to make stem cell-derived muscle cells that are mature enough to model DMD or to be used for cell replacement therapies.

Dr. April Pyle, senior author on the study and Associate Professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA explained in a news release:

April Pyle, UCLA.

“We have found that just because a skeletal muscle cell produced in the lab expresses muscle markers, doesn’t mean it is fully functional. For a stem cell therapy for Duchenne to move forward, we must have a better understanding of the cells we are generating from human pluripotent stem cells compared to the muscle stem cells found naturally in the human body and during the development process.”

By comparing the proteins expressed on the cell surface of human fetal and adult muscle cells, the team identified two proteins, ERBB3 and NGFR, that represented a regenerative population of skeletal muscle cells. They used these two markers to isolate these regenerative muscle cells, but found that the muscle fibers they created in a lab dish were smaller than those found in human muscle.

First author, Michael Hicks, discovered that using a drug to block a human developmental signaling pathway called TGF Beta pushed these ERBB3/NGFR cells past this intermediate stage and allowed them to mature into functional skeletal muscle cells similar to those found in human muscle.

Putting It All Together

In their final experiments, the team combined the new stem cell techniques developed in the current study with their previous work using CRISPR gene editing technology. First, they removed the dystrophin mutations in DMD patient iPSCs using CRISPR. Then, they coaxed the iPSCs into skeletal muscle cells in a dish and isolated the regenerative cells that expressed ERBB3 and NGFR. Mice that lacked the dystrophin protein were then transplanted with these cells and were simultaneously given an injection of a TGF Beta blocking drug.

The results were exciting. The transplanted cells were able to produce human dystrophin and restore the expression of this protein in the Duchenne mice.

Skeletal muscle cells isolated using the ERBB3 and NGFR surface markers (right) restore human dystrophin (green) after transplantation significantly greater than previous methods (left). (Image courtesy of UCLA)

Dr. Pyle concluded,

“The results were exactly what we’d hoped. This is the first study to demonstrate that functional muscle cells can be created in a laboratory and restore dystrophin in animal models of Duchenne using the human development process as a guide.”

In the long term, the UCLA team hopes to translate this research into a patient-specific stem cell therapy for DMD patients. In the meantime, the team will use funding from a recent CIRM Quest award to make skeletal muscle cells that can regenerate long-term in response to chronic injury in hopes of developing a more permanent treatment for DMD.

The UCLA study discussed in this blog received funding from Discovery stage CIRM awards, which you can read more about here and here.

CIRM interviews Lorenz Studer: 2017 recipient of the Ogawa-Yamanaka Stem Cell Prize [Video]

For eight long years, researchers who were trying to develop a stem cell-based therapy for Parkinson’s disease – an incurable movement disorder marked by uncontrollable shaking, body stiffness and difficulty walking – found themselves lost in the proverbial wilderness. In initial studies, rodent stem cells were successfully coaxed to specialize into dopamine-producing nerve cells, the type that are lost in Parkinson’s disease. And further animal studies showed these cells could treat Parkinson’s like symptoms when transplanted into the brain.



Lorenz Studer, MD
Photo Credit: Sloan Kettering

But when identical recipes were used to make human stem cell-derived dopamine nerve cells the same animal experiments didn’t work. By examining the normal developmental biology of dopamine neurons much more closely, Lorenz Studer cracked the case in 2011. Now seven years later, Dr. Studer, director of the Center for Stem Cell Biology at the Memorial-Sloan Kettering Cancer Center, and his team are on the verge of beginning clinical trials to test their Parkinson’s cell therapy in patients

It’s for these bottleneck-busting contributions to the stem cell field that Dr. Studer was awarded the Gladstone Institutes’ 2017 Ogawa-Yamanaka Stem Cell Prize. Now in its third year, the prize was founded by philanthropists Hiro and Betty Ogawa along with  Shinya Yamanaka, Gladstone researcher and director of the Center for iPS Cell Research and Application at Kyoto University, and is meant to inspire and celebrate discoveries that build upon Yamanaka’s Nobel prize winning discovery of induced pluripotent stem cells (iPSCs).


(L to R) Shinya Yamanaka, Andrew Ogawa, Deepak Srivastava present Lorenz Studer the 2017 Ogawa-Yamanaka Stem Cell Prize at Gladstone Institutes. Photo Credit: Todd Dubnicoff/CIRM

Studer was honored at the Gladstone in November and presented the Ogawa-Yamanka Stem Cell Prize Lecture. He was kind enough to sit down with me for a brief video interview (watch it below) a few minutes before he took the stage. He touched upon his Parkinson’s disease research as well as newer work related to hirschsprung disease, a dangerous intestinal disorder often diagnosed at birth that is caused by the loss of nerve cells in the gut. Using human embryonic stem cells and iPSCs derived from hirschsprung patients, Studer’s team has worked out the methods for making the gut nerve cells that are lost in the disease. This accomplishment has allowed his lab to better understand the disease and to make solid progress toward a stem cell-based therapy.

His groundbreaking work has also opened up the gates for other Parkinson’s researchers to make important insights in the field. In fact, CIRM is funding several interesting early stage projects aimed at moving therapy development forward:

We posted the 8-minute video with Dr. Studer today on our official YouTube channel, CIRM TV. You can watch the video here:

And for a more detailed description of Studer’s research, watch Gladstone’s webcast recording of his entire lecture: