Stem cell stories that caught our eye: better heart muscle, first patient with eye cell patch, brain cross talk and gut bugs

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

Growing better heart muscle in the lab. While researchers have been able to grow beating heart cells from stem cells in a dish for many years, those beating blobs of cells have not looked or acted much like the long strong muscle fibers found in a normal heart. A team at Stanford, with collaborators at the Gladstone Institutes have spent much of the past five years looking for ways to make lab-grown heart muscle more like the real thing.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

Heart muscle matured from stem cells functions better when grown in long, thin shapes.

They published a couple of solutions in the Proceedings of the National Academy of Sciences this week. One of the keys was to make the stem cells feel more like they are in their natural environment, which is full of physical tension. When they grew the stem cells on substrates that provided that type of tension they got stronger heart muscle better able to beat in a synchronized rhythm. They also found that stem cells grown in long, narrow chambers produced heart muscle closer in appearance and function to the narrow muscle fibers found in normal hearts.

The press release, written by our former colleague Amy Adams who now works for the University, was picked up by Medical Express.

First patient in trial for blindness. Doctors at the Moorfields Eye Hospital in London have used specialized eye cells derived from embryonic stem cells and grown on a synthetic scaffold to try to reverse blindness caused by age-related macular degeneration(AMD). Prior clinical trials have injected similar cells but without the supporting structure of the patch to hold them in place.

Also, prior trials have aimed to halt the progressive loss of vision in the dry form of macular degeneration. This trial is trying to reverse damage already done by the wet form of AMD. Each of the groups use embryonic stem cells and first mature the cells into a type of cell found in the back of the eye’s retina, retinal pigmented epithelium (RPE) cells.

“The reason we are very excited is that we have been able to create these very specific cells and we have been able to transfer them to the patient,” lead researcher Lyndon Da Cruz told a writer for the Huffington Post. “It’s the combination of being able to create the cells that are missing and demonstrate that we can safely transplant them.”

CIRM funds a team at the University of Southern California and the University of California, Santa Barbara that has collaborated with the London team and plans to use a similar patch system on a trial set to begin in the next few weeks.

The London news got broad pick up in the media, including this BBC Video.

Cross-talk in the brain linked to success. The National Institutes of Health issued a press release this week describing two early results of its major Brain Initiative. One team from the University of California, San Francisco, provided an explanation about why primate brains are so much bigger than other mammals, and a team from Oxford and Washington University in St. Louis mapped cross talk between different parts of the brain to various personality traits.

The second group collected data on 280 measures such as IQ, language performance, rule-breaking behavior and anger that they mined from the initiative’s Connectome Project. Their analysis of 461 people found a strong correlation to sections of the brain talking to each other when in a resting state and positive personality and demographic traits. Those included high performance on memory tests, life satisfaction, years of education and income.

The UCSF team showed that brain stem cells during early development produce as much as 1,000-fold more neurons in primates than in lower mammals. More important, they isolated a reason for this strong performance. As the brain gets bigger the stem cells don’t have to continually migrate greater distance from their homes, called the stem cell niche. Instead they seem to pack their bags and take the niche with them.

“It is great to see data from large investments like the Human Connectome Project and the BRAIN Initiative result in such interesting science so quickly,” said Greg Farber of the National Institute of Mental Health in the release.

Have to agree.

The interplay of bugs and genes in our gut. The consumer press spends a considerable amount of time talking about the bacteria in our digestive tract, and now a team a Baylor College of Medicine in Houston has produced some data that suggests these microbial cohabitants of our bodies, called the microbiome, become important early in our development.

In research published in the journal Genome Biology and in a press release picked up by Medical Express, the researchers showed that the microbiome in mice during the period they are nursing helps determine which genes are turned on or turned off, and those settings, called epigenetics, follow the mice through their adult life. Specifically, they found that the gut microbiome impacted the function of gut stem cells that we rely on to replace the lining of our digestive system approximately every four days.

“This promises some exciting opportunities to understand how we might be able to tailor one’s microbiome exposure during infancy to maximize health and reduce gastrointestinal disease throughout life,” said one member of the team, Robert Waterland.

Stem cell stories that caught our eye: lab-grown kidneys that work, finding blood stem cells’ home and colitis

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

Lab grown kidneys able to take a leak. While a few teams have been able to grow parts of kidneys in the lab using stem cells, they could never show full function because kidneys are not a closed system. They need connecting plumbing and a shutterstock_251360653bladder to collect fluid before urine can be expelled. Now, a team in Japan has built kidneys as well as those other parts in the lab. When they were implanted in rats and pigs and connected to the animals’ own plumbing the man-made organs successfully peed.

The BBC ran a story on the work that included a quote from noted stem cell expert Chris Mason of University College, London:

”This is an interesting step forward. The science looks strong and they have good data in animals. But that’s not to say this will work in humans. We are still years off that. It’s very much mechanistic. It moves us closer to understanding how the plumbing might work.”

The team published the research in the U.S. Proceedings of the National Academy of Sciences.

Seeing through bone to track stem cells. Yes we know blood-forming stem cells reside in bone marrow, but that is a pretty big base of operations. We really haven’t known where in the marrow they tend to hang out and in what sort of groupings. A team at Children’s Research Institute at the University of Texas Southwestern published research this week using new imaging techniques to map the home of all the blood stem cells in marrow and it showed some surprising results.

“The bone marrow and blood-forming stem cells are like a haystack with needles inside. Researchers in the past have been able to find a few stem cells, but they’ve only seen a small percentage of the stem cells that are there, so there has been some controversy about where exactly they’re located,” said UT’s Sean Morrison in a press release posted by Technology Networks.

“We developed a technique that allows us to digitally reconstruct the entire haystack and see all the needles – all the blood-forming stem cells that are present in the bone marrow – and to know exactly where they are and how far they are from every other cell type.”

They found the blood-forming stem cells clustered in the center of the bone marrow rather than near the edges of the bone as was presumed. This improved understanding of the stem cells’ natural environment should make it easier to replicate the cells behavior in the lab and, in turn, lead to improved stem cell therapies.

Help for colitis patients resistant to therapy. About two-thirds of patients with colitis and Crohn’s disease do not respond to one of the leading medications that blocks a protein considered key to the inflammatory process, Tumor Necrosis Factor (TNF). A CIRM-funded team at the Children’s Hospital Los Angeles published research this week suggesting why and offering possible new options for treatment.

“Understanding this mechanism allows us to target new therapeutic approaches for patients who don’t respond to current therapies,” said principal investigator Brent Polk in a university press release posted at Eurekalert.

The mechanism surprised his team. They found that TNF in these patients actually protected against inflammation by inhibiting one type of the immune system’s T cells. The interplay between TNF and those culprit T cells now becomes a target to therapeutic intervention.

Stem cell stories that caught our eye: new CRISPR fix for sickle cell disease, saving saliva stem cells, jumping genes in iPSCs and lung stem cells.

An end run around sickle cell disease with CRISPR
The CRISPR-based gene editing technique has got to be the hottest topic in biomedical research right now. And I sense we’re only at the tip of the iceberg with more applications of the technology popping up almost every week. Just two days ago, researchers at the Dana Farber Cancer Institute in Boston reported in Nature that they had identified a novel approach to correcting sickle cell disease (SCD) with CRISPR.

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels

A mutation in the globlin gene leads to sickled red blood cells that clog up blood vessels (image: CIRM video)

Sickle cell anemia is a devastating blood disorder caused by a single, inherited DNA mutation in the adult form of the hemoglobin gene (which is responsible for making blood). A CIRM-funded team at UCLA is getting ready to start testing a therapy in clinical trials that uses a similar but different gene editing tool to correct this mutation. Rather than directly fixing the SCD mutation as the UCLA team is doing, the Dana Farber team focused on a protein called BCL11A. Acting like a molecular switch during development, BCL11A shifts hemoglobin production from a fetal to an adult form. The important point here is that the fetal form of hemoglobin can substitute for the adult form and is unaffected by the SCD mutation.

So using CRISPR gene editing, they deleted a section of DNA from a patient’s blood stem cells that reduced BCL11A and increased production of the fetal hemoglobin. This result suggests the technique can, to pardon the football expression, do an end run around the disease.

But if there’s already a recipe for directly fixing the SCD mutation, why bother with this alternate CRISPR DNA deletion method? In a press release Daniel Bauer, one of the project leaders, explains the rationale:

“It turns out that blood stem cells, the ultimate targets for this kind of therapy, are much more resistant to genetic repair than to genetic disruption.”

Whatever the case, we’re big believers in the need to have several shots on goal to help ensure a victory for patients.

Clinical trial asks: does sparing salivary stem cells protect against severe dry mouth?
I bet you rarely think about or appreciate your saliva. But many head and neck cancer patients who undergo radiation therapy develop severe dry mouth caused by damage to their salivary glands. It doesn’t sound like a big deal, but in reality, the effects of dry mouth are life-changing. A frequent need to drink water disrupts sleep and leads to chronic fatigue. And because saliva is crucial for preventing tooth decay, these patients often lose their teeth. Eating and speaking are also very difficult without saliva, which cause sufferers to retreat from society.

Help may now be on the way. On Wednesday, researchers from University of Groningen in the Netherlands reported in Science Translational Medicine the identification of stem cells in a specific region within the large salivary glands found near each ear. In animal experiments, the team showed that specifically irradiating the area where the salivary stem cells lie shuts down saliva production. And in humans, the amount of radiation to this area is linked to the severity of dry mouth symptoms.

Doctors have confirmed that focusing the radiation therapy beams can minimize exposure to the stem cell-rich regions in the salivary glands. And the research team has begun a double-blind clinical trial to see if this modified radiation treatment helps reduce the number of dry mouth sufferers. They’re looking to complete the trial in two to three years.

Keeping a Lid on Jumping Genes
Believe it or not, you have jumping genes in your cells. The scientific name for them is retrotransposons. They are segments of DNA that can literally change their location within your chromosomes.

While retrotransposons have some important benefits such as creating genetic diversity, the insertion or deletion of DNA sequences can be bad news for a cell. Such events can cause genetic mutations and chromosome instability, which can lead to an increased risk of cancer growth or cell death.

To make its jump, the DNA sequence of a retrotransposon is copied with the help of an intermediary RNA (the green object in the picture below). A special enzyme converts the RNA back into DNA and this new copy of the retrotransposon then gets inserted at a new spot in the cell’s chromosomes.

Retrotransposons: curious pieces of DNA that can be transcribed into RNA, copied into DNA, and inserted to a new spot in your chromosomes.

The duplication and insertion of transposons into our chromosomes can be bad news for a cell

Most of our cells keep this gene jumping activity in check by adding inhibitory chemical tags to the retrotransposon DNA sequence. Still, researchers have observed that in unspecialized cells, like induced pluripotent stem (iPS) cells, these inhibitory chemical tags are reduced significantly.

So you’d think that iPS cells would be prone to the negative consequences of retrotransposon reactivation and unleashed jumping genes. But in a CIRM-funded paper published on Monday in Nature Structural and Molecular Biology, UC Irvine researchers show that despite the absence of those inhibitory chemical tags, the retrotransposon activity is reduced due to the presence of microRNA (miRNA), in this case miRNA-128. This molecule binds and blocks the retrotransposon’s RNA intermediary so no duplicate jumping gene is made.

The team’s hope is that by using miRNA-128 to curb the frequency of gene jumping, they can reduce the potential for mutations and tumor growth in iPS cells, a key safety step for future iPS-based clinical trials.

Great hope for lung stem cells
Chronic lung disease is the third leading cause of death in the U.S. but sadly doctors don’t have many treatment options except for a full lung transplant, which is a very risky procedure with very limited sources of donated organs. For these reasons, there is great interest in better understanding the location and function of lung stem cells. Harnessing the regenerative abilities of these cells may lead to more alternatives for people with end stage lung disease.

In a BioMedicine Development commentary that’s geared for our scientist readers, UCSF researchers summarize the evidence for stem cell population in the lung. We’re proud to say that one of the lead authors, Matt Donne, is a former CIRM Scholar.

Related links

Stem cell stories that caught our eye: diabetes drug hits cancer, video stem cell tracker and quick n’ easy stem cells for fatal lung disease

The chemical structure of Metformin (Image source: WikiMedia Commons)

The chemical structure of Metformin (Image source: WikiMedia Commons)

Teaching an old drug new tricks.
One the quickest way to get a drug to market is to find one that’s already been FDA approved for other diseases. Reporting this week in Cell Metabolism, researchers from London and Madrid identified the mechanisms that enable the anti-diabetic drug, metformin, to kill pancreatic cancer stem cells (PanCSCs).

Though they make up a tiny portion of a tumor, cancer stem cells (CSCs) are thought to lie dormant most of the time. As a result, they evade chemotherapy only to later revive the tumor and cause relapse. So, the hypothesis goes, target and kill the CSCs and you’ll eradicate the cancer.


Mitochondria – a cell’s power station (image source: WikiMedia Commons)

While most cancer cells produce their energy needs without the use of oxygen, the team found that PanCSCs use oxygen-dependent energy production that occurs in a cell structure called the mitochondria. Because metformin blocks key components of the mitochondria’s energy factory, the drug essentially shuts down power to the PanCSCs leading to cell death.

The PanCSCs still have another trick up their proverbial sleeves: some switch over to a mitochondria-independent form of energy production so the metformin becomes useless against the PanCSCs. However, by tweaking the levels of two proteins, the researchers forced the PanCSCs to only use the mitochondria for energy production, which restored metformin’s cancer-killing ways.

Pancreatic cancer has very poor survival rates with very limited treatment options. Let’s hope this work leads to alternatives for patients and their doctors.

It’s all about location, location, location. Or is it?
We’ve written numerous times at the Stem Cellar about the importance of a stem cell’s “neighborhood” for determining the cell type into which it will eventually specialize. But a study published this week in Stem Cell Reports put the role of a cell’s surroundings somewhat into question.

A research team at Drexel University in Philadelphia compared stem cells in the back of the brain – an area that interprets visual information – with stem cells in the front of the brain – an area responsible for controlling movement. A fundamental question about brain development is how these areas form very different structures. Are the stem cells in each part of the brain already programmed to take on different fates or are they blank slates which rely on protein signals in the local environment to determine the type of nerve cell they become?

To chip away at this question, the team isolated mouse stem cells from the back and the front on the brain. Each set was grown in the lab using the same nutrients and conditions. You might have guessed the stem cells would behave the same but that’s not what happened. Compared to the stem cells from the back of the brain, the front brain stem cells gave rise to smaller daughter cells that divided more slowly. This suggests these brain stem cells already have some built-in properties that set them apart.

The methods used in the study are as fascinating as the results themselves. The team developed a time-lapse cell-tracking system from scratch that, with minimal human intervention, tags individual daughter cells and analyzes their fate as they grow, move and specialize on the petri dish. In the movie below, Professor Andrew Cohen, one of the authors who helped design the web-based software, succinctly describes the work. Also this movie of the tracking system in action is stunning.

Kudos to the team for making the software and their data set open access. There’s no doubt this technology will lead to important new discoveries.

Quick and easy stem cells to fight deadly lung disease
Lung disease is the 3rd deadliest disease in the U.S. It afflicts 33 million people and accounts for one in six deaths. One of those diseases is Idiopathic Pulmonary Fibrosis (IPF), an incurable disease that causes scarring and thickening of the lungs and makes breathing more and more labored. People often succumb to the disease within 3 to 5 years of their diagnosis. Use of lung stem cells to replace and heal damaged tissue is a promising therapeutic strategy for IPF.

Red and green indicate lung stem cells within a spheroid. (Image credit: Henry et al. Stem Cells Trans Med September 2015-0062)

Red and green indicate lung stem cells within a spheroid. (Image credit: Henry et al. Stem Cells Trans Med September 2015-0062)

This week, a research team from North Carolina State University reported in Stem Cells Translational Medicine on a quick and easy method for growing large amounts of lung stem cells from healthy lung tissue. The typical process of harvesting the tissue, sorting the individual lung cells, and growing the cells on petri dishes can be costly and time-consuming.

Instead, the NCSU team grew the human lung stem cells in three dimensional spheres containing multiple cell types and allowed them to float in liquid nutrients. The lung stem cells are at the center of the sphere surrounded by support cells. This method better resembles the natural cellular environment of the stem cells compared to a flat homogenous lawn of cells in a petri dish.

When introduced intravenously into mice with IPF-like symptoms, these lung spheroids reduced lung scarring and inflammation, nearly matching the animals without IPF. And in a head-to-head comparison, the lung spheroids were more effective than fat-derived mesenchymal stem cells, another proposed cell source for treating lung disease. Alas, humans are not mice and more studies are necessary to reach the ultimate goal of treating IPF patients. But I’m excited about this team’s progress and look forward to hearing more from them.

Related Press Releases:

Stem cell stories that caught our eye: our earliest days, cell therapy without the cells and unproven therapies

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

2-cell embryoMapping our earliest days—as an embryo. We have some 23,000 genes in every cell of our body, but on day two after fertilization just 32 are switched on. A team at Sweden’s Karolinska Institute has for the first time mapped all the gene activity for the first few days of embryo development—information that is yielding clues for developing better fertility treatments.

One of their more interesting finding was that by day three, the number of active genes has grown to 129 even though the embryo has only grown from four to eight cells.

“These genes are the ‘ignition key’ that is needed to turn on human embryonic development. It is like dropping a stone into water and then watching the waves spread across the surface,” said the project leader Juha Kere in an article in Health News Digest.

As with much science today, the team took advantage of rapidly advancing technology in genetic analysis to map the gene activation.

Sending the message without the messenger. In many experimental stem cell therapies it’s not the stem cells themselves that are expected to make the repair but rather other cells in the body that respond to chemical messages released by the stem cells. Stem cells often send out those messages in packets called exosomes, which has led several teams to start using the exosomes alone for repair.

A stem cell releasing exosomes, sort of like little medicine bags.

A stem cell releasing exosomes, sort of like little medicine bags.

One group in Germany just published results in Stem Cells Translational Medicine suggesting that in at least one disease, a mouse model of stroke, exosomes trigger as much repair as whole stem cells. The researchers from the University of Duisburg-Essen claim to be the first to publish a side-by-side comparison of exosomes, which are also called extracellular vesicles (EVs) and whole stem cells.

“The fact that intravenous EV delivery alone was enough to protect the post-stroke brain and help it recover highlights the clinical potential of EVs in future stroke treatment,” said the two lead researchers in a press release distributed by the journal and picked up by BioSpace.

 They reported that the exosomes promoted brain recovery and protected the mice from post stroke inflammation that can cause ongoing damage.

Three hits on unproven stem cell therapy. Yesterday’s news feed brought in three welcomed pieces trying to explain why so many stem cell treatments being offered today are unproven, skirt regulations and may be a rip-off.  

 A group of neurologists from Ohio State University wrote a piece on the growing problem of “stem cell tourism” in the journal JAMA Neurology. The piece got picked up by many news outlets including Fox News. In particular, the authors noted internet advertisements suggesting stem cells are proven to help multiple sclerosis, ALS (Lou Gehrig’s disease) and other hard or impossible to treat neurological conditions. They called upon their fellow neurologists to do a better job of advising their patients on the issue.

“We must help educate our patients not only in the clinic setting, but also by working with patient advocacy groups such as the National Multiple Sclerosis Society and the ALS Association,” said one of the Ohio State authors, Jaime Imitola.

USA Today published a pair of pieces. One dealt with athletes making very visible trips to clinics offering unproven stem cell therapies and the power their fame has to attract other customers. The second piece discussed face creams that claim to have benefit due to stem cells and the lack of data and often lack of logic behind most of those claims.

stem cell drive through

From Paul Knoepfler’s Stem Cell Blog

Brent Schrotenboer wrote both pieces and he did the best job I’ ve seen in the consumer press of explaining how the US-based clinics skirt FDA regulation and fail to provide data showing their stem cells caused an improvement in the athletes beyond the other therapies they received at the same time. At almost 3,000 words the piece is unusually long for USA Today and at that length he has the opportunity to cover quite a bit of nuance between some of the various clinic offerings. He quotes a CIRM-grantee from the University of California, San Diego, Lawrence Goldstein a couple times, including in the concluding paragraph:

“It’s hard to write good law and regulation that allows legitimate work to proceed as rapidly as possible while prohibiting illegitimate work. Part of the problem is it is a new area of medicine where the regulations didn’t anticipate this sort of thing. The regulators on the ground in the field, they themselves don’t have adequate background to tell what’s legit and what’s not. It’s hard.”

Stem cell stories that caught our eye: getting the right cell, an energy booster, history of controversy and a fun video

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

Light used to direct stem cell fate. Stem cells respond to a symphony of cellular signals telling them to remain stem cells or to mature into a specific type of tissue. Much of stem cell biology today has researchers hitting various notes in various rhythms until the score produces a reasonable percentage of the desired tissue.

It’s often a rather discordant process because the cell is not a simple keyboard. A team at the University of California, San Francisco, has used a neat light trick to make the music a little easier to understand. They started with two known facts: that the protein made by the BRN2 gene can drive stem cells to become nerves and that the gene is often turned on in stem cells and they ignore it, choosing to remain stem cells. The UCSF team genetically engineered mouse stem cells so that they could turn on the BRN2 gene with light.

They found that the gene could only drive the production of nerve cells when it was turned on for a relatively long time. They then discovered that the stem cells were responding to another note in the score, a protein that kept the cells in the stem cell state but became depleted after a prolonged period of BRN2 expression.

“There’s lots of promise that we can do these miraculous things like tissue repair or even growing new organs, but in practice, manipulating stem cells has been notoriously noisy, inefficient, and difficult to control,” said Mather Thomson, one of the senior authors on the paper published in Cell Systems and quoted in a university press release widely picked up, including by News Medical. “I think it’s because the cell is not a puppet. It’s an agent that is constantly interpreting information, like a brain. If we want to precisely manipulate cell fate, we have to understand the information-processing mechanisms in the cell that control how it responds to the things we’re trying to do to it.”

Stem cells delivering engines. Jan Nolte, one of our grantees at the University of California, Davis, and editor of the journal Stem Cells, likes to refer to mesenchymal stem cells (MSCs) as little ambulances that rush emergency medical kits to sites of injury. These stem cells that normally hang out in the bone marrow can generate bone, cartilage and blood vessels, but also can deliver a number of chemicals that either tamp down inflammation or summons other repair cells to the scene. The Scientist published a good overview on how MSCs deliver a key repair tool: mitochondria, known as the powerhouse of cells, to cells in need of an energy boost.

Mitochondria are very susceptible to stressors like a heart attack and often are the first parts of a cell to succumb to the stress. While researchers have known for a decade that MSCs can deliver mitochondria to cells, they haven’t known how this happens. They are rapidly gathering that knowledge hoping they to find better ways to harness that particular MSC skill for therapy.

The author walks through a number of discoveries over the past couple years that have begun to paint a picture of this paramedic skill. She also briefly discusses some potential therapies that have been tested in animals.

Embryonic stem cell controversy waning. Pacific Standard, which has become my favorite “thought” magazine even though I have never seen a print copy, published a pretty thorough overview of the early controversy about embryonic stem cells (ESCs) and the many recent scientific advances that may make them unnecessary. The author closes with the fact that for now, advancing those alternatives requires the continued use of ESCs.

Leading with the George W. Bush quote about ESCs being “the leading edge of a series of moral hazards,” he goes on to note that the controversy drove the creation of CIRM and helped Democrats take control of the Senate in 2006. But the bulk of the piece focuses on the alternatives starting with the Nobel Prize-winning discovery of reprogramed adult cells called induced pluripotent stem cells that mimic ESCs. It also covers most recent advances in converting one type of adult cell directly into another type of tissue.

The author closes with a caveat on the ongoing importance of ESCs, at least for now.

“The controversy isn’t over quite yet though—while the newer techniques are immediately useful in research, they have yet to yield any therapies. And because embryonic stem cells are useful for studying how different types of cells develop naturally in the body, they still play an important role in ongoing biomedical research.”

However, he does suggest that eventually, technology will end this controversy.

NOVA video on imagingNOVA video on the brain. Alright, this video only tangentially relates to stem cells and only mentions them toward the end. But it does get at one of the pressing problems in advancing our field: actually seeing what stem cells do at the cell-to-cell and molecular level.

If you are even a casual fan of science, how can you not like a video that starts out with two young scientists using phrases like, “crazy idea,” “wild dream” and “told we’re wasting our time.” It even goes on to talk about “your brain on diapers.” It’s got to be worth the five and a half minutes on the NOVA PBS web site.

It let’s two MIT researchers narrate their effort to image the tiniest of cellular interactions in the brain. Since they found limitations in every existing attempt to see smaller detail, they decided to inflate the brain and make the details larger. They did this by adding the same absorbent material found in diapers to thin slices of mouse brain that had different types of tissues dyed in varying colors. When they added water the brain slice swelled expanding the details.

The result: some really cool images and a tool already being used by scientists around the world. It is now called “expansion microscopy.”

Stem cell stories that caught our eye: A groove for healing hearts, model for muscular dystrophy and the ice bucket worked

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

A tight groove could help heal a heart.  We have written several posts with the theme “It takes a village to raise a stem cell.” If you want a stem cell to mature into a desired tissue you have to pay attention to all aspects of its environment—both the chemicals around it and the physical space.

A team at the Imperial College London has provided the latest chapter to this tale. It turns out if you want stem cells to consistently turn into long fibers of heart muscle, besides providing them with the right chemical signals making them grow in long narrow grooves on lab plate also helps. They got a two-fold increase in heart muscle cells compared to stem cells grown on a flat lab plate.

They’re now trying to figure out why the etched silicon chips worked so well for generating heart muscle. The journal Biomaterials and Regenerative Medicine published the work and the web portal myScience picked up the university’s press release.

Stem cell model for muscular dystrophy. In the past, when scientists have looked at muscle samples from patients with Duchenne muscular dystrophy (DMD) to see why they have the characteristic muscle weakening, they ‘ve arrived at the scene of the crime too late. At that point, the cellular missteps had already occurred and all that is left to observe was the damage.

Healthy muscle cells express dystrophin (green), not cells from DMD patients (middle), but treated stem cells from patients do (right)

Healthy muscle cells express dystrophin (green), not cells from DMD patients (middle), but treated stem cells from patients do (right)

So, a team at Kyoto University reprogrammed a patient’s cells to create iPS type stem cells. They then used genetic cues to direct the stem cells to become muscle and watched to see how what went wrong as this process happened.

“Our model allows us to use the same genetic background to study the early stage of pathogenesis which was not possible in the past,” said first author Emi Shoji.

The research published in Scientific Reports and highlighted in a university press release picked up by MedicalXpress documented the level of inappropriate influx of calcium into the cells and showed that a specific cell surface receptor channel was to blame. That receptor will now become a target for new drug therapy for DMD pateints.

Ice bucket results.  The ALS Association raised $220 million in the past year for amyotrophic lateral sclerosis, or Lou Gehrig’s disease, by getting people to dump bucket of ice water over their heads and then make a donation. More important, in just a year a major paper funded by the proceeds of the ice bucket challenge has shown a defect in the nerves of ALS patients and shown that correcting the defect makes the cells healthier. Those are pretty fast results for science.

In a paper published in the prestigious journal Science a team at Johns Hopkins found that one protein, TDP-43, was not doing its job well. When they genetically modified stem cell from ALS patients to correct that defect the cells worked properly. YahooFinance ran a story about the challenge and the new research.

“If we are able to mimic TDP-43’s function in the human neurons of ALS patients, there’s a good chance that we could slow down progression of the disease!” said Jonathan Ling, a researcher on the team. “And that’s what we’re putting all our efforts into right now.”

Of the initial $115 million raised during the early months of the challenge, 67 percent went to research, 20 percent to patient services, and nine percent to public and professional education. Just four percent went to overhead costs of fund raising.

China says it’s cracking down on clinics. I spend a considerable amount of time suggesting callers to our agency be very cautious about considering spending large sums of money to go overseas to get unregulated and unproven stem cell treatment. So, I was pleased to read this morning’s news that China’s top health authority issued regulation to control some of the most questionable clinics.

The regulations reported in China Daily note that any treatments using stem cells for conditions other than proven uses in blood diseases would be considered experimental and could only be conducted in approved hospitals. It noted conditions touted by clinics there including epilepsy, cerebral palsy, spinal cord injury and autism.

“Only eligible hospitals can perform the practice as a clinical trial for research purpose and it must not be charged or advertised. Anyone caught breaking the rules will be punished according to the new regulation,” said Zhang Linming, a senior official of the science and technology department of the commission.

Stem cell stories that caught our eye: shutting down cancer stem cells, safer BMT, better gene therapy and a 3rd ear

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

A new route to shut down cancer stem cells. A team at Texas A&M University has discovered a specific protein’s role in keeping cancer stem cells active and shown the pathway it uses to do its dirty deed. That pathway immediately became a target for future cancer therapy.

Although not universally accepted by all cancer researchers, the theory that cancer stem cells circumvent traditional therapy and keep cancers coming back is gaining credence through studies like the current one. The Texas team looked at the protein FGF that has been implicated in cancer but has not been a target of drug research because it is involved in so much of normal cell processes. It has seemed impossible to halt its bad behavior without inhibiting its good behavior. They tracked down its impact on cells believed to be cancer stem cells and found the pathway it uses for that effect. So, future teams can target this pathway rather than FGF itself and its many roles.

“If we understand how to keep these cells dormant it means that although we may have to live with the presence of cancer stem cells, we can prevent them from causing the cancer to come back,” said one of the study lead authors, Fen Wang. “That’s what we are trying to understand. That is the future of cancer therapy.”

The NewsMedical web portal picked up the university’s release about the research published in The Journal of Biological Chemistry.  CIRM funds several teams trying to thwart cancer stem cells both in blood cancers and in solid tumors.


Safer bone marrow transplant. The most common stem cell therapy, commonly called bone marrow transplant, has a more than three-decade record of success treating cancer patients. As doctors have grown more comfortable with the procedure, they expanded its use beyond using a person’s own stem cells and stem cells from immunologically well-matched donors to using cells from only partially matched donors. As this has increased the number of lives saved it has also increased the number of patients put at risk for the horrible complication known as graft versus host disease (GVHD). Besides being painful and debilitating, GVHD frequently ends in death.

A team at Seattle’s Fred Hutchinson Cancer Center completed a genetic analysis of transplant patients that did and did not develop GVHD. They found a specific gene marker that increases the risk of the complication by more than 50 percent and the risk of death by 25 percent. The results should push physicians with patients who have the at-risk gene to search harder for a matching donor before they resort to a mismatched transplant.

“Our data provide new information on the role of HLA-DPB1 expression in transplantation associated risks that can be used to guide the selection of donors for future transplant recipients in order to minimize the risk of acute GVHD,” said Effie Petersdorf, one the study authors in an article in MEDPAGETODAY.

The study appears in this week’s New England Journal of Medicine, but anyone who does not want to climb the journal’s pay wall, can get considerable more detail in the MEDPAGE article written by a former colleague from my days editing a national medical magazine, Charles Bankhead. You can trust Charlie to get the story right.


Using evolution science to improve gene therapy. The field of gene therapy—providing a correct copy of a gene to someone born with a mutation or using a gene to deliver a desired protein—is finally starting to take off. But one of the oldest tools for getting desired genes into cells, a family of viruses called adeno-associated viruses (AAVs) has serious limitations when trying to directly deliver the gene into people. Most of us have been infected with various AAVs and developed immunity to them. So, our immune system may wipe out the virus carrying the desired payload before it can deliver its goods.

Many teams have developed various forms of AAV that help a bit; making the viruses a little less likely to be recognized. Now, a team at the Harvard Stem Cell Institute has taken a major step down that path using evolutionary science. They used existing records of how the virus has changed over time to construct surface proteins that would not be recognized by the immune systems of most people alive today. wrote about the research that appeared in the journal Cell Reports.


ear on arm jpegListen up for the week’s oddest story. An Australian performance artist who goes by the name Stelarc has worked with a team of surgeons to grow an ear on his forearm, which he intends to implant with a microphone connected to the internet so followers of his art can hear what he hears 24/7. Not surprisingly, his family is a little skeptical.

Surgeons built the main part of the ear by implanting a scaffold made from standard materials used in plastic surgery and the artist’s own cells populated it with blood vessels and other tissues. But to grow the exterior ear lobe he intends to work with a team using stem cells, which is why this story appeared in my news feed dozens of times this week.

CNN Style did one of the most thorough write-ups including a good discussion of the ethics of wasting valuable time of medical professionals, something Stelarc himself discussed. He concluded that the value grew from getting the science world and art world to intermingle and better understand each other, something that has been on our soapbox for years.

“But I’ve found there’s a lot of goodwill from people who ordinarily would not have contact with an artist, and ordinarily would not see the reason for wasting time and money and their expertise on doing something like this, and that’s heartening,” Stelarc said.

Stem cell stories that caught our eye: potentially safer cell reprogramming, hair follicle cells become nerve and liver stem cells

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

A potentially safer way to reprogram cells. Ever since then soon-to-be Nobel Prize winner Shinya Yamanaka showed how to reprogram adult cells to an embryonic stem cell-like state labs around the world have jumped on that band wagon. But many of their experiments have not just been using those cells but rather looking for ways to make them more efficiently and possibly safer for clinical use.

The four “Yamanaka factors” traditionally used to make what are now called induced pluripotent stem cells (iPSCs) include genes that can induce cancer. So, folks have been justifiably nervous about using cells derived from iPSCs in patients.

Today in the journal Science two different Chinese teams report slightly different methods of using only chemicals to reprogram skin cells directly into nerves. One team worked at the Shanghai Institutes for Biological Sciences and the other worked at Peking University.

“In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible,” Hongkui Deng of the Peking team said in a press release used to write a piece in the International Business Times.


Stem cells in hair follicles may repair nerve. The base of our hair follicles contains skin stem cells as you would expect, but it also contains cells with markers suggesting they come from the area of the embryo known as the neural crest. A team at the University of Newcastle in the U.K. tested those cells to see if they have stem cell properties and they do.

They were able to use those cells to create Schwann cells, support cells that our bodies use to repair nerves and help with certain systems like sensation. The team’s Schwann cells interacted with nerve cells in lab dishes the way natural cells do in the body.

“We observed that the bulge, a region within hair follicles, contains skin stem cells that are intermixed with cells derived from the neural crest – a tissue known to give rise to Schwann cells,” said Maya Sieber-Blum, in a university press release picked up by Yahoo. “This observation raised the question whether these neural crest-derived cells are also stem cells and whether they could be used to generate Schwann cells.”

They showed that the cells can indeed become Schwann cells. The researchers now want to see if their cells can repair nerve damage in an animal model.

Prior work at Stanford had turned embryonic stem cells into liver cells.

Prior work at Stanford had turned embryonic stem cells into liver cells.

Drink up. Liver stem cells found. The liver creates new liver cells quite readily, whether damaged by alcohol or other factors. But no one has known exactly where the new cells come from, with most researchers assuming the remaining health cells divide to create new tissue. But a team at Stanford suggested that the liver works too hard for that to be the case. In order to remove all the toxins that come its way adult liver cells have amplified certain chromosomes, and team leader Roel Nusse said that would make them unable to divide and create new cells.

So, his team set out to track down previously elusive liver stem cells. They bred mice that had cells that would have a green florescent glow if they carried a protein usually found only on stem cells. They indeed did find stem cells and tracked them as the animals matured and saw them both divide to create more stem cells and mature into adult liver cells.

“We’ve solved a very old problem,” said Nusse, who is a Howard Hughes investigator. “We’ve shown that like other tissues that need to replace lost cells, the liver has stem cells that both proliferate and give rise to mature cells, even in the absence of injury or disease.”

The Hughes Institute issued a press release and the International Business Times wrote the story and illustrated it with a photo from CIRM’s Flickr site.

Stem cell stories that caught our eye: Prostate cancer and BPA, mini organs and diabetes trial

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

Latest mini-organ, a prostate, fingers BPA. A team at the University of Illinois, at Chicago, has added the prostate gland to the growing list of “organoids” that have been grown from stem cells in the lab. The tiny gland that produces semen in men has an unusually high rate of cancer compared to other organs. Prior research has linked that cancerous nature to exposure to the hormone estrogen during fetal growth, including synthetic estrogen mimics like the chemical BPA (bisphenol A) found in many plastics.

Unlike the other organs associated with male gender, which form very early in fetal development, the prostate develops later when stem cells’ roles are more narrowly defined to creating specific tissues. The team, led by Gail Prins, had previously shown that prostate stem cells grown in the presence of BPA formed cells more likely to show signs of cancer. But that did not allow them to determine what really triggered the increase in cancer. So, they decided to grow mini prostates and look at all the cells as they developed in the organoid.

“What we were doing originally with the human prostate stem cells is we were mixing and growing them in vivo,” Prins told Medical Daily. “The idea to generate this organoid came from the first author, Esther Calderon-Gierszal; she was my graduate student. ‘They’ve done it for other organs,’ she thought. ‘Let’s try it for a prostate.’”

The researchers pushed embryonic stem cells to grow into the several different tissues found in a prostate gland using a cocktail of hormones. Although much smaller than a normal prostate the cells did self-organize into structures that resembled the gland. When they grew the organoid in the presence of BPA they found an unusually large number of prostate specific stem cells. So, it appears just the increased number of stem cells increases the likelihood a few will go bad and form cancer.

A round up of all the mini-organs. The journal Nature has written a very accessible wrap up in its news section on all the various organs that have been simulated in a lab dish since a Japanese team reported the phenomenon for the first time in 2008. After a fun lead-in explaining the science, Cassandra Willyard runs through what has been accomplished so far in the stomach, kidney, and liver.

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

Part of a miniature stomach grown in the lab, stained to reveal various cells found in normal human stomachs [Credit: Kyle McCracken]

The fun in the opening section comes from the fact that given the right environment, stem cells are pretty darn good at self-organizing into the multiple tissue types that become a specific organ. So much so, that the early teams that saw it in the lab were shocked and did not at first know what they had.

Willyard starts with quotes from Madeline Lancaster, a post-doctoral fellow in a lab at the Institute for Molecular Biotechnology in Vienna, Austria. She found milky looking spheres in the lab cultures and when she cut into them she found multiple types of nerves. So she grabbed her mentor and reported:

“I’ve got something amazing. You’ve got to see it.”

She also discusses the work that led Hans Clevers, a researcher at Hubrecht Institute in Utrecht, the Netherlands, to report the creation of mini-guts in 20009. They grew the cells in a gel that resembled the structure that naturally surrounds cells. In this “at-home” environment stem cells formed much more complex tissue than he had hoped.

“The structures, to our total astonishment, looked like real guts,” Clevers said. “They were beautiful.”

The author also lets Clevers talk about taking his work the next step, using the gut organoids to screen for drugs for related diseases. If you have been following this work, Willyard’s piece is a must read.

Second clinical trial site for diabetes. Opening multiple clinical trial sites accelerates the process of determining whether a new therapy is safe and effective. So we were thrilled to get the announcement from ViaCyte that they would begin enrolling patients at a second location for the diabetes trial we helped them launch by funding the first clinical trial site at the University of California, San Diego.

That trial uses pancreatic cells grown from embryonic stem cells that are protected from immune attack by a semi-permeable pouch. The second site, at the University of Alberta Hospitals in Edmonton, Canada, is being funded in part by Alberta Innovates as well as by the JDRF Canadian Clinical Trials Network. JDRF also helps support the San Diego trial through its US office.

The lead researcher for the Alberta trial, James Shapiro, developed the procedure for transplanting pancreatic tissue from cadavers that became known as “the Edmonton Protocol.” That protocol has changed many lives, but because it requires life-long immunosuppression, doctors only recommend it for the most severe diabetics. The small number of donor pancreases also limits its use. Shapiro commented about the value and need for something like the ViaCyte therapy in a company press release picked up by Yahoo Finance, and dozens of other sites:

“The fact remains that new treatments are sorely needed, not only for the high risk patients but for all patients suffering from this life-altering disease.  The remarkable promise of the (ViaCyte) product candidate is that a virtually limitless source of appropriate human cells can be transplanted without the need for lifetime immunosuppression.”