Stem cell stories that caught our eye: making vocal cords, understanding our brain and the age of donor cells matters

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.

Tissue engineered vocal cords. A report from the University of Wisconsin that researchers there had grown new vocal cords got quite a bit of play in the media including this piece on the NBC News web site. It caught my attention not so much because of what they had created, but rather because of the vivid example it provides of cells having a memory of their role and their ability to communicate with each other to function in that role.

In the rather simple experiment, the team took vocal fold tissue from patients who had their larynxes removed for reasons other than cancer. They then used a solution to separate the tissue into individual cells and seeded those cells onto collagen scaffolding. Within 14 days they had fully formed tissue. One of the researchers stated in a phone briefing that the cells knew what they should be doing:

“They’re effectively talking to each other and producing the structural proteins that make this special tissue capable of vibration,” said Brian Frey.

The team transplanted the tissue into a larynx from a deceased dog and was able to demonstrate that the cells could make sound. In the artificial lab setting it evidently sounded a bit like a Kazoo, but the researchers maintained that if transplanted into a human it could easily sound like a voice.

Never ending quest to understand our brain. We’ve known for some time that the gene NeuroD1 plays a critical role in the early development of the brain. Now work by researchers at the Institute of Molecular Biology in Mainz, Germany report that this one gene seems to be the master switch to creating the brain.

Neurons using NeuroD1

Cells in which NeuroD1 is turned on are reprogrammed to become neurons. Cell nuclei are shown in blue and neurons are shown in red

They used several popular new techniques to track the activity of NeuroD1 in living tissue. They found it turned on a large number of genes that act to maintain cells’ trajectory to become nerves. Another indication of NeuroD1’s Svengali role came when they realized that even after it is turned off, the other genes stay active and keep driving cells to become more brain tissue.

“Our research has shown how a single factor, NeuroD1, has the capacity to change the epigenetic landscape of the cell, resulting in a gene expression program that directs the generation of neurons,” wrote the investigators in the EMBO Journal.

A story in Genetic Engineering News describes the potential impact this finding could have on understanding brain development as well as in figuring out how to repair brain damage.

Age of donor cells matters. Stem cells in older individuals just don’t do their jobs as well as those in younger people. Now a team at the Miller School of Medicine in Miami has provided clear evidence that this difference matters when selecting donor stem cells—at least in the mice in this study.

The study, published in Translational Research, looked at the ability of mesenchymal stem cells (MSCs) to protect lungs from injury. HealthCanal picked up the institution’s press release that quoted one of the researchers.

“Donor stem cells from younger mice were effective in preventing damage when infused into older mice at the same time as a disease-causing agent,” said Marilyn K. Glassberg. “However, donor MSCs from older mice had virtually no effect.”

The issue becomes key when debating the merits of autologous cells (from the patient themselves) versus allogeneic cells (from donors). This study adds weight to the side that says for older patients choose allogeneic—and make sure the donor is young.

Stem cell stories that caught our eye: three teams refine cell reprogramming, also stem cell tourism

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.

Why stem cells in the lab don’t grow up right. A classic cartoon among stem cell fans shows a stem cell telling a daughter cell it can grow up to become anything, and in a living creature that is pretty much true. But in the lab those daughter cells often don’t behave and mature properly. This seems particularly true for stem cells made by reprogramming adult cells through the iPS cell technology.

Tissues, such as heart muscle grown in the lab from stem cells too often look and behave like heart tissue found in a growing embryo rather than like a mature adult. A team at Johns Hopkins decided the best way to solve this problem was to understand the differences between those heart tissues maturing in a lab and those grown naturally and to understand those differences at the molecular level. They looked at which molecular and genetic signaling pathways were turned on in each during development.

After studying 17,000 genes in 200 heart cell samples they found that the pathways in the lab-grown cells were like a map in which the roads don’t line up. Pathways that were supposed to be turned on were not and ones that were supposed to be blocked were open. In a university press release picked up by they explain that they now intend to look for ways to correct some of those misguided cellular pathways, in part by making the lab conditions better mimic normal growing conditions.

The result should be tissues grown for research that result in a more accurate model of disease and, potentially, better tissue for transplantation and repair.

Getting the cells needed faster. Pretty much everyone’s cell therapy wish list contains cells that genetically match the patient—to reduce the chance of immune system rejection—and often with the added feature of genetic modification to correct an in-born error. We have the technology to do this. You can use the iPS cell system to reprogram a patient’s adult cells into stem cells and use any number of gene modifying tools to correct the error. But the combined processes can take three months or more; time patients often don’t have.

Researchers at the University of Wisconsin’s Morgridge Institute and the Murdoch Children’s Research Institute in Australia have sped up that process to just two weeks. They found a way to do the stem cell conversion and the genetic correction at the same time and used the trendy new gene-editing tool, CRISPR, which is faster and simpler than other methods. Wisconsin’s stem cell pioneer James Thompson commented on the work led by Sara Howden:

James Thompson

James Thompson

“If you want to conduct therapies using patient-specific iPS cells, the timeline makes it hard to accomplish. If you add correcting a genetic defect, it really looks like a non-starter. You have to make the cell line, characterize it, correct it, then differentiate it to the cells of interest. In this new approach, Dr. Howden succeeded in combining the reprogramming and the gene correction steps together using the new Cas9/CRISPR technology, greatly reducing the time required.”

Howden discussed the work with Australian Broadcasting Corp and her institute issued a press release. In the release she noted than when iPS-based therapies become a reality, the faster method will be critical for certain patients such as children with severe immune deficiency or people with rapidly deteriorating vision.

Skipping the stem cell step. A team at Guangzhou Medical University created unusually pure heart muscle cells directly from skin samples without first turning them into iPS type stem cells. This so-called “direct reprogramming” has been accomplished for a few years, but mostly in nerve tissue and with much less efficiency. This team got 80 percent pure heart muscle.

Heart muscle cells created with traditional iPS cell reprogramming

Heart muscle cells created with traditional iPS cell reprogramming

They also avoided one of the potential problems with iPS technology. Most often, the reprogramming happens using viruses to carry genetic factors into adult cells. The Chinese team used proteins to do the reprogramming, which are much less likely to leave lasting, and potentially cancer-causing, changes in the cells.

“While additional research is needed to fully understand the properties of these cells, the results suggest a potentially safer method to generate cardiac progenitor cells for use as a regenerative therapy after a heart attack,” said Anthony Atala, Editor-in-Chief of STEM CELLS Translational Medicine, which published the work and released a press release picked up by BioSpace.

The research team noted one bit of needed work that reflected back to the first item in this post. They need to see if the new heart cells function like mature native cells and can interact properly with native cells if transplanted.

Stemming stem cell tourism. A pair of medical ethicists, one from Rice University in Houston and one from Wake Forest University in North Carolina, published a call for reforms in how stem cell clinical trials are designed and regulated. They say our system should encourage people to get therapy in the U.S. at regulated clinics rather than go overseas or to seek out unproven therapies here.

“The current landscape of stem cell tourism should prompt a re-evaluation of current approaches to study cell-based interventions with respect to the design, initiation and conduct of U.S. clinical trials,” the authors wrote. “Stakeholders, including scientists, clinicians, regulators and patient advocates, need to work together to find a compromise to keep patients in the U.S. and within the clinical-trial process.”

The web portal MNT wrote an article on the paper based on a Rice press release. The piece notes that many of the same patients who came forward to secure state funding for stem cells like the voter initiative that created CIRM are now tired of waiting for therapies and are seeking out unproven therapies. The authors noted that the problems this causes, in addition to the risks for patients, include the lack of any systematic way to collect data on whether those therapies are really working.

“Policy should be aimed at bringing patients home and fostering responsible scientific research as well as access for patients,” they wrote. “This will require discussions about alternative approaches to the design and conduct of clinical trials as well as to how interventions are approved by the Food and Drug Administration.”

Stem cell stories that caught our eye: mini-brains in a dish, blood stem cells and state funded stem cell research

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.

Great review of brains in a dish. The veteran Associated Press science journalist Malcolm Ritter produced the most thorough overview I have seen of the recent spate of research projects that have grown “mini-brains” in lab dishes. He provides the perspective from the first report in 2013 to a recent, and as he noted, unconfirmed claim of a more complex ball of brain cells.

Alysson Muotri

Alysson Muotri

He uses CIRM grantee Alysson Muotri to discuss the value of modeling diseases with these pea-sized brains. In the case of this University of California, San Diego researcher that involves finding out how nerves in people with autism are different from those in other people. But Ritter does not leave the false impression that these very rudimentary clumps of cells—that each self-organize in slightly different ways—are functioning brains. He makes this point with great quote from Madeline Lancaster of the Medical Research Council in England:

“Lancaster compares the patchwork layout to an airplane that has one wing on top, a propeller at the back, the cockpit on the bottom and a wheel hanging off the side. ‘It can’t actually fly,’ she said. But ‘you can study each of the components individually and learn a lot about them.’”

Ritter also discusses the broader trend of creating various miniature “organoids” in the lab including a quote from CIRM grantee at the University of California, San Francisco, Arnold Kriegstein:

This overall approach “is a major change in the paradigm in terms of doing research with human tissues rather than animal tissues that are substitutes. … It’s truly spectacular.” Organoids “are poised to make a major impact on the understanding of disease, and also human development.”

Unfortunately, this AP piece did not get as broad a pick up as the wire service often achieves. But here is the version from the Seattle Times.

Throw out the textbook on blood stem cells. A new study suggests that the textbook roadmap showing blood stem cells slowly going down various paths to eventually produce specific adult blood cells may be like a faulty GPS system. In this case that voice saying “redirect” is the renown stem cell scientist John Dick of the University of Toronto.

plateletsDick’s research team showed that very early in the process the daughter cell of the stem cell is already committed to a specific adult cell, for instance a red blood cell or a platelet needed for clotting. Low cell counts for one of those cell is the most common cause for patients needing transfusions. Now, with these cell-specific progenitor cells discovered, it may be easier to generate those adult cells for therapy. The discovery will also help the research community better understand many blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases – from anemia, where there are not enough blood cells, to leukemia, where there are too many blood cells,” said Dick in a press release from the University affiliated Princess Margaret Cancer Center. “Think of it as moving from the old world of black-and-white television into the new world of high definition.”

The journal Science published the study today.

The power of states to fund stem cells. The Daily Beast published a good review of state efforts to fund stem cell research with the slightly mischievous title, “George W., Father of Stem-Cell Revolution.” It recounts how several states stepped into the breach after then President George W. Bush restricted stem cell research. The story originally ran in Kaiser Health News under a more subdued headline.


The article states that today seven states offer some level of stem cell research funding. And the author asserts that as an engine for generating economic development and local scientific prestige “stem cell research for many states appears to be worth the investment.” We have to agree.

The story does retell some of the early criticisms of CIRM, but goes on to discuss some of our reforms and quotes our new president C. Randal Mills on the “systems-based agency” he is creating:

“We’re setting up continuous paths to move basic research to clinical trials. It’s like a train moving down a track, where each grant is the link to the next step down the line.”

The piece ends with a great forward-looking quote from Jakub Tolar, head of the University of Minnesota’s Stem Cell Institute:

“We started on drugs a hundred years ago. Then we went to monoclonal antibodies—biological. We are now getting ready to use cells as a third way of doing medicine. We are at a historical sweet spot.”

Stem cell stories that caught our eye: Fertility after chemo, blood shortages, modeling kidney disease and “good” stress

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.

Fertility restoration after chemo—Maybe. A research paper presented at the American Society of Reproductive Medicine annual meeting in Baltimore this week got considerable attention on the web because it suggested women who had lost their fertility due to cancer chemotherapy could have it restored.

A team of Egyptian and US scientists, led by Sarah Mohamed of Mansoura Medical School in Egypt injected bone marrow mesenchymal stem cells directly into the ovaries of mice that had received chemotherapy. They saw restoration of function in the ovaries and the mice were also able to become pregnant and give birth to healthy pups.

While this is potentially exciting news, the stories tended to have headlines that were way too positive. This was a mouse study presented at a meeting, which has some peer review, but not nearly as rigorous as the review that happens before a journal publication. Much more research needs to verify this report before the thousands of women rendered infertile by their cancer therapy can consider baring children again.

The British paper The Telegraph, which had one of the most hyped headlines, also provided some good caveats for readers who stuck with the story to the end:

“Theoretically if you are regenerating the ovary you should be getting better quality eggs,” said Geoffrey Trew of Hammersmith Hospital in London. “Clearly we’re not there yet, and it’s good that the researchers are not over-claiming their findings, but it’s a great proof of concept.”

Potential way to end blood shortages. With the holiday season just a month away, another season is approaching for hospitals; a time of blood shortages as regular donors get too busy and distracted to roll up their sleeves. A team at Dana Farber Cancer Institute and Children’s Hospital, Boston, may have developed a way to eliminate those shortages. They used a gene editing technique to triple the number of red blood cells stem cells make. A major advance given the oxygen carrying capacity of red cells is the main reason for transfusions.

Previous studies had shown a certain gene, when active in the stem cells, resulted in lower numbers of red cells. So they used a genetic technique called RNA interference to turn that gene off. The resulting stem cells produced three times as many red cells as usual.

“We know that if we can make these cells, and improve upon the process, hopefully future blood shortages will not be a problem at all,” lead researcher Vijay Sankaran told Alice Park at Time.

 The team published their work in Cell Stem Cell and a press release from Dana Farber provides a bit more detail.

A mini-kidney (1mm diameter) grown from a patient's stem cells.

A mini-kidney (1mm diameter) grown from a patient’s stem cells.

Mini-kidneys mimic disease. Kidneys were once considered too complex for these early days of using stem cells to create organs. But creating mini-kidneys in the lab has turned out to be much easier than researcher thought. Stem cells, when given the right signals in the lab, self organize into organoids with the various components of kidneys as a few teams around the world have demonstrated over the past year.

But now, a team at Harvard and Brigham and Women’s Hospital has taken these mini organoids to a new level. They have used genetic engineering to model two debilitating kidney diseases in a dish. They used the popular gene editing technique CRISPR to give the stem cells the ability to create organoids that mimic polycystic kidney disease and glomerulonephritis.

“Mutation of a single gene results in changes in kidney structures associated with human disease, thereby allowing better understand of the disease and serving as models to develop therapeutic agents to treat these diseases,” explained senior author Joseph Bonventre of Brigham and Women’s.

The lead author on the study, Benjamin Freedman is now at the University of Washington, which put out a press release on the work picked up by MedicalXpress.

 Stem Cells can benefit from stress. The Huffington Post picked up a Q&A piece on stress that originally appeared in Berkeley Wellness. While detractors of the “Peoples’ Republic of Berkeley” might assume any article in that publication on stress would be long on psychology and short on hard science, they would be wrong.

The Q&A with University of California, Berkeley’s Daniela Kaufer features her work looking at the impact of stress on the stem cells in the brains of rats. It turns out short-term stress can actually enhance the proliferation of stem cells and in turn the number of new nerve cells they produce, which we wrote about based on her early results.

“The stress response is designed to help us react when something potentially threatening happens, to help us deal with it and learn from it. Our research shows that moderate, short-lived stress can improve alertness and performance and boost memory.”

However, she notes that chronic stress suppresses stem cell growth and the generation of new nerve cells. And being a Berkeley publication, the last question does get around to yoga for managing stress.

Stem cell stories that caught our eye: sleepy stem cells, pig organ donors, therapy in the womb and dementia

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 rested stem cell is a better stem cell. A bone marrow stem cell donor who has a sleep deficit of as little as four hours results in stem cells that, when injected into a recipient, lose as much as 50 percent of their normal ability. When transplanted, they don’t migrate to where they belong in the bone marrow as well and they produce fewer of the desired new immune system cells. A CIRM-funded team at Stanford worked with mice in the current study, but suggest in a university press release that their findings could have implications for human patients.

“Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,” said Asya Rolls, a former postdoctoral scholar at Stanford now at Israeli Institute of Technology. “We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation. However, it’s heartening to think that this is not an insurmountable obstacle; a short period of recovery sleep before transplant can restore the donor’s cells’ ability to function normally.”

The team published their work in Nature Communications and the Bioscience Technology web portal picked up the release.

Genetically cleaned up pigs as organ donors. Since pigs have organs similar in size and function to humans, they are often discussed as possible organ donors to overcome the acute organ shortage. One problem: pig cells are full of PERVs—that is porcine endogenous retroviruses. Those viruses, normally inactive for many generations in the pigs, can be activated if transplanted into people. So, the pig donor idea got put on the back burner after some early work in the 1990s uncovered the problem.


Now, a team in the lab of one my favorite faculty members when I was at Harvard, George Church, has inactivated all 62 PERVs in living pig cells. They used the hot new technology called CRISPR that Church helped to refine. The CRISPR gene-editing tool usually requires a separate molecule for each gene to be edited, but the team was able to use just one identifier molecule because all the PERVs come from one long-ago ancestor and share common DNA.

This major advance will not result in pig hearts for humans on its own. Researchers have to find ways to alter certain of the pig’s own genes that produce proteins that could result in immune system rejection of the organs in humans. Making that gene modification in a way that still results in a living pig will be much more difficult. The research got considerable coverage including in the New York Times and in Genetic Engineering and Biotechnology News.

Clinical trial to use stem cells in the womb. Researchers at Sweden’s Karolinska Institute will begin a clinical trial in January to determine if injecting stem cells into a fetus known to carry the genetic defect for “brittle bone” disease can result in a healthier child. The injection will be at 20 to 34 weeks of pregnancy and be repeated every six months for the child’s first two years of life. Fifteen babies will be treated in the womb and another 15 will begin injections after birth to try to determine if early intervention makes a difference.

The Swedish team gave the therapy to two people some years ago, with one now 13 years old and doing better than most with the genetic disorder that results in most patients suffering dozens of fractures during what is often a shortened life span. But since the disorder presents so differently in each patient, the team felt a clinical trial was needed to determine the impact of in utero therapy.

They will be injecting the cells known as mesenchymal stem cells derived from donated fetal tissue. The upcoming trial for the disease formally known as osteogenesis imperfecta was widely covered including in London’s Daily Star and in the industry newsletter FierceBiotech.

Neural stem cells (green) migrate throughout a brain and mature into astrocytes (red).

Neural stem cells (green) migrate throughout a brain and mature into astrocytes (red).

Stem cells and Lewy body dementia. The second leading cause of dementia, after Alzheimer’s disease, carries the acronym DLB for Dementia with Lewy Bodies and a team at the University of California, Irvine, thinks they may have a way to improve the lives of people with DLB. They injected nerve stem cells into mice with a form of DLB and saw improvements in both motor function and cognitive skills.

When the Irvine team looked at the effects of the treatment on the brains of the mice they determined that much of the impact came from the stem cells releasing a protective growth factor Brain-Derived Neurotrophic Factor (BDNF). They found benefit on both of the two types of nerve most affected by DLB, dopamine-making nerves and glutamate-making nerves.

“Our experiments revealed that neural stem cells can enhance the function of both dopamine-and glutamate-producing neurons, coaxing the brain cells to connect and communicate more appropriately. This, in turn, facilitates the recovery of both motor and cognitive function,” said lead researcher Natalie Goldberg in a university press release.

To further test the role of BDNF the team injected the growth factor by itself and saw improvement in motor skill but only very limited gain in cognitive skills. So, the stem cells clearly had a role beyond carrying the BDNF pill bottle.

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.”