Stem cell stories that caught our eye: new baldness treatments?, novel lung stem cells, and giraffe stem cells

Novel immune system/stem cell interaction may lead to better treatments for baldness. When one thinks of the immune system it’s usually in terms of the body’s ability to fight off a bad cold or flu virus. But a team of UCSF researchers this week report in Cell that a particular cell of the immune system is key to instructing stem cells to maintain hair growth. Their results suggest that the loss of these immune cells, called regulatory T cells (Tregs for short), may be the cause of baldness seen in alopecia areata, a common autoimmune disorder and may even play a role in male pattern baldness.

Alopecia, a common autoimmune disorder that causes baldness. Image: Shutterstock

While most cells of the immune system recognize and kill foreign or dysfunctional cells in our bodies, Tregs act to subdue those cells to avoid collateral damage to perfectly healthy cells. If Tregs become impaired, it can lead to autoimmune disorders in which the body attacks itself.

The UCSF team had previously shown that Tregs allow microorganisms that are beneficial to skin health in mice to avoid the grasp of the immune system. In follow up studies they intended to examine what happens to skin health when Treg cells were inhibited in the skin of the mice. The procedure required shaving away small patches of hair to allow observation of the skin. Over the course of the experiment, the scientists notice something very curious. Team lead Dr. Michael Rosenblum recalled what they saw in a UCSF press release:

“We quickly noticed that the shaved patches of hair never grew back, and we thought, ‘Hmm, now that’s interesting. We realized we had to delve into this further.”

That delving showed that Tregs are located next to hair follicle stem cells. And during the hair growth, the Tregs grow in number and surround the stem cells. Further examination, found that Tregs trigger the stem cells through direct cell to cell interactions. These mechanisms are different than those used for their immune system-inhibiting function.

With these new insights, Dr. Rosenblum hopes this new-found role for Tregs in hair growth may lead to better treatments for Alopecia, one of the most common forms of autoimmune disease.

Novel lung stem cells bring new insights into poorly understood chronic lung disease. Pulmonary fibrosis is a chronic lung disease that’s characterized by scarring and changes in the structure of tiny blood vessels, or microvessels, within lungs. This so-called “remodeling” of lung tissue hampers the transfer of oxygen from the lung to the blood leading to dangerous symptoms like shortness of breath. Unfortunately, the cause of most cases of pulmonary fibrosis is not understood.

This week, Vanderbilt University Medical Center researchers report in the Journal of Clinical Investigation the identification of a new type of lung stem cell that may play a role in lung remodeling.

Susan Majka and Christa Gaskill, and colleagues are studying certain lung stem cells that likely contribute to the pathobiology of chronic lung diseases.  Photo by: Susan Urmy

Up until now, the cells that make up the microvessels were thought to contribute to the detrimental changes to lung tissue in pulmonary fibrosis or other chronic lung diseases. But the Vanderbilt team wasn’t convinced since these microvessel cells were already fully matured and wouldn’t have the ability to carry out the lung remodeling functions.

They had previously isolated stem cells from both mouse and human lung tissue located near microvessels. In this study, they tracked these mesenchymal progenitor cells (MPCs) in normal and disease inducing scenarios. The team’s leader, Dr. Susan Majka, summarized the results of this part of the study in a press release:

“When these cells are abnormal, animals develop vasculopathy — a loss of structure in the microvessels and subsequently the lung. They lose the surfaces for gas exchange.”

The team went on to find differences in gene activity in MPCs from healthy versus diseased lungs. They hope to exploit these differences to identify molecules that would provide early warnings of the disease. Dr. Majka explains the importance of these “biomarkers”:

“With pulmonary vascular diseases, by the time a patient has symptoms, there’s already major damage to the microvasculature. Using new biomarkers to detect the disease before symptoms arise would allow for earlier treatment, which could be effective at decreasing progression or even reversing the disease process.”

The happy stem cell story of Mahali the giraffe. We leave you this week with a feel-good story about Mahali, a 14-year old giraffe at the Cheyenne Mountain Zoo in Colorado. Mahali had suffered from chronic arthritis in his front left leg. As a result, he could not move well and was kept isolated from his herd.

Giraffes at Cheyenne Mountain Zoo. Photo: Denver Post

The zoo’s head veterinarian, Dr. Liza Dadone, decided to try a stem cell therapy procedure to bring Mahali some relief and a better quality of life. It’s the first time such a treatment would be performed on a giraffe. With the help of doctors at Colorado State University’s James L. Voss Veterinary Teaching Hospital, 100 million stem cells grown from Mahali’s blood were injected into his arthritic leg.

Before treatment, thermograph shows inflammation (red/yellow) in Mahali’s left front foot (seen at far right of each image); after treatment inflammation resolved (blue/green). Photos: Cheyenne Mountain Zoo

In a written statement to the Colorado Gazette, Dr. Dadone summarized the positive outcome:

“Prior to the procedure, he was favoring his left front leg and would lift that foot off the ground almost once per minute. Since then, Mahali is no longer constantly lifting his left front leg off the ground and has resumed cooperating for hoof care. A few weeks ago, he returned to life with his herd, including yard access. On the thermogram, the marked inflammation up the leg has mostly resolved.”

Now, Dr. Dadone made sure to state that other treatments and medicine were given to Mahali in addition to the stem cell therapy. So, it’s not totally clear to what extent the stem cells contributed to Mahali’s recovery. Maybe future patients will receive stem cells alone to be sure. But for now, we’re just happy for Mahali’s new lease on life.

Stem cell stories that caught our eye: lab-grown blood stem cells and puffer fish have the same teeth stem cells as humans

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.

Scientists finally grow blood stem cells in the lab!

Two exciting stem cell studies broke through the politics-dominated headlines this week. Both studies, published in the journal Nature, demonstrated that human hematopoietic or blood stem cells can be grown in the lab.

This news is a big deal because scientists have yet to make bonafide blood stem cells from pluripotent stem cells or other human cells. These stem cells not only create all the cells in our blood and immune systems, but also can be used to develop therapies for patients with blood cancers and genetic blood disorders.

But to do these experiments, you need a substantial source of blood stem cells – something that has eluded scientists for decades. That’s where these two studies come to the rescue. One study was spearheaded by George Daley at the Boston Children’s Hospital in Massachusetts and the other was led by Shahin Rafii at the Weill Cornell Medical College in New York City.

Researchers have made blood stem cells and progenitor cells from pluripotent stem cells. Credit: Steve Gschmeissner Getty Images

George Daley and his team developed a strategy that matured human induced pluripotent stem cells (iPS cells) into blood-forming stem and progenitor cells. It’s a two-step process that first uses a cocktail of chemicals to make hemogenic endothelium, the embryonic tissue that generates blood stem cells. The second step involved treating these intermediate cells with a combination of seven transcription factors that directed them towards a blood stem cell fate.

These modified human blood stem cells were then transplanted into mice where they developed into blood stem cells that produced blood and immune cells. First author on the study, Ryohichi Sugimura, explained the applications that their technology could be used for in a Boston Children’s Hospital news release,

“This step opens up an opportunity to take cells from patients with genetic blood disorders, use gene editing to correct their genetic defect and make functional blood cells. This also gives us the potential to have a limitless supply of blood stem cells and blood by taking cells from universal donors. This could potentially augment the blood supply for patients who need transfusions.”

The second study by Shahin Rafii and his team at Cornell used a different strategy to generate blood-forming stem cells. Instead of genetically manipulating iPS cells, they selected a more mature cell type to directly reprogram into blood stem cells. Using four transcription factors, they successfully reprogrammed mouse endothelial cells, which line the insides of blood vessels, into blood-forming stem cells that repopulated the blood and immune systems of irradiated mice.

Raffii believe his method is simpler and more efficient than Daley’s. In coverage by Nature News, he commented,

“Using the most efficient method to generate stem cells matters because every time a gene is added to a batch of cells, a large portion of the batch fails to incorporate it and must be thrown out. There is also a risk that some cells will mutate after they are modified in the lab, and could form tumors if they are implanted into people.”

To play devil’s advocate, Daley’s technique might appeal more to some because the starting source of iPS cells is much easier to obtain and culture in the lab than endothelial cells that have to be extracted from the blood vessels of animals or people. Furthermore, Daley argued that his team’s method could “be made more efficient, and [is] less likely to spur tumor growth and other abnormalities in modified cells.”

The Nature News article compares the achievements of both studies and concluded,

“Time will determine which approach succeeds. But the latest advances have buoyed the spirits of researchers who have been frustrated by their inability to generate blood stem cells from iPS cells.”

 

Humans and puffer fish have the same tooth-making stem cells.

Here’s a fun fact for your next blind date: humans and puffer fish share the same genes that are responsible for making teeth. Scientists from the University of Sheffield in England discovered that the stem cells that make teeth in puffer fish are the same stem cells that make the pearly whites in humans. Their work was published in the journal PNAS earlier this week.

Puffer fish. Photo by pingpogz on Flickr.

But if you look at this puffer fish, you’ll see a dramatic difference between its smile and ours – their teeth look more like a beak. Research has shown that the tooth-forming stem cells in puffer fish produce tooth plates that form a beak-like structure, which helps them crush and consume their prey.

So why is this shared evolution between humans and puffer fish important when our teeth look and function so differently? The scientists behind this research believe that studying the pufferfish could unearth answers about tooth loss in humans. The lead author on the study, Dr. Gareth Fraser, concluded in coverage by Phys.org,

“Our study questioned how pufferfish make a beak and now we’ve discovered the stem cells responsible and the genes that govern this process of continuous regeneration. These are also involved in general vertebrate tooth regeneration, including in humans. The fact that all vertebrates regenerate their teeth in the same way with a set of conserved stem cells means that we can use these studies in more obscure fishes to provide clues to how we can address questions of tooth loss in humans.”

Engineered bone tissue improves stem cell transplants

Bone marrow transplants are currently the only approved stem cell-based therapy in the United States. They involve replacing the hematopoietic, or blood-forming stem cells, found in the bone marrow with healthy stem cells to treat patients with cancers, immune diseases and blood disorders.

For bone marrow transplants to succeed, patients must undergo radiation therapy to wipe out their diseased bone marrow, which creates space for the donor stem cells to repopulate the blood system. Radiation can lead to complications including hair loss, nausea, fatigue and infertility.

Scientists at UC San Diego have a potential solution that could make current bone marrow transplants safer for patients. Their research, which was funded in part by a CIRM grant, was published yesterday in the journal PNAS.

Engineered bone with functional bone marrow in the center. (Varghese Lab)

Led by bioengineering professor Dr. Shyni Varghese, the team engineered artificial bone tissue that contains healthy donor blood stem cells. They implanted the engineered bone under the skin of normal mice and watched as the “accessory bone marrow” functioned like the real thing by creating new blood cells.

The implant lasted more than six months. During that time, the scientists observed that the cells within the engineered bone structure matured into bone tissue that housed the donor bone marrow stem cells and resembled how bones are structured in the human body. The artificial bones also formed connections with the mouse circulatory system, which allowed the host blood cells to populate the implanted bone tissue and the donor blood cells to expand into the host’s bloodstream.

Normal bone structure (left) and engineered bone (middle) are very similar. Bone tissue shown on top right and bone marrow cells on bottom right. (Varghese lab)

The team also implanted these artificial bones into mice that received radiation to mimic the procedures that patients typically undergo before bone marrow transplants. The engineered bone successfully repopulated the blood systems of the irradiated mice, similar to how blood stem cell functions in normal bone.

In a UC San Diego news release, Dr. Varghese explained how their technology could be translated into the clinic,

“We’ve made an accessory bone that can separately accommodate donor cells. This way, we can keep the host cells and bypass irradiation. We’re working on making this a platform to generate more bone marrow stem cells. That would have useful applications for cell transplantations in the clinic.”

The authors concluded that engineered bone tissue would specifically benefit patients who needed bone marrow transplants for non-cancerous bone marrow-related diseases such as sickle cell anemia or thalassemia where there isn’t a need to destroy cancer-causing cells.

Knocking out sexually transmitted disease with stem cells and CRISPR gene editing

When used in tandem, stem cells and gene editing make a powerful pair in the development of cell therapies for genetic diseases like sickle cell anemia and bubble baby disease. But the applications of these cutting-edge technologies go well beyond cell therapies.

This week, researchers at the Wellcome Trust Sanger Institute in the UK and the University of British Columbia (UBC) in Canada, report their use of induced pluripotent stem cells (iPSCs) and the CRISPR gene editing to better understand chlamydia, a very common sexually transmitted disease. And in the process, the researchers gained insights for developing new drug treatments.

BodyChlamydia

Human macrophage, a type of white blood cell, interacting with a Chlamydia trachomatis bacteria cell. Image: Sanger Institute / Genome Research Limited

Chlamydia is caused by infection with the bacteria Chlamydia trachomatis. According to the Centers for Disease Control (CDC), there were over 1.5 million cases of Chlamydia reported in the U.S. in 2015. And there are thought to be almost 3 million new cases each year. Men with Chlamydia usually do not face many health issues. Women, on the other hand, can suffer serious health complications like pelvic inflammatory disease and infertility.

Although it’s easily treatable with antibiotics, the disease often goes unnoticed because infected people may not show symptoms. And because of the rising fear of antibiotic-resistant bacteria, there’s a need to develop new types of drugs to treat Chlamydia.

To tackle this challenge, the research teams focused first on better understanding how the bacteria infects the human immune system. As first author Dr. Amy Yeung from the Wellcome Trust Sanger Institute explained in a press release, researchers knew they were up against difficult to treat foe:

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Amy Yeung

“Chlamydia is tricky to study because it can permeate and hide in macrophages [a type of white blood cell] where it is difficult to reach with antibiotics. Inside the macrophage, one or two chlamydia cells can replicate into hundreds in just a day or two, before bursting out to spread the infection.”

In the study, published in Nature Communications, the teams chose to examine human macrophages derived from iPSCs. This decision had a few advantages over previous studies.  Most Chlamydia studies up until this point had either used macrophages from mice, which don’t always accurately reflect what’s going on in the human immune system, or human macrophage cell lines, which have genetic abnormalities that allow them to divide indefinitely.

With these human iPSC-derived macrophages, the team then used CRISPR gene editing technology to systematically delete, or “knockout”, genes that may play a role in Chlamydia infection. Lead author Dr. Robert Hancock from UBC described the power of this approach:

about-bob-200x200

Robert Hancock

“We can knock out specific genes in stem cells and look at how the gene editing influences the resulting macrophages and their interaction with chlamydia. We’re effectively sieving through the genome to find key players and can now easily see genes that weren’t previously thought to be involved in fighting the infection.”

In fact, they found two genes that appear to play an important role in Chlamydia infection. When they knocked out either the IRF5 or IL-10RA gene, the macrophages were much more vulnerable to infection. The team is now eager to examine these two genes as possible targets for novel Chlamyia drug treatments. But as Dr. Gordon Dougan –the senior author from the Sanger Institute – explains, these studies could be far-reaching:

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Gordon Dougan

“This system can be extended to study other pathogens and advance our understanding of the interactions between human hosts and infections. We are starting to unravel the role our genetics play in battling infections, such as chlamydia, and these results could go towards designing more effective treatments in the future.”

A life-threatening childhood disease and the CIRM-funded team seeking a stem cell cure featured in new video

“My hope for Brooke is she can one day look back and we have to remind her of the disease she once had.”

That’s Clay Emerson’s biggest hope for his young daughter Brooke, who has cystinosis, a life-threatening genetic disease that appears by the age of two and over time causes damage to many organs, especially the kidneys and eyes but also the liver, muscle, brain, pancreas and other tissues. The Emersons and other families affected by the disease are featured in a recent video produced by the Cystinosis Research Foundation.

I doubt many can watch the seven-minute piece without getting a lump in their throat or watery eyes. One of many heart wrenching scene shows Brooke’s mother, Jill Emerson, preparing a day’s worth of medicine that she administers through a tube connected to Brook’s stomach.

“Brooke takes about 20 doses of medication a day and that’s throughout the 24hr period in a day. The poor kid hasn’t had a full night’s sleep ever in her entire life because I have to wake her up to take her life-saving medicine.”

Jill Emerson prepares a day’s worth of medicine for her daughter Brooke. Unfortunately, the treatments only slow the progression of cystinosis but don’t cure it. (Video Still: Cystinosis Research Foundation)

But these treatments only slow down the progression of this incurable disease. Even perfect compliance with taking the medicine doesn’t stop severe complications of the disease including kidney failure, diabetes, muscle weakness, and difficulty swallowing just to name a few. Cystinosis also shorten life spans. Natalie, the video’s narrator, a young woman with cystinosis wonders how much time she has left:

“There are people in their 20s who have recently died from cystinosis. I am 25 years old and I often think about how long I have to live. I’m praying for a cure for all of us.”

Her prayers may be answered in the form of a stem cell gene therapy treatment. UCSD researcher Dr. Stephanie Cherqui, who is also featured in the video, received $5 million in CIRM funding to bring her team’s therapy to clinical trials in people.

At a cellular level, cystinosis is caused by mutations in a gene called CTNS which lead to an accumulation of the amino acid cysteine. The excess cysteine eventually forms crystals causing devastating damage to cells throughout the body. Cherqui’s treatment strategy is to take blood stem cells from affected individuals, insert a good copy of the CTNS gene using genome editing into the cells’ DNA, and then transplant the cells back into the patient.

Cystinosis_Cherqui

Dr. Stephanie Cherqui and her team are working hard to bring a stem cell gene therapy treatment for cystinosis to clinical trials. (Video Still: Cystinosis Research Foundation)

Her team has preliminary evidence that the strategy works in mice. Now, they will use the CIRM grant to complete these pre-clinical studies and prepare the genetically engineered blood stem cells for use in patients. These steps are necessary to get the green light from the Food and Drug Administration (FDA) to begin clinical trials, hopefully some time this year.

Cherqui says that if all goes well, the treatment approach may have benefits beyond cystinosis:

“If we can bring this to the finish line, we can then show the way to maybe hundreds, maybe thousands of other genetic diseases. So this could be a real benefit to mankind.”

Stem cell stories that caught our eye: spinal cord injury trial update, blood stem cells in lungs, and using parsley for stem cell therapies

More good news on a CIRM-funded trial for spinal cord injury. The results are now in for Asterias Biotherapeutics’ Phase 1/2a clinical trial testing a stem cell-based therapy for patients with spinal cord injury. They reported earlier this week that six out of six patients treated with 10 million AST-OPC1 cells, which are a type of brain cell called oligodendrocyte progenitor cells, showed improvements in their motor function. Previously, they had announced that five of the six patients had shown improvement with the jury still out on the sixth because that patient was treated later in the trial.

 In a news release, Dr. Edward Wirth, the Chief Medical officer at Asterias, highlighted these new and exciting results:

 “We are excited to see the sixth and final patient in the AIS-A 10 million cell cohort show upper extremity motor function improvement at 3 months and further improvement at 6 months, especially because this particular patient’s hand and arm function had actually been deteriorating prior to receiving treatment with AST-OPC1. We are very encouraged by the meaningful improvements in the use of arms and hands seen in the SciStar study to date since such gains can increase a patient’s ability to function independently following complete cervical spinal cord injuries.”

Overall, the trial suggests that AST-OPC1 treatment has the potential to improve motor function in patients with severe spinal cord injury. So far, the therapy has proven to be safe and likely effective in improving some motor function in patients although control studies will be needed to confirm that the cells are responsible for this improvement. Asterias plans to test a higher dose of 20 million cells in AIS-A patients later this year and test the 10 million cell dose in AIS-B patients that a less severe form of spinal cord injury.

 Steve Cartt, CEO of Asterias commented on their future plans:

 “These results are quite encouraging, and suggest that there are meaningful improvements in the recovery of functional ability in patients treated with the 10 million cell dose of AST-OPC1 versus spontaneous recovery rates observed in a closely matched untreated patient population. We look forward to reporting additional efficacy and safety data for this cohort, as well as for the currently-enrolling AIS-A 20 million cell and AIS-B 10 million cell cohorts, later this year.”

Lungs aren’t just for respiration. Biology textbooks may be in need of some serious rewrites based on a UCSF study published this week in Nature. The research suggests that the lungs are a major source of blood stem cells and platelet production. The long prevailing view has been that the bone marrow was primarily responsible for those functions.

The new discovery was made possible by using special microscopy that allowed the scientists to view the activity of individual cells within the blood vessels of a living mouse lung (watch the fascinating UCSF video below). The mice used in the experiments were genetically engineered so that their platelet-producing cells glowed green under the microscope. Platelets – cell fragments that clump up and stop bleeding – were known to be produced to some extent by the lungs but the UCSF team was shocked by their observations: the lungs accounted for half of all platelet production in these mice.

Follow up experiments examined the movement of blood cells between the lung and bone marrow. In one experiment, the researchers transplanted healthy lungs from the green-glowing mice into a mouse strain that lacked adequate blood stem cell production in the bone marrow. After the transplant, microscopy showed that the green fluorescent cells from the donor lung traveled to the host’s bone marrow and gave rise to platelets and several other cells of the immune system. Senior author Mark Looney talked about the novelty of these results in a university press release:

Mark Looney, MD

“To our knowledge this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia [low platelet count].”

If this newfound role of the lung is shown to exist in humans, it may provide new therapeutic approaches to restoring platelet and blood stem cell production seen in various diseases. And it will give lung transplants surgeons pause to consider what effects immune cells inside the donor lung might have on organ rejection.

Add a little vanilla to this stem cell therapy. Typically, the only connection between plants and stem cell clinical trials are the flowers that are given to the patient by friends and family. But research published this week in the Advanced Healthcare Materials journal aims to use plant husks as part of the cell therapy itself.

Though we tend to focus on the poking and prodding of stem cells when discussing the development of new therapies, an equally important consideration is the use of three-dimensional scaffolds. Stem cells tend to grow better and stay healthier when grown on these structures compared to the flat two-dimensional surface of a petri dish. Various methods of building scaffolds are under development such as 3D printing and designing molds using materials that aren’t harmful to human tissue.

Human fibroblast cells growing on decellularized parsley.
Image: Gianluca Fontana/UW-Madison

But in the current study, scientists at the University of Wisconsin-Madison took a creative approach to building scaffolds: they used the husks of parsley, vanilla and orchid plants. The researchers figured that millions of years of evolution almost always leads to form and function that is much more stable and efficient than anything humans can create. Lead author Gianluca Fontana explained in a university press release how the characteristics of plants lend themselves well to this type of bioengineering:

Gianluca Fontana, PhD

“Nature provides us with a tremendous reservoir of structures in plants. You can pick the structure you want.”

The technique relies on removing all the cells of the plant, leaving behind its outer layer which is mostly made of cellulose, long chains of sugars that make up plant cell walls. The resulting hollow, tubular husks have similar shapes to those found in human intestines, lungs and the bladder.

The researchers showed that human stem cells not only attach and grow onto the plant scaffolds but also organize themselves in alignment with the structures’ patterns. The function of human tissues rely on an organized arrangement of cells so it’s possible these plant scaffolds could be part of a tissue replacement cell product. Senior author William Murphy also points out that the scaffolds are easily altered:

William Murphy, PhD

“They are quite pliable. They can be easily cut, fashioned, rolled or stacked to form a range of different sizes and shapes.”

And the fact these scaffolds are natural products that are cheap to manufacture makes this a project well worth watching.

Stem Cell Stories that Caught our Eye: stem cell insights into anorexia, Zika infection and bubble baby disease

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.

Stem cell model identifies new culprit for anorexia.

Eating disorders like anorexia nervosa are often thought to be caused by psychological disturbances or societal pressure. However, research into the genes of anorexia patients suggests that what’s written in your DNA can be associated with an increased vulnerability to having this disorder. But identifying individual genes at fault for a disease this complex has remained mostly out of scientists’ reach, until now.

A CIRM-funded team from the UC San Diego (UCSD) School of Medicine reported this week that they’ve developed a stem cell-based model of anorexia and used it to identify a gene called TACR1, which they believe is associated with an increased likelihood of getting anorexia.

They took skin samples from female patients with anorexia and reprogrammed them into induced pluripotent stem cells (iPSCs). These stem cells contained the genetic information potentially responsible for causing their anorexia. The team matured these iPSCs into brain cells, called neurons, in a dish, and then studied what genes got activated. When they looked at the genes activated by anorexia neurons, they found that TACR1, a gene associated with psychiatric disorders, was switched on higher in anorexia neurons than in healthy neurons. These findings suggest that the TACR1 gene could be an identifier for this disease and a potential target for developing new treatments.

In a UCSD press release, Professor and author on the study, Alysson Muotri, said that they will follow up on their findings by studying stem cell lines derived from a larger group of patients.

Alysson Muotri UC San Diego

“But more to the point, this work helps make that possible. It’s a novel technological advance in the field of eating disorders, which impacts millions of people. These findings transform our ability to study how genetic variations alter brain molecular pathways and cellular networks to change risk of anorexia nervosa — and perhaps our ability to create new therapies.”

Anorexia is a disease that affects 1% of the global population and although therapy can be an effective treatment for some, many do not make a full recovery. Stem cell-based models could prove to be a new method for unlocking new clues into what causes anorexia and what can cure it.

Nature versus Zika, who will win?

Zika virus is no longer dominating the news headlines these days compared to 2015 when large outbreaks of the virus in the Southern hemisphere came to a head. However, the threat of Zika-induced birth defects, like microcephaly to pregnant women and their unborn children is no less real or serious two years later. There are still no effective vaccines or antiviral drugs that prevent Zika infection but scientists are working fast to meet this unmet need.

Speaking of which, scientists at UCLA think they might have a new weapon in the war against Zika. Back in 2013, they reported that a natural compound in the body called 25HC was effective at attacking viruses and prevented human cells from being infected by viruses like HIV, Ebola and Hepatitis C.

When the Zika outbreak hit, they thought that this compound could potentially be effective at preventing Zika infection as well. In their new study published in the journal Immunity, they tested a synthetic version of 25HC in animal and primate models, they found that it protected against infection. They also tested the compound on human brain organoids, or mini brains in a dish made from pluripotent stem cells. Brain organoids are typically susceptible to Zika infection, which causes substantial cell damage, but this was prevented by treatment with 25HC.

Left to right: (1) Zika virus (green) infects and destroys the formation of neurons (pink) in human stem cell-derived brain organoids.  (2) 25HC blocks Zika infection and preserves neuron formation in the organoids. (3) Reduced brain size and structure in a Zika-infected mouse brain. (4) 25HC preserves mouse brain size and structure. Image courtesy of UCLA Stem Cell.

A UCLA news release summarized the impact that this research could have on the prevention of Zika infection,

“The new research highlights the potential use of 25HC to combat Zika virus infection and prevent its devastating outcomes, such as microcephaly. The research team will further study whether 25HC can be modified to be even more effective against Zika and other mosquito-borne viruses.”

Harnessing a naturally made weapon already found in the human body to fight Zika could be an alternative strategy to preventing Zika infection.

Gene therapy in stem cells gives hope to bubble-babies.

Last week, an inspiring and touching story was reported by Erin Allday in the San Francisco Chronicle. She featured Ja’Ceon Golden, a young baby not even 6 months old, who was born into a life of isolation because he lacked a properly functioning immune system. Ja’Ceon had a rare disease called severe combined immunodeficiency (SCID), also known as bubble-baby disease.

 

Ja’Ceon Golden is treated by patient care assistant Grace Deng (center) and pediatric oncology nurse Kat Wienskowski. Photo: Santiago Mejia, The Chronicle.

Babies with SCID lack the body’s immune defenses against infectious diseases and are forced to live in a sterile environment. Without early treatment, SCID babies often die within one year due to recurring infections. Bone marrow transplantation is the most common treatment for SCID, but it’s only effective if the patient has a donor that is a perfect genetic match, which is only possible for about one out of five babies with this disease.

Advances in gene therapy are giving SCID babies like Ja’Ceon hope for safer, more effective cures. The SF Chronicle piece highlights two CIRM-funded clinical trials for SCID run by UCLA in collaboration with UCSF and St. Jude Children’s Research Hospital. In these trials, scientists isolate the bone marrow stem cells from SCID babies, correct the genetic mutation causing SCID in their stem cells, and then transplant them back into the patient to give them a healthy new immune system.

The initial results from these clinical trials are promising and support other findings that gene therapy could be an effective treatment for certain genetic diseases. CIRM’s Senior Science Officer, Sohel Talib, was quoted in the Chronicle piece saying,

“Gene therapy has been shown to work, the efficacy has been shown. And it’s safe. The confidence has come. Now we have to follow it up.”

Ja’Ceon was the first baby treated at the UCSF Benioff Children’s Hospital and so far, he is responding well to the treatment. His great aunt Dannie Hawkins said that it was initially hard for her to enroll Ja’Ceon in this trial because she was a partial genetic match and had the option of donating her own bone-marrow to help save his life. In the end, she decided that his involvement in the trial would “open the door for other kids” to receive this treatment if it worked.

Ja’Ceon Golden plays with patient care assistant Grace Deng in a sterile play area at UCSF Benioff Children’s Hospital.Photo: Santiago Mejia, The Chronicle

It’s brave patients and family members like Ja’Ceon and Dannie that make it possible for research to advance from clinical trials into effective treatments for future patients. We at CIRM are eternally grateful for their strength and the sacrifices they make to participate in these trials.

Mixed Matches: How Your Heritage Can Save a Life

Today we bring you a guest blog from Athena Mari Asklipiadis. She’s the founder of Mixed Marrow, which is an organization dedicated to finding bone marrow and blood cell donors to patients of multiethnic descent. Athena helped produce a 2016 documentary film called Mixed Match that encourages mixed race and minority donors to register as adult donors.

Athena Asklipiadis

Due to the lack of diversity on the national and world bone marrow donor registries, Mixed Marrow was started in 2009 to increase the numbers of mixed race donors.

Prior to Mixed Marrow starting, other ethnic recruiters like Asians for Miracle Marrow Matches (A3M), based in Los Angeles, CA and Asian American Donor Program (AADP), based in Alameda, CA had been raising awareness in the Asian and minority communities for decades.  Closing the racial gap on the registry was something I was very much interested in helping them with so I began my outreach on the most familiar medium I knew—social media.

Because matching relies heavily on similar inherited genetic markers, I was particularly astonished seeing the less than 3% (back in 2009) sliver of the ethnic pie that mixed race donors made up.  Caucasians made up for about 70% at the time, with all minorities making up for the difference.  The ethnic breakdown made sense when comparing against actual population numbers, but a larger pool of minority donors was definitely something needed especially when multiracial people were being reported as the fastest growing demographic in the US.  Odds were just not in the favor of non-white searching patients.

Current Be The Match ethnic breakdown as of 2016.

After getting to know a local mixed race searching patient, Krissy Kobata, and hearing of her struggles finding a match, I knew I had to do my best to reach out to fellow multiracial people, most of which were young and likely online.  At the time, I was engaged with fellow hapas (half in Hawaiian Pidgin, referring mixed heritage) and mixed people via multiracial community Facebook groups and other internet forums.  One common thing I noticed, unlike topics like identity, food and culture– health was definitely not widely talked about. So with that lack of awareness, Mixed Marrow began as a facebook page and later as a website.  With the help of organizations like A3M supplying Be The Match testing kits, Mixed Marrow was able to also exist outside of the virtual world by hosting donor recruitment drives at different cultural and college events.

Athena Asklipiadis, Krissy Kobata and Mixed Match director, Jeff Chiba Stearns

After about a year of advocacy, in 2010, I connected with filmmaker Jeff Chiba Stearns to pitch an idea for a documentary on the patients I worked with.  Telling their stories in words and on flyers was not effective enough for me, I felt that more people would be inclined to register as a donor if they got to know the patients as well as I did.  Thus, the film Mixed Match was born.

Still from Mixed Match, Imani (center) and parents, Darrick and Tammy.

Still from Mixed Match, Imani mother, Tammy.

Over the course of the next 6 years, Jeff and I went on a journey across the US to gather not only patient stories, but input from pioneers in stem cell transplantation like Dr. Paul Terasaki and Dr. John E. Wagner.  It was so important to share these transplant tales while being as accurate and informed as possible.

Still from Mixed Match – Dr. Paul Teriyaki.

Our goal was to educate audiences and present a call-to-action where everyone can learn how they can save a life. Mixed Match not only highlights bone marrow and peripheral blood stem cell (PBSC) donation, but it also shares the possibilities of umbilical cord stem cells.

Mixed Match director, Jeff Chiba Stearns decided a great way to explain stem cell science and matching was through animation.  Stearns, with the help of animator, Kaho Yoshida, was able to reach across to non-medical expert audiences and create digestible and engaging imagery to teach what is usually very complex science.

Animation Still from Mixed Match.

At every screening we also make sure to host a bone marrow registry drive so audiences have the opportunity to sign up.  We have partnered with both the US national registry, Be The Match and Canadian Blood Services’ One Match registry.

Bone marrow drive at a Mixed Match screening in Toronto.

Nearly 8 years and about 40 cities later, Mixed Marrow has managed to spread advocacy for the need for more mixed race donors all over the US and even other countries like Canada, Japan, Korea and Austria all the while being completely volunteer-run.  It is our hope that through social media and film, Mixed Match, we can help share these important stories and save lives.

Further Information

Three people left blind by Florida clinic’s unproven stem cell therapy

Unproven treatment

Unproven stem cell treatments endanger patients: Photo courtesy Healthline

The report makes for chilling reading. Three women, all suffering from macular degeneration – the leading cause of vision loss in the US – went to a Florida clinic hoping that a stem cell therapy would save their eyesight. Instead, it caused all three to go blind.

The study, in the latest issue of the New England Journal of Medicine, is a warning to all patients about the dangers of getting unproven, unapproved stem cell therapies.

In this case, the clinic took fat and blood from the patient, put the samples through a centrifuge to concentrate the stem cells, mixed them together and then injected them into the back of the woman’s eyes. In each case they injected this mixture into both eyes.

Irreparable harm

Within days the women, who ranged in age from 72 to 88, began to experience severe side effects including bleeding in the eye, detached retinas, and vision loss. The women got expert treatment at specialist eye centers to try and undo the damage done by the clinic, but it was too late. They are now blind with little hope for regaining their eyesight.

In a news release Thomas Alibini, one of the lead authors of the study, says clinics like this prey on vulnerable people:

“There’s a lot of hope for stem cells, and these types of clinics appeal to patients desperate for care who hope that stem cells are going to be the answer, but in this case these women participated in a clinical enterprise that was off-the-charts dangerous.”

Warning signs

So what went wrong? The researchers say this clinic’s approach raised a number of “red flags”:

  • First there is almost no evidence that the fat/blood stem cell combination the clinic used could help repair the photoreceptor cells in the eye that are attacked in macular degeneration.
  • The clinic charged the women $5,000 for the procedure. Usually in FDA-approved trials the clinical trial sponsor will cover the cost of the therapy being tested.
  • Both eyes were injected at the same time. Most clinical trials would only treat one eye at a time and allow up to 30 days between patients to ensure the approach was safe.
  • Even though the treatment was listed on the clinicaltrials.gov website there is no evidence that this was part of a clinical trial, and certainly not one approved by the Food and Drug Administration (FDA) which regulates stem cell therapies.

As CIRM’s Abla Creasey told the San Francisco Chronicle’s Erin Allday, there is little evidence these fat stem cells are effective, or even safe, for eye conditions.

“There’s no doubt there are some stem cells in fat. As to whether they are the right cells to be put into the eye, that’s a different question. The misuse of stem cells in the wrong locations, using the wrong stem cells, is going to lead to bad outcomes.”

The study points out that not all projects listed on the Clinicaltrials.gov site are checked to make sure they are scientifically sound and have done the preclinical testing needed to reduce the likelihood they may endanger patients.

goldberg-jeffrey

Jeffrey Goldberg

Jeffrey Goldberg, a professor of Ophthalmology at Stanford and the co-author of the study, says this is a warning to all patients considering unproven stem cell therapies:

“There is a lot of very well-founded evidence for the positive potential of stem therapy for many human diseases, but there’s no excuse for not designing a trial properly and basing it on preclinical research.”

There are a number of resources available to people considering being part of a clinical trial including CIRM’s “So You Want to Participate in a Clinical Trial”  and the  website A Closer Look at Stem Cells , which is sponsored by the International Society for Stem Cell Research (ISSCR).

CIRM is currently funding two clinical trials aimed at helping people with vision loss. One is Dr. Mark Humayun’s research on macular degeneration – the same disease these women had – and the other is Dr. Henry Klassen’s research into retinitis pigmentosa. Both these projects have been approved by the FDA showing they have done all the testing required to try and ensure they are safe in people.

In the past this blog has been a vocal critic of the FDA and the lengthy and cumbersome approval process for stem cell clinical trials. We have, and still do, advocate for a more efficient process. But this study is a powerful reminder that we need safeguards to protect patients, that any therapy being tested in people needs to have undergone rigorous testing to reduce the likelihood it may endanger them.

These three women paid $5,000 for their treatment. But the final cost was far greater. We never want to see that happen to anyone ever again.

Stem cell stories that caught our eye: building an embryo and reviving old blood stem cells

Building an embryo in the lab from stem cells
The human body has been studied for centuries yet little is known about the first 14 days of human development when the fertilized embryo implants into the mother’s uterus and begins to divide and grow. Being able to precisely examine this critical time window may help researchers better understand why 75% of conceptions never implant and why 30% of pregnancies end in miscarriage.

This lack of knowledge is due in part to a lack of embryos to study. Researchers rely on embryos donated by couples who’ve gone through in vitro fertilization to get pregnant and have left over embryos that are otherwise discarded. Using mouse stem cells, a research team from Cambridge University reports today in Nature that they’ve generated a cellular structure that has the hallmarks of a fertilized embryo.

embryo

Stem cell-modeled mouse embryo (left) Mouse embryo (right); The red part is embryonic and the blue extra-embryonic.
Credit: Sarah Harrison and Gaelle Recher, Zernicka-Goetz Lab, University of Cambridge

This technique has been tried before without success. The breakthrough here was in the types of cells used. Rather that only relying on embryonic stems cells (ESCs), this study also included extra-embryonic trophoblast stem cells (TSCs), the cell type that goes on to form the placenta.

When grown on a 3D scaffold made from biological materials, the two cell types self-organized themselves into a pattern that closely resembles the early development of a true embryo. In a press release that was picked up by many media outlets, senior author Zernicka-Goetz spoke about the importance of including both TSCs and ESCs:

“We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership – these cells truly guide each other. Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesn’t take place properly.”

The researchers think that lab-made embryos from mouse or human stem cells have little chance of developing into a fetus because other cell types critical for continued growth are not included. And there’s much to be learned by focusing on these very early events:

“We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on embryos.  Knowing how development normally occurs will allow us to understand why it so often goes wrong,” says Zernicka-Goetz.

Reviving old blood stem cells, part 1: repair the garbage collectors
One of the reasons that our bodies begin to deteriorate in old age is a weakening, dysfunctional immune system that increases the risk for serious infection, blood cancers and chronic inflammatory diseases like atherosclerosis (hardening of the arteries). Reporting this week in Nature, a UCSF research team presents evidence that a breakdown in our cell’s natural garbage collecting system may be partially to blame.

The team focused on a process called autophagy (literally meaning self “auto”-eating “phagy”) that keeps cells functioning properly by degrading faulty proteins and cellular structures. In particular, they examined autophagy in blood-forming stem cells, which give rise to all the cell types of the immune system. They found that autophagy was not working in 70 percent of blood stem cells from old mice. And these cells had all the hallmarks of an old cell. And the other 30 percent? In those cells, autophagy was fully functional and they looked like blood stem cells found in young mice.

The team went on to show that in blood stem cells, autophagy had an additional role that until now had not been observed: it helped slow the activity of the stem cells back to its default state by gobbling up excess mitochondria, the structures that produces a cell’s energy needs. Without this quieting of the stem cell, the over-active mitochondria led to chemical modification of the cell’s DNA that disrupted the blood stem cells’ ability to give rise to a proper balance of immune cells. In fact, young mice with genetic modifications that block autophagy generated blood stem cells with these old age-related characteristics.

But the researchers were also able to restore autophagy in blood stem cells collected from old mice by adding various drugs. Team lead Emmanuelle Passegué is optimistic this result could be translated into a therapeutic approach:

“This discovery might provide an interesting therapeutic angle to use in re-activating autophagy in all of the old HSCs, to slow the aging of the blood system and to improve engraftment during bone marrow or HSC transplantation,” Passegué said in a university press release.

Reviving old blood stem cells, part 2: fix the aging neighborhood
Another study this week focused on age-related disruptions in the function of blood stem cells but in this case an aging neighborhood is to blame. Blood stem cells form and hang out in areas of the bone marrow called niches. Researchers at the Cincinnati Children’s Hospital Medical Center and the University of Ulm in Germany reported this week in EMBO that the age of the niche affects blood stem cell function.

bonemarrow

Microscopy of bone marrow. Red staining indicates osteopotin, blue staining indicates cell nuclei. Credit: University of Ulm

 

When blood stem cells from two-year old mice were transplanted into the bone marrow of eight-week old mice, the older stem cells took on characteristics of young stem cells including an enhance ability to form all the different cell types of the immune system. In trying to understand what was going on, the researchers focused on a bone marrow cell called an osteoblast which gives rise to bone. Osteoblasts produce osteopontin, a protein that plays an important role in the structure of the bone marrow. The team showed that as the bone marrow ages, osteopontin levels go down. And this reduction had effects on the health of blood stem cells. But, as team lead Hartmut Geiger mentions in a press release, this impact could be reversed which points to a potential new therapeutic strategy for age-related disease:

“We show that the place where HSCs form in the bone marrow loses osteopontin upon aging, but if you give back the missing protein to the blood-forming cells they suddenly rejuvenate and act younger. Our study points to exciting novel ways to have a better immune system and possibly less blood cancer upon aging by therapeutically targeting the place where blood stem cells form.”