Stem Cell Stories that Caught our Eye: finding the perfect match, imaging stem cells and understanding gene activity

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

LAPD officer in search of the perfect match.

LAPD Officer Matthew Medina with his wife, Angelee, and their daughters Sadie and Cassiah. (Family photo)

This week, the San Diego Union-Tribune featured a story that tugs at your heart strings about an LAPD officer in desperate need of a bone marrow transplant. Matthew Medina is a 40-year-old man who was diagnosed earlier this year with aplastic anemia, a rare disorder that prevents the bone marrow from producing enough blood cells and platelets. Patients with this disorder are prone to chronic fatigue and are at higher risk for infection and uncontrolled bleeding.

Matthew needs a bone marrow transplant to replace his diseased bone marrow with healthy marrow from a donor, but so far, he has yet to find a match. Part of the reason for this difficulty is the lack of diversity in the national bone marrow registry, which has over 25 million registered donors, the majority of which are white Americans of European decent. As a Filipino, Matthew has a 40% chance of finding a perfect match in the national registry compared to a 75% chance if he were white. An even more unsettling fact is that Filipinos make up less than 1% of donors on the national registry.

Matthew has a sister, but unfortunately, she wasn’t a match. For now, Matthew is being kept alive with blood transfusions at his home in Bellflower while he waits for good news. With the support of his family and friends, the hope is that he won’t have to wait for long. Already 1000 people in his local community have signed up to be bone marrow donors.

On a larger scale, organizations like A3M and Mixed Marrow are hoping to help patients like Matthew by increasing the diversity of the national bone marrow registry. A3M specifically recruits Asian donors while Mixed Match focuses on people with multi-ethnic backgrounds. Ayumi Nagata, a recruitment manager at A3M, said their main challenge is making healthy people realize the importance of being a bone marrow donor.

“They could be the cure for someone’s cancer or other disease and save their life. How often do we have that kind of opportunity?”

An algorithm that makes it easier to see stem cell development.

To understand how certain organs like the brain develop, scientists rely on advanced technologies that can track individual stem cells and monitor their fate as they mature into more specialized cells. Scientists can observe stem cell development with fluorescent proteins that light up when a stem cell expresses specific transcription factors that help decide the cell’s fate. Using a time-lapse microscope, these fluorescent stem cells can easily be identified and tracked throughout their lifetime.

But the pictures don’t always come out crystal clear. Just as a dirty camera lens makes for a dirty picture, images produced by time-lapse microscopy images can be plagued by shadows, artifacts and lighting inconsistencies, making it difficult to observe the orchestrated expression of transcription factors involved in a stem cell’s development.

This week in the journal Nature Communications, a team of scientists from Germany reported a solution that gives a clear view of stem cell development. The team developed a computer algorithm called BaSiC that acts like a filter and removes the background noise from time-lapse images of individual cells. Unlike previous algorithms, BaSiC requires fewer reference images to make its corrections.

The software BaSiC improves microscope images. (Credit: Tingying Peng / TUM/HMGU)

In coverage by Phys.org, author Dr. Tingying Peng explained the advantages of their algorithm,

“Contrary to other programs, BaSiC can correct changes in the background of time-lapse videos. This makes it a valuable tool for stem cell researchers who want to detect the appearance of specific transcription factors early on.”

The team proved that BaSiC is an effective image correcting tool by using it to study the development of hematopoietic or blood stem cells. They took time-lapse videos of blood stem cells over six days and observed that the stem cells chose between two developmental tracks that produced different types of mature blood cells. Using BaSiC, they found that blood stem cells that specialized into white blood cells expressed the transcription factor Pu.1 while the stem cells that specialized into red blood cells did not. Without the algorithm, they didn’t see this difference.

Senior author on the study, Dr. Nassir Navab, concluded by highlighting the importance of their technology and sharing his team’s vision for the future.

“Using BaSiC, we were able to make important decision factors visible that would otherwise have been drowned out by noise. The long-term goal of this research is to facilitate influencing the development of stem cells in a targeted manner, for example to cultivate new heart muscle cells for heat-attack patients. The novel possibilities for observation are bringing us a step closer to this goal.”

Silenced vs active genes: it’s like oil and water (Todd Dubicoff)

The DNA from just one of your cells would be an astounding six feet in length if stretched out end to end. To fit into a nucleus that is a mere 4/10,000th of an inch in diameter, DNA’s double helical structure is organized into intricate twists within twists with the help of proteins called histones.

Together the DNA and histones are called chromatin. And it turns out that chromatin isn’t just for stuffing all that genetic material into a tiny space. The amount of DNA folding also affects the regulation of genes. Areas of chromatin that are less densely packed are more accessible to DNA-binding proteins called transcription factors that activate gene activity. Other regions, called heterochromatin, are compacted which leads to silencing of genes because transcription factors are shut out.

But there’s a wrinkle in this story. More recently, scientists have shown that large proteins are able to wriggle their way into heterochromatin while smaller proteins cannot. So, there must be additional factors at play. This week, a CIRM-funded research project published in Nature provides a possible explanation.

Liquid-like fusion of heterochromatin protein 1a droplets is shown in the embryo of a fruit fly. (Credit: Amy Strom/Berkeley Lab)

Examining the nuclei of fruit fly embryos, a UC Berkeley research team report that various regions of heterochromatin coalesce into liquid droplets which physically separates them from regions where gene activity is high. This phenomenon, called phase-phase separation, is what causes oil droplets to fuse together when added to water. Lead author Dr. Amy Strom explained the novelty of this finding and its implications in a press release:

“We are excited about these findings because they explain a mystery that’s existed in the field for a decade. That is, if compaction [of chromatin] controls access to silenced [DNA] sequences, how are other large proteins still able to get in? Chromatin organization by phase separation means that proteins are targeted to one liquid or the other based not on size, but on other physical traits, like charge, flexibility, and interaction partners.”

Phase-phase separation can also affect other cell components, and problems with it have been linked to neurological disorders like dementia. In diseases like Alzheimer’s and Huntington’s, proteins aggregate causing them to become more solid than liquid over time. Strom is excited about how phase-phase separation insights could lead to novel therapeutic strategies:

“If we can better understand what causes aggregation, and how to keep things more liquid, we might have a chance to combat these types of disease.”

Latest space launch sends mice to test bone-building drug

Illustration of mice adapting to their custom-designed space habitat on board the International Space Station. Image courtesy of the Center for the Advancement of Science in Space

Astronauts on the International Space Station (ISS) received some furry guests this weekend with the launch of SpaceX’s Dragon supply capsule. On Saturday June 3rd, 40 mice were sent to the ISS along with other research experiments and medical equipment. Scientists will be treating the mice with a bone-building drug in search of a new therapy to combat osteoporosis, a disease that weakens bones and affects over 200 million people globally.

The bone-building therapy comes out of CIRM-funded research by UCLA scientists Dr. Chia Soo, Dr. Kang Ting and Dr. Ben Wu. Back in 2015, the UCLA team published that a protein called NELL-1 stimulates bone-forming stem cells, known as mesenchymal stem cells, to generate new bone tissue more efficiently in mice. They also found that NELL-1 blocked the function of osteoclasts – cellular recycling machines that break down and absorb bone – thus increasing bone density in mice.

Encouraged by their pre-clinical studies, the team decided to take their experiments into space. In collaboration with NASA and a grant from the Center for the Advancement of Science in Space (CASIS), they made plans to test NELL-1’s effects on bone density in an environment where bone loss is rapidly accelerated due to microgravity conditions.

Bone loss is a major concern for astronauts living in space for extended periods of time. The earth’s gravity puts pressure on our bones, stimulating bone-forming cells called osteoblasts to create new bone. Without gravity, osteoblasts stop functioning while the rate of bone resorption increases by approximately 1.5% per month. This translates to almost a 10% loss in bone density for every 6 months in space.

In a UCLA news release, Dr. Wu explained how they modified the NELL-1 treatment to stand up to the tests of space:

“To prepare for the space project and eventual clinical use, we chemically modified NELL-1 to stay active longer. We also engineered the NELL-1 protein with a special molecule that binds to bone, so the molecule directs NELL-1 to its correct target, similar to how a homing device directs a missile.”

The 40 mice will receive NELL-1 injections for four weeks on the ISS, at which point, half of the mice will be sent back to earth to receive another four weeks of NELL-1 treatment. The other half will stay in space and receive the same treatment so the scientists can compare the effects of NELL-1 in space and on land.

The Rodent Research Hardware System includes three modules: Habitat, Transporter, and Animal Access Unit.
Credits: NASA/Dominic Hart

The UCLA researchers hope that NELL-1 will prevent bone loss in the space mice and could lead to a new treatment for bone loss or bone injury in humans. Dr. Soo explained in an interview with SpaceFlight Now,

“We are hoping this study will give us some insights on how NELL-1 can work under these extreme conditions and if it can work for treating microgravity-related bone loss, which is a very accelerated, severe form of bone loss, then perhaps it can (be used) for patients one day on Earth who have bone loss due to trauma or due to aging or disease.”

If you want to learn more about this study, watch this short video below provided by UCLA. 

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.”

Bridging the Gap: Regenerating Injured Bones with Stem Cells and Gene Therapy

Scientists from Cedars-Sinai Medical Center have developed a new stem cell-based technology in animals that mends broken bones that can’t regenerate on their own. Their research was published today in the journal Science Translational Medicine and was funded in part by a CIRM Early Translational Award.

Over two million bone grafts are conducted every year to treat bone fractures caused by accidents, trauma, cancer and disease. In cases where the fractures are small, bone can repair itself and heal the injury. In other cases, the fractures are too wide and grafts are required to replace the missing bone.

It sounds simple, but the bone grafting procedure is far from it and can cause serious problems including graft failure and infection. People that opt to use their own bone (usually from their pelvis) to repair a bone injury can experience intense pain, prolonged recovery time and are at risk for nerve injury and bone instability.

The Cedars-Sinai team is attempting to “bridge the gap” for people with severe bone injuries with an alternative technology that could replace the need for bone grafts. Their strategy combines “an engineering approach with a biological approach to advance regenerative engineering” explained co-senior author Dr. Dan Gazit in a news release.

Gazit’s team developed a biological scaffold composed of a protein called collagen, which is a major component of bone. They implanted these scaffolds into pigs with fractured leg bones by inserting the collagen into the gap created by the bone fracture. Over a two-week period, mesenchymal stem cells from the animal were recruited into the collagen scaffolds.

To ensure that these stem cells generated new bone, the team used a combination of ultrasound and gene therapy to stimulate the stem cells in the collagen scaffolds to repair the bone fractures. Ultrasound pulses, or high frequency sound waves undetectable by the human ear, temporarily created small holes in the cell membranes allowing the delivery of the gene therapy-containing microbubbles into the stem cells.

Image courtesy of Gazit Group/Cedars-Sinai.

Animals that received the collagen transplant and ultrasound gene therapy repaired their fractured leg bones within two months. The strength of the newly regenerated bone was comparable to successfully transplanted bone grafts.

Dr. Gadi Pelled, the other senior author on this study, explained the significance of their research findings for treating bone injuries in humans,

“This study is the first to demonstrate that ultrasound-mediated gene delivery to an animal’s own stem cells can effectively be used to treat non-healing bone fractures. It addresses a major orthopedic unmet need and offers new possibilities for clinical translation.”

You can learn more about this study by watching this research video provided by the Gazit Group at Cedars-Sinai.


Related Links:

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.

Could revving up stem cells help senior citizens heal as fast as high school seniors?

All physicians, especially surgeons, sport medicine doctors, and military medical corps share a similar wish: to able to speed up the healing process for their patients’ incisions and injuries. Data published this week in Cell Reports may one day fulfill that wish. The study – reported by a Stanford University research team – pinpoints a single protein that revs up stem cells in the body, enabling them to repair tissue at a quicker rate.

Screen Shot 2017-04-19 at 5.37.38 PM

Muscle fibers (dark areas surrounding by green circles) are larger in mice injected with HGFA protein (right panel) compared to untreated mice (left panel), an indication of faster healing after muscle injury.
(Image: Cell Reports 19 (3) p. 479-486, fig 3C)

Most of the time, adult stem cells in the body keep to themselves and rarely divide. This calmness helps preserve this important, small pool of cells and avoids unnecessary mutations that may happen whenever DNA is copied during cell division.

To respond to injury, stem cells must be primed by dividing one time, which is a very slow process and can take several days. Once in this “alert” state, the stem cells are poised to start dividing much faster and help repair damaged tissue. The Stanford team, led by Dr. Thomas Rando, aimed to track down the signals that are responsible for this priming process with the hope of developing drugs that could help jump-start the healing process.

Super healing serum: it’s not just in video games
The team collected blood serum from mice two days after the animals had been subjected to a muscle injury (the mice were placed under anesthesia during the procedure and given pain medication afterwards). When that “injured” blood was injected into a different set of mice, their muscle stem cells became primed much faster than mice injected with “uninjured” blood.

“Clearly, blood from the injured animal contains a factor that alerts the stem cells,” said Rando in a press release. “We wanted to know, what is it in the blood that is doing this?”

 

A deeper examination of the priming process zeroed in on a muscle stem cell signal that is turned on by a protein in the blood called hepatocyte growth factor (HGF). So, it seemed likely that HGF was the protein that they had been looking for. But, to their surprise, there were no differences in the amount of HGF found in blood from injured and uninjured mice.

HGFA: the holy grail of healing?
It turns out, though, that HGF must first be chopped in two by an enzyme called HGFA to become active. When the team went back and examined the injured and uninjured blood, they found that it was HGFA which showed a difference: it was more active in the injured blood.

To show that HGFA was directly involved in stimulating tissue repair, the team injected mice with the enzyme two days before the muscle injury procedure. Twenty days post injury, the mice injected with HGFA had regenerated larger muscle fibers compared to untreated mice. Even more telling, nine days after the HGFA treatment, the mice had better recovery in terms of their wheel running activity compared to untreated mice.

To mimic tissue repair after a surgery incision, the team also looked at the impact of HGFA on skin wound healing. Like the muscle injury results, injecting animals with HGFA two days before creating a skin injury led to better wound healing compared to untreated mice. Even the hair that had been shaved at the surgical site grew back faster. First author Dr. Joseph Rodgers, now at USC, summed up the clinical implications of these results :

“Our research shows that by priming the body before an injury you can speed the process of tissue repair and recovery, similar to how a vaccine prepares the body to fight infection. We believe this could be a therapeutic approach to improve recovery in situations where injuries can be anticipated, such as surgery, combat or sports.”

Could we help senior citizens heal as fast as high school seniors?
Another application for this therapeutic approach may be for the elderly. Lots of things slow down when you get older including your body’s ability to heal itself. This observation sparks an intriguing question for Rando:

“Stem cell activity diminishes with advancing age, and older people heal more slowly and less effectively than younger people. Might it be possible to restore youthful healing by activating this [HGFA] pathway? We’d love to find out.”

I bet a lot of people would love for you to find out, too.

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

License to heal: UC Davis deal looks to advance stem cell treatment for bone loss and arthritis

Nancy Lane

Wei Yao and Nancy Lane of UC Davis: Photo courtesy UC Davis

There are many challenges in taking even the most promising stem cell treatment and turning it into a commercial product approved by the Food and Drug Administration (FDA). One of the biggest is expertise. The scientists who develop the therapy may be brilliant in the lab but have little experience or expertise in successfully getting their work through a clinical trial and ultimately to market.

That’s why a team at U.C. Davis has just signed a deal with a startup company to help them move a promising stem cell treatment for arthritis, osteoporosis and fractures out of the lab and into people.

The licensing agreement combines the business acumen of Regenerative Arthritis and Bone Medicine (RABOME) with the scientific chops of the UC Davis team, led by Nancy Lane and Wei Yao.

They plan to test a hybrid molecule called RAB-001 which has shown promise in helping direct mesenchymal stem cells (MSCs) – these are cells typically found in the bone marrow and fat tissue – to help stimulate bone growth and increase existing bone mass and strength. This can help heal people suffering from conditions like osteoporosis or hard to heal fractures. RAB-001 has also shown promise in reducing inflammation and so could prove helpful in treating people with inflammatory arthritis.

Overcoming problems

In a news article on the UC Davis website, Wei Yao, said RAB-001 seems to solve a problem that has long puzzled researchers:

“There are many stem cells, even in elderly people, but they do not readily migrate to bone.  Finding a molecule that attaches to stem cells and guides them to the targets we need provides a real breakthrough.”

The UC Davis team already has approval to begin a Phase 1 clinical trial to test this approach on people with osteonecrosis, a disease caused by reduced blood flow to bones. CIRM is funding this work.

The RABOME team also hopes to test RAB-001 in clinical trials for healing broken bones, osteoporosis and inflammatory arthritis.

CIRM solution

To help other researchers overcome these same regulatory hurdles in developing stem cell therapies CIRM created the Stem Cell Center with QuintilesIMS, a leading integrated information and technology-enabled healthcare service provider that has deep experience and therapeutic expertise. The Stem Cell Center will help researchers overcome the challenges of manufacturing and testing treatments to meet FDA standards, and then running a clinical trial to test that therapy in people.