Stories that caught our eye: Spinal cord injury trial milestone, iPS for early cancer diagnosis, and storing videos in DNA

Spinal cord injury clinical trial hits another milestone (Kevin McCormack)
We began the week with good news about our CIRM-funded clinical trial with Asterias for spinal cord injury, and so it’s nice to end the week with more good news from that same trial. On Wednesday, Asterias announced it had completed enrolling and dosing patients in their AIS-B 10 million cell group.

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People with AIS-B spinal cord injuries have some level of sensation and feeling but very little, if any, movement below the site of injury site. So for example, spinal cord injuries at the neck, would lead to very limited movement in their arms and hands. As a result, they face a challenging life and may be dependent on help in performing most daily functions, from getting out of bed to eating.astopc1

In another branch of the Asterias trial, people with even more serious AIS-A injuries – in which no feeling or movement remains below the site of spinal cord injury – experienced improvements after being treated with Asterias’ AST-OPC1 stem cell therapy. In some cases the improvements were quite dramatic. We blogged about those here.

In a news release Dr. Ed Wirth, Asterias’ Chief Medical Officer, said they hope that the five people treated in the AIS-B portion of the trial will experience similar improvements as the AIS-A group.

“Completing enrollment and dosing of the first cohort of AIS-B patients marks another important milestone for our AST-OPC1 program. We have already reported meaningful improvements in arm, hand and finger function for AIS-A patients dosed with 10 million AST-OPC1 cells and we are looking forward to reporting initial efficacy and safety data for this cohort early in 2018.”

Asterias is already treating some AIS-A patients with 20 million cells and hopes to start enrolling AIS-B patients for the 20 million cell therapy later this summer.

Earlier diagnosis of pancreatic cancer using induced pluripotent stem cells Reprogramming adult cells to an embryonic stem cell-like state is as common in research laboratories as hammers and nails are on a construction site. But a research article in this week’s edition of Science Translational Medicine used this induced pluripotent stem cell (iPSC) toolbox in a way I had never read about before. And the results of the study may lead to earlier detection of pancreatic cancer, the fourth leading cause of cancer death in the U.S.

Zaret STM pancreatic cancer tissue July 17

A pancreatic ductal adenocarcinoma
Credit: The lab of Ken Zaret, Perelman School of Medicine, University of Pennsylvania

We’ve summarized countless iPSCs studies over the years. For example, skin or blood samples from people with Parkinson’s disease can be converted to iPSCs and then specialized into brain cells to provide a means to examine the disease in a lab dish. The starting material – the skin or blood sample – typically has no connection to the disease so for all intents and purposes, it’s a healthy cell. It’s only after specializing it into a nerve cell that the disease reveals itself.

But the current study by researchers at the University of Pennsylvania used late stage pancreatic cancer cells as their iPSC cell source. One of the reasons pancreatic cancer is thought to be so deadly is because it’s usually diagnosed very late when standard treatments are less effective. So, this team aimed to reprogram the cancer cells back into an earlier stage of the cancer to hopefully find proteins or molecules that could act as early warning signals, or biomarkers, of pancreatic cancer.

Their “early-stage-cancer-in-a-dish” model strategy was a success. The team identified a protein called thrombospodin-2 (THBS2) as a new candidate biomarker. As team lead, Dr. Ken Zaret, described in a press release, measuring blood levels of THBS2 along with a late-stage cancer biomarker called CA19-9 beat out current detection tests:

“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer. Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.”

DNA: the ultimate film archive device?
This last story for the week isn’t directly related to stem cells but is too cool to ignore. For the first time ever, researchers at Harvard report in Nature that they have converted a video into a DNA sequence which was then inserted into bacteria. As Gina Kolata states in her New York Times article about the research, the study represents the ultimate data archive system which can “be retrieved at will and multiplied indefinitely as the host [bacteria] divides and grows.”

A video file is nothing but a collection of “1s” and “0s” of binary code which describe the makeup of each pixel in each frame of a movie. The researchers used the genetic code within DNA to describe each pixel in a short clip of one of the world’s first motion pictures: a galloping horse captured by Eadward Muybridge in 1878.

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The resulting DNA sequence was then inserted into the chromosome of E.Coli., a common bacteria that lives in your intestines, using the CRISPR gene editing method. The video code was still retrievable after the bacteria was allowed to multiply.

The Harvard team envisions applications well beyond a mere biological hard drive. Dr. Seth Shipman, an author of the study, told Paul Rincon of BBC news that he thinks this cell system could be placed in various parts of the body to analyze cell function and “encode information about what’s going on in the cell and what’s going on in the cell environment by writing that information into their own genome”.

Perhaps then it could be used to monitor the real-time activity of stem cell therapies inside the body. For now, I’ll wait to hear about that in some upcoming science fiction film.

Wall Street Journal features CIRM-funded clinical trials aiming for a diabetes cure

We think CIRM-funded clinical trials hold so much promise that it doesn’t surprise us when major news organizations publish stories about these projects that aim to provide stem cell treatments to patients with unmet medical needs. But we certainly don’t mind the attention!

This past Saturday, for example, the Wall Street Journal featured two CIRM-funded clinical trials, run by ViaCyte and Caladrius, in an article covering cutting-edge research approaches to tackling type 1 diabetes. Also mentioned was Semma Therapeutics, who have a CIRM-funded pre-clinical diabetes research grant.

ViaCyte is tackling diabetes with implantable devices containing stem cell-based products that release insulin on demand rather than requiring continual monitoring of blood sugar level. Image: ViaCyte.

People with type 1 diabetes lack insulin, a hormone that’s critical for transporting blood sugar, digested from the food we eat, into our energy-hungry organs and tissues. They lack insulin because the insulin-producing beta cells in the pancreas have been attacked and killed off by the body’s own immune system. Without insulin, blood sugar levels go through the roof and over time that build up can cause vision loss, kidney disease, nerve damage, heart disease and the list goes on.

Families unaffected by type 1 diabetes often mistake insulin injections as a cure for diabetes. But they’re not. Julia Greenstein, vice president of discovery research for the JDRF, states injected insulin’s limitation very concisely but clearly in the WSJ article:

“It is [in] no way an easy life trying to manage blood glucose.”

Her statement echoes the thoughts of Chris Stiehl who we interviewed for a video a few years ago:

“It’s a 24-hour a day job, 7 days a week you never get a day off. I would give anything for a day off. Just to not have to think about it. Besides all the things you have to do for your work and your family and everything, you have to be constantly thinking: “What’s my blood sugar? What have I eaten? Have I exercised too much or too little? How much insulin should I take based on the exercise I just did? Gee by the way is my insulin pump running out of insulin?

The WSJ article points out that a pancreas or beta cell transplant, received from a deceased donor, is currently the best option for long-term treatment of type 1 diabetes. But there are big drawbacks and limitations to this approach: the pancreas transplant requires major surgery, both require life-long immunosuppressing drugs that can cause serious infection and cancer and donor organs and cells are hard to come by.

That’s where regenerative medicine technology comes into the picture. The article goes on to highlight ViaCyte’s therapeutic product, PEC-EncapTM which is composed of embryonic stem cell-derived insulin-producing beta cells that are encased by a capsule that is transplanted under the skin. The capsule has pores that allow blood glucose and insulin to flow freely but protects the cell product from destruction from the body’s immune cells.

Because the cell product stems from, er, stem cells, there’s the potential of a limitless supply that doesn’t rely on cadavers.

Dr. Gordon Weir, a Harvard Medical School professor and diabetes researcher at the Joslin Diabetes Center in Boston, spoke about the excitement of such a device along with a reality check:

“Everyone’s waiting for the next generation of beta-cell replacement that hopefully will change the whole way in which we treat diabetes. In spite of the excitement and extraordinary things that have happened in the last 10 years, there are still a lot of challenges.”

Indeed, since beginning the clinical trial in 2014, ViaCyte has encountered some speed bumps. They had hoped that blood vessels growing around but not into the device would facilitate the transfer of blood sugar into the device where the beta cells would sense the level of sugar and release the appropriate amount of insulin. But it turns out that some cells of the immune system cells mucked up the blood vessel network. The company is working on improvements to the device to get the clinical trial back on track in the next 24 months. To jump start that effort they recently secured a partnership with the makers of Gore-Tex fabrics who also specialize in medical implantable devices.

That collaboration is also motivating a next generation device called PEC-DirectTM which contains larger pores that would allow direct interaction between the body’s blood vessels and the beta cells inside the device. Because of the larger openings, immune cells could infiltrate the device and so immunosuppressive drugs would be needed in this case. But for patients with severe type 1 diabetes, this approach would be a more available treatment source compared to cadaver cells or organs.

The WSJ article also discusses the CIRM-funded Caladrius clinical trial that takes quite a different approach to treating type 1 diabetes. The company is trying to disarm the T cells that attack the body’s own pancreatic beta cells. Because diabetics don’t lose all their beta cells at once, this approach could help maintain the insulin-producing cells that are still intact. The company’s strategy is to reprogram these attacking T-cells to convert them into so-called regulatory T-cells that act as a natural inhibitor of the immune response.

While each company works diligently on their own approach, eager patients are routing for both. Dara Melnick, of Woodbury, N.Y., who was diagnosed with type 1 diabetes at 8 years old and is now 36, summed up the patient’s perspective perfectly in the article:

“A cure would be the sweetest thing I could ever taste.”

Cancer-causing mutations in blood stem cells may also link to heart disease

Whether we read about it in the news or hear it from our doctor, when we think about the causes of heart disease it’s usually some combination of inheriting bad genes from our parents and making poor life style choices like smoking or eating a diet high in fat and cholesterol. But in a fascinating research published yesterday in the New England Journal of Medicine, scientists show evidence that in some people, heart disease may develop much in the same way that a blood cancer does; that is, through a gradual, lifetime accumulation of mutations in hematopoietic cells, or blood stem cells.

This surprising discovery began as a project, published in 2014, aimed at early detection of blood cancers in the general population. This earlier study focused on the line of evidence that cells don’t become cancerous overnight but rather progress slowly as we age. So, in the case of a blood cancer, or leukemia, a blood stem cell can acquire a mutation that transforms the cell into a pre-cancerous state. When that stem cell multiplies it creates “clones” of the blood stem cell that had the cancer-initiating mutation. It’s only after additional genetic insults that these stem cells become full blown cancers.

The research team, composed of scientists from Brigham and Women’s Hospital as well as the Broad Institute of Harvard and MIT, examined DNA sequences from blood samples of over 17,000 people who didn’t have blood cancer. They analyzed these samples, specifically looking at 160 genes that are often mutated in blood cancer. The results from the 2014 study showed that mutations in these genes in people 40 years and under were few and far between. Interestingly, the frequency noticeably increased in older folks with those 10% over 70 years of age carrying the mutations.

Most of these so-called “clonal hematopoiesis of indeterminate potential”, or CHIP, mutations occurred in three genes called DNMT3A, TET2, and ASXL1. While these mutations were indeed associated with a 10-fold higher risk of blood cancer, the team also saw an unexpected correlation: people with these mutations had a 40% higher overall risk of dying due to other causes compared to those who did not carry the mutations. They pinpointed heart disease as one primary cause of the increased mortality risk.

The current follow-up study not only sought to confirm this correlation between the mutations and heart disease but also show the mutations cause the increased risk. This time around, the team looked for the mutations in a group of four different populations totaling over 8000 people. Again, they saw a correlation between the mutations and the risk of heart disease or a heart attack later in life. One of the team leads, Dr. Sekar Kathiresan from the Broad Institute, talked about his team’s reaction to these results in a Time Magazine interview:

Sekar Kathiresan, Photo: Broad Institute

“We were fully expecting not to find anything here. But the odds of having an early heart attack are four-fold higher among younger people with CHIP mutations.”

 

To show a causal link, they turned to mouse studies. They collected bone marrow stem cells from mice engineered to lack Tet2, one of the three genes that when mutated had been associated with increased risk of heart disease. The bone marrow cells were then transplanted into mice which are prone to have increased blood cholesterol and symptoms of heart disease. The presence of these cells that lacked Tet2 led to increased hardening of major arteries – a precursor to clogged blood vessels, heart disease and heart attacks – compared to mice that received normal bone marrow cells.

Though more work remains, Kathiresan thinks these current results offer some tantalizing therapeutic possibilities:

“This is a totally different type of risk factor than hypertension or hypercholestserolemia [high blood cholesterol] or smoking. And since it’s a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present.”

Stories that caught our eye: color me stem cells, delivering cell therapy with nanomagnets, and stem cell decisions

Nanomagnets: the future of targeted stem cell therapies? Your blood vessels are made up of tightly-packed endothelial cells. This barrier poses some big challenges for the delivery of drugs via the blood. While small molecules are able make their way through the small gaps in the blood vessel walls, larger drug molecules, including proteins and cells, are not able to penetrate the vessel to get therapies to diseased areas.

This week, researchers at Rice University report in Nature Communications on an ingenious technique using tiny magnets that may overcome this drug delivery problem.

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At left, the nanoparticles are evenly distributed among the microtubules that help give the cells their shape. At right, after a magnetic field is applied, the nanoparticles are pulled toward one end of the cells and change their shapes. Credit: Laboratory of Biomolecular Engineering and Nanomedicine/Rice University

Initial studies showed that adding magnetic nanoparticles to the endothelial cells and then applying a magnetic field affected the cells’ internal scaffolding, called microtubules. These structures are responsible for maintaining the tight cell to cell connections. The team took the studies a step further by growing the cells in specialized petri dishes containing tiny, tube-shaped channels. Applying a magnetic field to the cells caused the cell-cell junctions to form gaps, making the blood vessel structures leaky. Simply turning off the magnetic field closed up the gaps within a few hours.

Though a lot of research remains, the team aims to apply this on-demand induction of cell leakiness along with adding the magnetic nanoparticles to stem cell therapy products to help target the treatment to specific area. In a press release, team leader Dr. Gang Bao spoke about possible applications to arthritis therapy:

“The problem is how to accumulate therapeutic stem cells around the knee and keep them there. After injecting the nanoparticle-infused cells, we want to put an array of magnets around the knee to attract them.”

To differentiate or not differentiate: new insights During the body’s development, stem cells must differentiate, or specialize, into functional cells – like liver, heart, brain. But once that specialization occurs, the cells lose their pluripotency, or the ability to become any type of cell. So, stem cells must balance the need to differentiate with the need to make copies of itself to maintain an adequate supply of stem cells to complete the development process. And even after a fully formed baby is born, it’s still critical for adult stem cells to balance the need to regenerate damaged tissue versus stashing away a pool of stem cells in various organs for future regeneration and replacement of damaged or diseased tissues.

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Visualizing activation of Nanog gene activity (bright green spot) within cell nucleus. 
Image: Courtesy of Bony De Kumar, Ph.D., and Robb Krumlauf, Ph.D., Stowers Institute for Medical Research

A report this week in the Proceedings of the National Academy of Sciences finds evidence that the two separate processes – differentiation and pluripotency – directly communicate with each other as way to ensure a proper balance between the two states.

The study, carried out by researchers at Stowers Institute for Medical Research in Kansas City, Missouri, focused on the regulation of two genes: Nanog and Hox. Nanog is critical for maintaining a stem cell’s ability to become a specialized cell type. In fact, it’s one of the four genes initially used to reprogram adult cells back into induced pluripotent stem cells. The Hox gene family is responsible for generating a blueprint of the body plan in a developing embryo. Basically, the pattern of Hox gene activity helps generate the body plan, basically predetermining where the various body parts and organs will form.

Now, both Nanog and Hox proteins act by binding to DNA and turning on a cascade of other genes that ultimately maintain pluripotency or promote differentiation. By examining these other genes, the researchers were surprised to find that both Nanog and Hox were bound to both the pluripotency and differentiation genes. They also found that Nanog and Hox can directly inhibit each other. Taken together, these results suggest that exquisite control of both processes occurs cross regulation of gene activity.

Dr. Robb Krumlauf one of authors on the paper talked about the significance of the result in a press release:

“Over the past 10 to 20 years, biologists have shown that cells are actively assessing their environment, and that they have many fates they can choose. The regulatory loops we’ve found show how the dynamic nature of cells is being maintained.”

Color me stem cells Looking to improve your life and the life of those around you? Then we highly recommend you pay a visit to today’s issue of Right Turn, a regular Friday feature of  Signals, the official blog of CCRM, Canada’s public-private consortium supporting the development of regenerative medicine technologies.

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Collage sample of CCRM’s new coloring sheets. Image: copyright CCRM 2017

As part of an public outreach effort they have created four new coloring sheets that depict stem cells among other sciency topics. They’ve set up a DropBox link to download the pictures so you can get started right away.

Adult coloring has swept the nation as the hippest new pastime. And it’s not just a frivolous activity, as coloring has been shown to have many healthy benefits like reducing stressed and increasing creativity. Just watch any kid who colors. In fact, share these sheet with them, it’s intended for children too.

New stem cell technique gives brain support cells a starring role

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The Salk team. From left: Krishna Vadodaria, Lynne Moore, Carol Marchetto, Arianna Mei, Fred H. Gage, Callie Fredlender, Ruth Keithley, Ana Diniz Mendes. Photo courtesy Salk Institute

Astrocytes are some of the most common cells in the brain and central nervous system but they often get overlooked because they play a supporting role to the more glamorous neurons (even though they outnumber them around 50 to 1). But a new way of growing those astrocytes outside the brain could help pave the way for improved treatments for stroke, Alzheimer’s and other neurological problems.

Astrocytes – which get their name because of their star shape (Astron – Greek for “star” and “kyttaron” meaning cell) – have a number of key functions in the brain. They provide physical and metabolic support for neurons; they help supply energy and fuel to neurons; and they help with detoxification and injury repair, particularly in terms of reducing inflammation.

Studying these astrocytes in the lab has not been easy, however, because existing methods of producing them have been slow, cumbersome and not altogether effective at replicating their many functions.

Finding a better way

Now a team at the Salk Institute, led by CIRM-funded Professor Fred “Rusty” Gage, has developed a way of using stem cells to create astrocytes that is faster and more effective.

Their work is published in the journal Stem Cell Reports. In a news release, Gage says this is an important discovery:

“This work represents a big leap forward in our ability to model neurological disorders in a dish. Because inflammation is the common denominator in many brain disorders, better understanding astrocytes and their interactions with other cell types in the brain could provide important clues into what goes wrong in disease.”

Stylized microscopy image of an astrocyte (red) and neuron (green). (Salk Institute)

In a step by step process the Salk team used a series of chemicals, called growth factors, to help coax stem cells into becoming, first, generic brain cells, and ultimately astrocytes. These astrocytes not only behaved like the ones in our brain do, but they also have a particularly sensitive response to inflammation. This gives the team a powerful tool in helping develop new treatment to disorders of the brain.

But wait, there’s more!

As if that wasn’t enough, the researchers then used the same technique to create astrocytes from induced pluripotent stem cells (iPSCs) – adult cells, such as skin, that have been re-engineered to have the ability to turn into any other kind of cell in the body. Those man-made astrocytes also showed the same characteristics as natural ones do.

Krishna Vadodaria, one of the lead authors on the paper, says having these iPSC-created astrocytes gives them a completely new tool to help explore brain development and disease, and hopefully develop new treatments for those diseases.

“The exciting thing about using iPSCs is that if we get tissue samples from people with diseases like multiple sclerosis, Alzheimer’s or depression, we will be able to study how their astrocytes behave, and how they interact with neurons.”

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.

New target for defeating breast cancer stem cells uncovered

Stashed away in most of your tissues and organs lie small populations of adult stem cells. They help keep our bodies functioning properly by replenishing dying or damaged cells. Their ability to make more copies of themselves, as needed, ensures that there’s always an adequate supply set aside. But this very same self-renewing, life-sustaining property of adult stem cells is deadly in the hands of cancer stem cells. Also called tumor-initiating cells, cancer stem cells sustain tumor growth even after chemotherapy and are thought to be a primary cause of cancer relapse.

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Microscopic image of normal mouse mammary ducts. Mammary stem cells are found among basal cells (green). Image courtesy of Toni Celià-Terrassa and Yibin Kang, Princeton University

By studying adult and cancer stem cells side-by-side, Princeton researchers report this week in Nature Cell Biology that they’ve uncovered a common function in both cells types that not only helps explain an adult stem cell’s self-renewing ability but also points to new therapeutic approaches to targeting breast cancer stem cells.

Both adult and cancer stem cells continually resist signals from their environment that encourage them to specialize, or differentiate, into a particular cell type. Once specialized, the cells lose their ability to self-renew and will eventually die off. Now, if all the adult stem cells in an organ followed that instruction, they would eventually become depleted and the organ would lose the ability to repair itself. The same holds true for cancer stem cells which actually would be a good thing since it would lead to the tumor’s death.

The Princeton team first identified a molecule called miR-199a that allows mammary (breast) stem cells to resist differentiation signals by directly blocking the production of a protein called LCOR. Artificially boosting the amount of miR-199a led to a decrease in LCOR levels and an increase in stem cell function. But when LCOR levels were increased, mammary stem cell function was restricted.

The researchers then turned their attention to breast cancer stem cells and found the same miR-199a/LCOR function at work. In a similar fashion, boosting miR-199a levels enhanced cancer stem cell function and increased tumor formation while increasing LCOR restricted the tumor-forming ability of the breast cancer stem cells.

These lab results also matched up with tissue samples taken from breast cancer patients. High miR-199a levels in the samples correlated with low patient survival rates. But those with high levels of LCOR showed a better prognosis.

It turns out that cells in our immune system are responsible for boosting LCOR in mammary and breast cancer stem cells by releasing a protein called interferon alpha. So the presence of interferon alpha nudges mammary stem cells to mature into mammary gland cells and inhibits breast cancer stems from forming tumors. But in the presence of elevated miR-199a levels, mammary and breast cancer stem cells are protected and maintain their numbers by deactivating the interferon alpha/LCOR signal.

If you’re still with me, these results point to miR-199a as a promising target for restoring interferon-alpha’s cancer interfering properties. Team leader Dr. Yibin Kang highlighted this possibility in a Princeton University press release:

“Interferons have been widely used for the treatment of multiple cancer types. These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway.”

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.”

Stem cell stories that caught our eye: update on Capricor’s heart attack trial; lithium on the brain; and how stem cells do math

Capricor ALLSTARToday our partners Capricor Therapeutics announced that its stem cell therapy for patients who have experienced a large heart attack is unlikely to meet one of its key goals, namely reducing the scar size in the heart 12 months after treatment.

The news came after analyzing results from patients at the halfway point of the trial, six months after their treatment in the Phase 2 ALLSTAR clinical trial which CIRM was funding. They found that there was no significant difference in the reduction in scarring on the heart for patients treated with donor heart-derived stem cells, compared to patients given a placebo.

Obviously this is disappointing news for everyone involved, but we know that not all clinical trials are going to be successful. CIRM supported this research because it clearly addressed an unmet medical need and because an earlier Phase 1 study had showed promise in helping prevent decline in heart function after a heart attack.

Yet even with this failure to repeat that promise in this trial,  we learned valuable lessons.

In a news release, Dr. Tim Henry, Director of the Division of Interventional Technologies in the Heart Institute at Cedars-Sinai Medical Center and a Co-Principal Investigator on the trial said:

“We are encouraged to see reductions in left ventricular volume measures in the CAP-1002 treated patients, an important indicator of reverse remodeling of the heart. These findings support the biological activity of CAP-1002.”

Capricor still has a clinical trial using CAP-1002 to treat boys and young men developing heart failure due to Duchenne Muscular Dystrophy (DMD).

Lithium gives up its mood stabilizing secrets

As far back as the late 1800s, doctors have recognized that lithium can help people with mood disorders. For decades, this inexpensive drug has been an effective first line of treatment for bipolar disorder, a condition that causes extreme mood swings. And yet, scientists have never had a good handle on how it works. That is, until this week.

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Evan Snyder

Reporting in the Proceedings of the National Academy of Sciences (PNAS), a research team at Sanford Burnham Prebys Medical Discovery Institute have identified the molecular basis of the lithium’s benefit to bipolar patients.  Team lead Dr. Evan Snyder explained in a press release why his group’s discovery is so important for patients:

“Lithium has been used to treat bipolar disorder for generations, but up until now our lack of knowledge about why the therapy does or does not work for a particular patient led to unnecessary dosing and delayed finding an effective treatment. Further, its side effects are intolerable for many patients, limiting its use and creating an urgent need for more targeted drugs with minimal risks.”

The study, funded in part by CIRM, attempted to understand lithium’s beneficial effects by comparing cells from patient who respond to those who don’t (only about a third of patients are responders). Induced pluripotent stem cells (iPSCs) were generated from both groups of patients and then the cells were specialized into nerve cells that play a role in bipolar disorder. The team took an unbiased approach by looking for differences in proteins between the two sets of cells.

The team zeroed in on a protein called CRMP2 that was much less functional in the cells from the lithium-responsive patients. When lithium was added to these cells the disruption in CRMP2’s activity was fixed. Now that the team has identified the molecular location of lithium’s effects, they can now search for new drugs that do the same thing more effectively and with fewer side effects.

The stem cell: a biological calculator?

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Can stem cells do math?

Stem cells are pretty amazing critters but can they do math? The answer appears to be yes according to a fascinating study published this week in PNAS Proceedings of the National Academy of Sciences.

Stem cells, like all cells, process information from the outside through different receptors that stick out from the cells’ outer membranes like a satellite TV dish. Protein growth factors bind those receptors which trigger a domino effect of protein activity inside the cell, called cell signaling, that transfers the initial receptor signal from one protein to another. Ultimately that cascade leads to the accumulation of specific proteins in the nucleus where they either turn on or off specific genes.

Intuition would tell you that the amount of gene activity in response to the cell signaling should correspond to the amount of protein that gets into the nucleus. And that’s been the prevailing view of scientists. But the current study by a Caltech research team debunks this idea. Using real-time video microscopy filming, the team captured cell signaling in individual cells; in this case they used an immature muscle cell called a myoblast.

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Behavior of cells over time after they have received a Tgf-beta signal. The brightness of the nuclei (circled in red) indicates how much Smad protein is present. This brightness varies from cell to cell, but the ratio of brightness after the signal to before the signal is about the same. Image: Goentoro lab, CalTech.

To their surprise the same amount of growth factor given to different myoblasts cells led to the accumulation of very different amounts of a protein called Smad3 in the cells’ nuclei, as much as a 40-fold difference across the cells. But after some number crunching, they discovered that dividing the amount of Smad3 after growth factor stimulation by the Smad3 amount before growth stimulation was similar in all the cells.

As team lead Dr. Lea Goentoro mentions in a press release, this result has some very important implications for studying human disease:

“Prior to this work, researchers trying to characterize the properties of a tumor might take a slice from it and measure the total amount of Smad in cells. Our results show that to understand these cells one must instead measure the change in Smad over time.”

Pleasant surprise reveals molecular insights about graying and balding hair

A lesson that every lab researcher learns early in their career is that experiments often don’t give you the results you expect. But that’s not always a bad thing. Sometimes surprising results can lead to new insights or can even steer your research in completely new, exciting directions.

That’s what happened to scientists at the University of Texas Southwestern Medical Center. What started out as a project to better understand a genetic disorder – called neurofibromatosis – that causes benign tumor growth on nerve cells, turned into new discoveries about the cellular basis for graying and balding hair – at least in mice.

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Starting at 30 days after birth (P30, upper right picture), mouse lacking the SCF gene (top mouse in each picture) gradually loses hair pigment while hair color of control mouse remains unchanged. Photo: Fig 1A, Genes Dev. 2017 May 2.

The team was studying neurofibromatosis in mouse cells that produce Krox20, a protein which plays a role in the development of nerve cells. Krox20, in turn, stimulates the production of another protein called Stem Cell Factor (SCF). With some genetic engineering tricks, a mouse strain lacking SCF specifically in these Krox20-producing cells was bred to uncover SCF’s impact on neurofibromatosis.

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Hair production and pigmentation occurs in hair follicle. Image: Shutterstock

But the researchers couldn’t help noticing something else: as reported in Genes and Development, just a month after birth, all 20 mice had graying fur and by nine months, their fur was completely white. Another set of mice was bred to lack Krox20-producing cells. The resulting animals completely lacked hair. Further experiments determined that the Krox20-producing cells in the hair follicle were stem cell-like progenitor cells that give rise to the cells responsible for hair production and pigmentation.

Piecing the data together, the researchers created a visual model of the hair follicle in which the progenitor cells maintain a steady supply of hair-producing cells with Krox20 playing a critical role. And the SCF produced by those cells allows the uptake of hair pigment called melanin, from nearby melanocyte cells also found in the hair follicle.

This model suggests that as we age, something causes a reduction in SCF in the hair follicle which leads to graying hair. The model also suggests that thinning hair, which is quite common in both men and women, is triggered by a reduction in the number of progenitor cells in the follicle.

Given that the treatment of hair loss and graying are multi-billion dollar industries, it’s no surprise that this story got a lot of attention in the press. Based on the titles of some of those news articles, you’d think new, game-changing hair products are just around the corner. In reality, this research is at a very early stage and will require many years of follow up experiments to figure out if and how commercialization of the technology is possible.

Still, as lead scientist Dr. Lu Le explains in a press release, the team has a vision for what their ultimate goal might look like:

“With this knowledge, we hope in the future to create a topical compound or to safely deliver the necessary gene to hair follicles to correct these cosmetic problems.”