Brain stem cells unintentionally talk with brain tumors, allowing their spread

A stem cell’s capacity to lay quiet and, when needed, to self-renew plays a key role in restoring and maintaining the health of our organs. Unfortunately, cancer stem cells possess that same property allowing them to evade radiation and chemotherapy treatments which leads to tumor regrowth. And a CIRM-funded study published today in Cell shows the deviousness of these cancer cells goes even further. The Stanford research team behind the study found evidence that brain stem cells, which normally guide brain development and maintenance, unintentionally communicate with brain cancer cells in deadly tumors, called gliomas, providing them a means to invade other parts of the brain. But the silver lining to this scary insight is that it may lead to new treatment options for patients.

High grade gliomas do not end well
The most aggressive forms of glioma are called high grade gliomas and they carry devastating prognoses. For instance, the most common form of these tumors in children has a median survival of just 9 months with a 5-year survival of less than 1%. Surgery or anti-cancer therapies may help for a while but the tumor inevitably grows back.

MRI image of high grade glioma brain tumor (white mass on left). Image: Wikipedia

Researchers have observed that gliomas typically originate in the brain stem and very often invade a brain stem cell-rich area, called the subventrical zone (SVZ), that provides a space for the therapy-resistant cancer stem cells to hole up. This path of tumor spread is associated with a shorter time to relapse and poorer survival but the exact mechanism wasn’t known. The Stanford team hypothesized that SVZ brain stem cells release some factor that attracts the gliomas to preferentially invade that part of the brain.

To test this chemo-attraction idea, they mimicked cancer cell invasion in a specialized, dual compartment petri dish called a Boyden chamber. In the bottom compartment, they placed the liquid food, or media, that SVZ brain stem cells had been grown in. On the upper compartment, they placed the cancerous glioma cells. A porous, gelatin membrane between the two compartments acts as a barrier but allows the cells to receive signals from the lower compartment and migrate down into the media if a chemoattractant is present. And that’s what they saw: a significant glioma cell migration through the gelatin toward the brain stem cell media.

Boyden chamber assay. Image: Integr. Biol., 2009,1, 170-181

Pleiotrophin: an unintentional communicator with brain cancer cells
Something or somethings in the SVZ brain stem cell media had to be attracting the glioma cells. So, the Stanford team analyzed the composition of the media and identified four proteins that, when physically complexed together, had the same chemo-attraction ability as the media. They were pleased to find that one of the four proteins is pleiotrophin which is known to not only play a role in normal brain development and regeneration but also to increase glioma cell migration. And in this study, they showed that higher levels of pleiotrophin are present in the SVZ brain stem cell area compared to other regions of the brain. They went on to show that blocking the production of pleiotrophin in mice reduced the invasion of glioma cells into the SVZ region. This result suggests that blocking the release of pleiotrophin by brain stem cells in the SVZ could help prevent or slow down the spread of glioma in patients’ brains without the need of irradiating this important part of the brain.

The silver lining: hsp90 inhibitors have therapeutic promise

Michelle Monje, MD, PhD

To further explore this potential therapeutic approach, the team examined hsp90, one of the other three proteins complexed with pleiotrophin. Though it doesn’t have chemoattractant properties, it still is a necessary component and may act to stabilize pleiotrophin. It also turns out that inhibitors for hsp90 have already been developed in the clinic for treating various cancers. When the researchers in this study blocked hsp90 production in the SVZ region of mice, they observed a reduced invasion of glioma cells. Though clinical grade hsp90 inhibitors exist, team lead  Michelle Monje, MD, PhD – assistant professor of neurology, Stanford University – tells me that some tweaking of these drugs will be necessary to reach gliomas:

“Our challenge is to find an hsp90 inhibitor that penetrates the brain at effective concentrations.”

Once they find that inhibitor, it could provide new options, and hope, for people diagnosed with this dreadful cancer.

CIRM weekly stem cell roundup: minibrain model of childhood disease; new immune insights; patient throws out 1st pitch

New human Mini-brain model of devastating childhood disease.
The eradication of Aicardi-Goutieres Syndrome (AGS) can’t come soon enough. This rare but terrible inherited disease causes the immune system to attack the brain. The condition leads to microcephaly (an abnormal small head and brain size), muscle spasms, vision problems and joint stiffness during infancy. Death or a persistent comatose state is common by early childhood. There is no cure.

Though animal models that mimic AGS symptoms are helpful, they don’t reflect the human disease closely enough to provide researchers with a deeper understanding of the mechanisms of the disease. But CIRM-funded research published this week may be a game changer for opening up new therapeutic strategies for the children and their families that are suffering from AGS.

Organoid mini-brains are clusters of cultured cells self-organized into miniature replicas of organs. Image courtesy of Cleber A. Trujillo, UC San Diego.

To get a clearer human picture of the disease, Dr. Alysson Muotri of UC San Diego and his team generated AGS patient-derived induced pluripotent stem cells (iPSCs). These iPSCs were then grown into “mini-brains” in a lab dish. As described in Cell Stem Cell, their examination of the mini-brains revealed an excess of chromosomal DNA in the cells. This abnormal build up causes various toxic effects on the nerve cells in the mini-brains which, according to Muotri, had the hallmarks of AGS in patients:

“These models seemed to mirror the development and progression of AGS in a developing fetus,” said Muotri in a press release. “It was cell death and reduction when neural development should be rising.”

In turns out that the excess DNA wasn’t just a bunch of random sequences but instead most came from so-called LINE1 (L1) retroelements. These repetitive DNA sequences can “jump” in and out of DNA chromosomes and are thought to be remnants of ancient viruses in the human genome. And it turns out the cell death in the mini-brains was caused by the immune system’s anti-viral response to these L1 retroelements. First author Charles Thomas explained why researchers may have missed this in their mouse models:

“We uncovered a novel and fundamental mechanism, where chronic response to L1 elements can negatively impact human neurodevelopment. This mechanism seems human-specific. We don’t see this in the mouse.”

The team went on to test the anti-retroviral effects of HIV drugs on their AGS models. Sure enough, the drugs decreased the amount of L1 DNA and cell growth rebounded in the mini-brains. The beauty of using already approved drugs is that the route to clinical trials is much faster and in fact a European trial is currently underway.

For more details, watch this video interview with Dr. Muotri:

New findings about immune cell development may open door to new cancer treatments
For those of you who suffer with seasonal allergies, you can blame your sniffling and sneezing on an overreaction by mast cells. These white blood cells help jump start the immune system by releasing histamines which makes blood vessels leaky allowing other immune cells to join the battle to fight disease or infection. Certain harmless allergens like pollen are mistaken as dangerous and can also cause histamine release which triggers tearing and sneezing.

Mast cells in lab dish. Image: Wikipedia.

Dysfunction of mast cells are also involved in some blood cancers. And up until now, it was thought a protein called stem cell factor played the key role in the development of blood stem cells into mast cells. But research reported this week by researchers at Karolinska Institute and Uppsala University found cracks in that previous hypothesis. Their findings published in Blood could open the door to new cancer therapies.

The researchers examine the effects of the anticancer drug Glivec – which blocks the function of stem cell factor – on mast cells in patients with a form of leukemia. Although the number of mature mast cells were reduced by the drug, the number of progenitor mast cells were not. The progenitors are akin to teenagers in that they’re at an intermediate stage of development, more specialized than stem cells but not quite mast cells. The team went on to confirm that stem cell factor was not required for the mast cell progenitors to survive, multiply and mature. Instead, their work identified two other growth factors, interleukin 3 and 6, as important for mast cell development.

In a press release, lead author Joakim Dahlin, explained how these new insights could lead to new therapies:

“The study increases our understanding of how mast cells are formed and could be important in the development of new therapies, for example for mastocytosis for which treatment with imatinib/Glivec is not effective. One hypothesis that we will now test is whether interleukin 3 can be a new target in the treatment of mast cell-driven diseases.”

Patient in CIRM-funded trial regains use of arms, hands and fingers will throw 1st pitch in MLB game.
We end this week with some heart-warming news from Asterias Biotherapeutics. You avid Stem Cellar readers will remember our story about Lucas Lindner several weeks back. Lucas was paralyzed from the neck down after a terrible car accident. Shortly after the accident, in June of 2016, he enrolled in Asterias’ CIRM-funded trial testing an embryonic stem cell-based therapy to treat his injury. And this Sunday, August 13th, we’re excited to report that due to regaining the use of his arms, hands and fingers since the treatment, he will throw out the first pitch of a Major League Baseball game in Milwaukee. Congrats to Lucas!

For more about Lucas’ story, watch this video produced by Asterias Biotherapeutics:

Reprogramming cells with a nanochip, electricity and DNA to help the body to heal itself

The axolotl, a member of the salamander family, has amazing regenerative abilities. You can cut off its limbs or crush its spinal cord and it will repair itself with no scarring. A human’s healing powers, of course, are much more limited.

To get around this unfortunate fact, the field of regenerative medicine aims to develop stem cell-based therapies that provide the body with that extra oomph of regenerative ability to rid itself of disease or injury. But most of the current approaches in development rely on complex and expensive manufacturing processes in clinical labs before the cells can be safely transplanted in a patient’s body. Wouldn’t it be nice if we could just give the cells already in our bodies some sort of spark to allow them to repair other diseased or damaged cells?

A research team at Ohio State University have taken a fascinating step toward that seemingly science fiction scenario. Reporting this week in Nature Nanotechnology, the scientists describe a technique that – with some DNA, a nanochip and an electric current placed on the skin – can help mice regrow blood vessels to restore dying tissue.

Researchers demonstrate a process known as tissue nanotransfection (TNT). In laboratory tests, this process was able to heal the badly injured legs of mice in just three weeks with a single touch of this chip. The technology works by converting normal skin cells into vascular cells, which helped heal the wounds. Photo: Wexner Medical Center/The Ohio State University

The foundation of this technique is cellular reprogramming. Induced pluripotent stem cells are the most well-known example of reprogramming in which adult cells, like skin or blood, are converted, in a lab dish, to an embryonic stem cell-like state by introducing a set of reprogramming genes into the cells. From there, the stem cells can be specialized into any cell type.

Now, you wouldn’t want to convert skin or blood cells inside the body into quasi embryonic stem cells because they could generate tumors due to their limitless ability to multiply. In this study, the researchers rely on a related method, direct reprogramming, that skips the stem cell step and uses a different set of genes to directly convert one cell type into another. They focused on the direct reprogramming of skin cells to endothelial cells, a key component of blood vessels, in mice that were given symptoms mimicking those seen in human injury-induced limb ischemia. This condition leads to a risk of gangrene and amputation when severely injured limbs deteriorate due to blocked blood vessels.

It’s one thing to introduce, or transfect, reprogramming genes into cells that are grown in the very controlled environment of a petri dish. But how the heck does one get DNA into skin cells on the leg of a mouse? That’s where the team’s tissue nano-transfection (TNT) approach comes into the picture. After rubbing off a small section of dead skin on the leg, the TNT device, composed of an nanochip electrode and tiny channels of liquid containing reprogramming DNA, is placed on the skin. A short pulse of electricity is applied which opens miniscule holes in the membranes of skin cells that are in contact with the electrode which allows the DNA to enter the cells. Here’s a short video describing the process:

Three weeks after the procedure, blood vessels had formed, blood flow was restored and the legs of the mice were saved. Team leader, Dr. Chandan Sen, described the results in an interview with National Public Radio:

“Not only did we make new cells, but those cells reorganized to make functional blood vessels that plumb with the existing vasculature and carry blood.”

It’s surprising that TNT reprogramming affects more than just the skin cells that were in contact with the device. But it appears the reprogramming instructions from the introduced DNA was somehow spread to other cells through tiny vesicles called exosomes. When Sen’s team extracted those exosomes and introduced them to skin cells in a petri dish, those cells specialized into blood vessel cells.

This result did attract some skepticism from the field. In the NPR story, stem cell expert Dr. Sean Morrison had this to say:

“There are all manners of claims of these vesicles. It’s not clear what these things are, and if it’s a real biological process or if it’s debris.”

Clearly, more work is needed before TNT is ready for clinical trials in humans. But if it holds up, the technique could bring us closer to the incredible self-healing powers of the axolotl.

UC Irvine scientists engineer stem cells to “feel” cancer and destroy it

By blocking cell division, chemotherapy drugs take advantage of the fact that cancer cells multiply rapidly in the body. Though this treatment can extend and even save the lives of cancer patients, it’s somewhat like destroying an ant hill with an atomic bomb: there’s a lot of collateral damage. The treatment is infused through the blood so healthy cells that also divide frequently – like those in hair follicles, the intestines and bone marrow – succumb to the chemotherapy. To add insult to injury, cancers often become resistant to these drugs and metastasize, or invade, other parts of the body. Sadly, this spreading of a cancer is responsible for 90% of cancer deaths.

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UCI doctoral students Shirley Zhang, left, and Linan Liu are co-leading authors of the study. Photo: UC Irvine

Developing more specific, effective anti-cancer therapies is the focus of many research institutes and companies. While some new strategies target cell surface proteins that are unique to cancer cells, a UC Irvine (UCI) team has devised a stem cell-based technique that can seek out and destroy breast cancer cells that have metastasized in the lungs of mice by sensing the stiffness of the surrounding tissue. The CIRM-funded study was published this week in Science Translational Medicine.

While cells make up the tissues and organs of our bodies, they also secrete proteins and molecules that form a scaffold between cells called the extracellular matrix. This cell scaffolding is not just structural, it also plays a key role in regulating cell growth and other functions. And previous studies have shown that at sites of tumors, accumulation of collagen and other proteins in the matrix increases tissue stiffness and promotes metastasis.

Based on this knowledge, the UCI team aimed to create a cell system that would release chemotherapy drugs in response to increased stiffness. It turns out that mesenchymal stem cells – which give rise to bone, muscle, cartilage and fat – not only migrate to tumors in the body but also activate particular genes in response to the stiffness of their local cellular environment.  The researchers engineered mesenchymal stem cells to carry a gene that codes for a protein involved in the activation of a chemotherapy drug which is given by mouth. They also designed the gene to turn on only when it encounters stiff, cancerous tissue. They called the method a mechanoresponsive cell system (MRCS).

To test the MRCS, mice were infused with human breast cancer cells, which metastasized or spread to the lung. The MRCS-engineered mesenchymal stem cells were infused through the blood and homed to the lungs where they activated the chemotherapy drug which caused localized killing of the tumor cells with minimal damage to lung tissue. When the MRSC stem cells were given to mice without tumors, no increase in tissue damage was seen, proving that the MRSC-induced chemotherapy drug is only activated in the presence of cancerous tissue and has few side effects.

In a press release, team leader Weian Zhao, explained that these promising results could have wide application:

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Weian Zhao
Photo: UC Irvine

“This published work is focused on breast cancer metastases in the lungs. However, the technology will be applicable to other metastases as well, because many solid tumors have the hallmark of being stiffer than normal tissue. This is why our system is innovative and powerful, as we don’t have to spend the time to identify and develop a new genetic or protein marker for every kind of cancer.”

 

The team envisions even more applications. The MRCS could be engineered to carry genes that would enable detection with imaging technologies like PET scans. In this scenario, the MRCS could act as a highly sensitive detection system for finding areas of very early metastases when current techniques would miss them. They could also design the MRCS to activate genes that code for proteins that can break down and soften the stiff cancerous tissues which may inhibit the ability for a tumor to spread.

Novel diabetes therapy uses stem cell “teachers” to calm immune cells

Type 1 diabetes is marked by a loss of insulin-producing beta cells in the pancreas. Without insulin, blood sugar can’t shuttle into the body’s energy-hungry organs and tissues. As a result, sugar accumulates in the blood which, over time, causes many serious complications such as kidney disease, heart disease and stroke.  An over-reactive immune system is to blame which mistakes the beta cells for foreign invaders and attacks them.

Much of the focus on diabetes therapy development is turning stem cells into beta cells in order to replace the lost cells.  But a recent Stem Cell Translational Medicine publication describes a different approach that uses umbilical cord blood stem cells to tame the immune system and preserve the beta cells that are still intact.

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Schematic diagram of the Stem Cell Educator therapy procedure.
Image: Tianhe Stem Cell Biotechnologies

The research team, composed of scientists from the U.S., China and Spain, devised a technology they call Stem Cell Educator (SCE) therapy that draws blood from a diabetic patient then separates out the lymphocytes – the white blood cells of the immune system – which trickle through a series of stacked petri dishes that contains cord blood stem cells. Because the stem cells are attached to the surface of the device, only the lymphocytes are recovered and returned to the patient’s blood.  The idea is that through this forced interaction with the cord blood stem cells – which have been shown to blunt immune cell activity – the patient’s own lymphocytes “learn” to quiet their damaging response to beta cells.

In a series of clinical trials in China and Spain from 2010 to 2014, the researchers showed that a single treatment of the SCE therapy restored beta cell function and blood sugar control in patients. Though the treatment appeared safe and effective after one year, how exactly it worked remained unclear. So, in this current study, the team aimed to better understand cord blood stem cell function and to perform a 4-year follow up on the patients.

Shortly after the SCE therapy, the researchers had observed elevated levels of platelets in the blood. They examined these cells more closely to see if they contained any factors that would dampen the immune response. Sure enough, the platelets carried a protein called autoimmune regulator (AIRE) which plays a role in inhibiting immune cells that react against the body.

Now, platelets do not contain a nucleus or nuclear DNA but they do have mitochondria – a cell’s energy producers – which contain their own DNA and genetic code. An analysis of the mitochondrial DNA revealed that it encoded proteins associated with the regeneration and growth of pancreatic beta cells. In an unusual finding in the lab, the researchers showed that the platelets release their mitochondria, which can be taken up by pancreatic beta cells where these beta cell associated proteins can exert their effects.

HealthDay reporter Serena Gordon interviewed Julia Greenstein, vice president of discovery research at JDRF, to get her take on these results:

“The platelets seem to be having a direct effect on the beta cells. This research is intriguing, but it needs to be reproduced.”

For the four-year follow up study, nine of the type 1 diabetes patients from the original trial in China were examined. Two patients who were treated less than a year after being diagnosed with diabetes still had normal levels of insulin in their blood and were still free of needing insulin injections. In the other seven patients, the single treatment had gradually lost its effectiveness. Team leader Dr. Yong Zhao of the University of Hackensack in New Jersey, felt that a single treatment possibly isn’t enough in those patients:

“Because this was a first trial, patients just got one treatment. Now we know it’s very safe so patients can receive two or three treatments.”

I imagine Dr. Zhao will be testing out multiple treatments in a clinical trial that is now in the works here in the states at Hackensack Medical Center. Stay tuned.

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.

asterias

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.

Harnessing DNA as a programmable instruction kit for stem cell function

DNA is the fundamental molecule to all living things. The genetic sequences embedded in its double-helical structure contain the instructions for producing proteins, the building blocks of our cells. When our cells divide, DNA readily unzips into two strands and makes a copy of itself for each new daughter cell. In a Nature Communications report this week, researchers at Northwestern University describe how they have harnessed DNA’s elegant design, which evolved over a billion years ago, to engineer a programmable set of on/off instructions to mimic the dynamic interactions that cells encounter in the body. This nano-sized toolkit could provide a means to better understand stem cell behavior and to develop regenerative therapies to treat a wide range of disorders.

Stupp

Instructing cells with programmable DNA-protein hybrids: switching bioactivity on and off Image: Stupp lab/Northwestern U.

While cells are what make up the tissues and organs of our bodies, it’s a bit more complicated than that. Cells also secrete proteins and molecules that form a scaffold between cells called the extracellular matrix. Though it was once thought to be merely structural, it’s clear that the matrix also plays a key role in regulating cell function. It provides a means to position multiple cell signaling molecules in just the right spot at the right time to stimulate a particular cell behavior as well as interactions between cells. This physical connection between the matrix, molecules and cells called a “niche” plays an important role for stem cell function.

Since studying cells in the laboratory involves growing them on plastic petri dishes, researchers have devised many methods for mimicking the niche to get a more accurate picture of how cells response to signals in the body. The tricky part has been to capture three main characteristics of the extracellular matrix all in one experiment; that is, the ability to add and then reverse a signal, to precisely position cell signals and to combine signals to manipulate cell function. That’s where the Northwestern team and its DNA toolkit come into the picture.

They first immobilized a single strand of DNA onto the surface of a material where cells are grown. Then they added a hybrid molecule – they call it “P-DNA” – made up of a particular signaling protein attached to a single strand of DNA that pairs with the immobilized DNA. Once those DNA strands zip together, that tethers the signaling protein to the material where the cells encounter it, effectively “switching on” that protein signal. Adding an excess of single-stranded DNA that doesn’t contain the attached protein, pushes out the P-DNA which can be washed away thereby switching off the protein signal. Then the P-DNA can be added back to restart the signal once again.

Because the DNA sequences can be easily synthesized in the lab, it allows the researchers to program many different instructions to the cells. For instance, combinations of different protein signals can be turned on simultaneously and the length of the DNA strands can precisely control the positioning of cell-protein interactions. The researchers used this system to show that spinal cord neural stem cells, which naturally clump together in neurospheres when grown in a dish, can be instructed to spread out on the dish’s surface and begin specializing into mature brain cells. But when that signal is turned off, the cells ball up together again into the neurospheres.

Team lead Samuel Stupp looks to this reversible, on-demand control of cell activity as means to develop patient specific therapies in the future:

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Samuel Stupp

“People would love to have cell therapies that utilize stem cells derived from their own bodies to regenerate tissue. In principle, this will eventually be possible, but one needs procedures that are effective at expanding and differentiating cells in order to do so. Our technology does that,” he said in a university press release.

 

 

Stories that caught our eye: smelling weight gain, colon cancer & diet and diabetes & broken bones

How smelling your food could cause weight gain (Karen Ring).
Here’s the headline that caught my eye this week: “Smelling your food first can make you fat…”

It’s a bizarre statement, but the claim is backed by scientific research coming from a new study in Cell Metabolism by researchers at the University of California Berkeley. The team found that obese mice who smelled their food before eating it were more likely to gain weight compared to obese mice that couldn’t smell their food.

Their experiments revealed a connection between the olfactory system, which is responsible for our sense of smell, and how the mice metabolize food into energy. Obese mice that lost their ability to smell actually lost weight on a high-fat diet, burned more fat, and became more sensitive to the hormone insulin. Insulin regulates how much glucose, or sugar, is in the blood by facilitating the absorption of glucose by fat, liver and muscle cells. In obese individuals, insulin resistance can occur where their cells are no longer sensitive to the hormone and therefore can’t regulate how much glucose is in the blood.

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Both mice in this picture were fed the same high-fat diet. The only difference: the lower mouse’s sense of smell was temporarily blocked. Image: UC Berkeley

For obese mice that could smell their food, the same high fat diet given to the “no-smellers” resulted in massive weight gain in the “smellers” because their metabolism was impaired. Even more interesting is the fact that other types of smells unrelated to food, such as the scent of other mice, influenced weight gain in the “smellers”.

The authors concluded that the centers in our brain that are responsible for smell (the olfactory system) and metabolism (the hypothalamus) are connected and that manipulating smell could be a future strategy to influence how the brain controls the balance of energy during food consumption.

In an interview with Tech Times, senior author on the study, Dr. Andrew Dillin, explained how their research could potentially lead to a new strategy to promote weight loss,

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Andrew Dillin. Image: HHMI

“Sensory systems play a role in metabolism. Weight gain isn’t purely a measure of the calories taken in; it’s also related to how those calories are perceived. If we can validate this in humans, perhaps we can actually make a drug that doesn’t interfere with smell but still blocks that metabolic circuitry. That would be amazing.”

A link between colorectal cancer and a Western diet identified
Weight gain isn’t the only concern of a eating a high-fat diet. It’s thought that 80% of colorectal cases are associated with a high-fat, Western diet. The basis for this connection hasn’t been well understood. But this week, researchers at the Cleveland Clinic report in Stem Cell Reports that they’ve pinpointed a protein signaling network within cancer stem cells as a possible source of the link.

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Cancer stem cells have properties that resemble embryonic stem cells and are thought to be the source of a cancer’s unlimited growth and spread. A cancer stem cell maintains its properties by exploiting various cell signaling processes that when functioning abnormally can lead to inappropriate cell division and tumor growth. In this study, the team focused on one cell signaling process carried out by a protein called STAT3, known to promote tumor growth in a mouse model of colon cancer. When the team blocked STAT3 activity, high fat diet-induced cancer stem cell growth subsided.

In a press release, Dr. Matthew Kalady, a colorectal surgeon at the Cleveland Clinic and an author on this study, explained how this new insight can open new therapeutic avenues:

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Matthew Kalady. Image: Cleveland Clinic

“We have known the influence of diet on colorectal cancer. However, these new findings are the first to show the connection between high-fat intake and colon cancer via a specific molecular pathway. We can now build upon this knowledge to develop new treatments aimed at blocking this pathway and reducing the negative impact of a high-fat diet on colon cancer risk.”

 

 

Scientists connect dots between diabetes and broken bones.
Type 2 diabetes carries a whole host of long-term complications including heart disease, nerve damage, kidney dysfunction and even an increased risk for bone fractures. The connection between diabetes and fragile bones has not been well understood. But this week, researchers at New York University of Dentistry, Stanford University and China’s Dalian Medical University published a report, funded in part by CIRM, in this week’s Nature Communications showing a biochemical basis for this connection. The new insight may lead to treatment options to prevent fractures.

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Chemical structure of succinate.
Image: Wikimedia Commons.

Fundamentally, diabetes is a disease that causes hyperglycemia, or abnormally high levels of blood sugar. The team ran a systematic analysis of hyperglycemia’s effects on bone metabolism using bone marrow samples from diabetic and healthy mice. They found that the levels of succinate, a key molecule involved in energy production, are over 20 times higher in the diabetic mice. In turns out that succinate also acts as a stimulator of bone breakdown. Now, bone is continually in a process of turnover and, in a healthy state, the breakdown of old bone is balanced with the formation of new bone. So, it appears that the huge increase of succinate is tipping the balance of bone turnover. In fact, the team found that the porous, yet strong inner region of bone, called trabecular bone, was significantly reduced in the diabetic mice, making them more susceptible to fractures.

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The density of spongy bone, or trabecular bone, is reduced in type 2 diabetes.
Image: Wikimedia commons

Dr. Xin Li, the study’s lead scientist, explained the importance of these new insights for people living with type 2 diabetes in a press release:

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Xin Li.
Image: NYU Dentistry

“The results are important because diabetics have a significantly higher fracture risk and their healing process is always delayed. In our study, the hyperglycemic mice had increased bone resorption [the breakdown and absorption of old bone], which outpaced the formation of new bone. This has implications for bone protection, as well as for the treatment of diabetes-associated collateral bone damage.”

 

Making brain stem cells act more like salmon than bloodhounds

Like salmon swimming against a river current, brain stem cells can travel against their normal migration stream with the help of electrical stimuli, so says CIRM-funded research published this week in Stem Cell Reports. The research, carried out by a team of UC Davis scientists, could one day provide a means for guiding brain stem cells, or neural stem cells (NSCs), to sites of disease or injury in the brain.

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Human neural stem cells (green) guided by electrical stimulation migrated to and colonized the subventricular zone of rats’ brains. This image was taken three weeks after stimulation. Image: Jun-Feng Feng/UC DAVIS, Sacramento and Ren Ji Hospital, Shanghai.

NSCs are a key ingredient in the development of therapies that aim to repair damaged areas of the brain. Given the incredibly intricate structure of nerve connections, targeting these stem cells to their intended location is a big challenge for therapy development. One obstacle is mobility. Although resident NSCs can travel long distances within the brain, the navigation abilities of transplanted NSCs gets disrupted and becomes very limited.

In earlier work, the research team had shown that electrical currents could nudge NSCs to move in a petri dish (watch team lead Dr. Min Zhao describe this earlier work in the 30 second video below) so they wanted to see if this technique was possible within the brains of living rats. By nature, NSCs are more like bloodhounds than salmon, moving from one location to another by sensing an increasing gradient of chemicals within the brain. In this study, the researchers transplanted human NSCs in the middle of such a such gradient, called the rostral migration stream, that normally guides the cells to the olfactory bulb, the area responsible for our sense of smell.

Electrodes were implanted into the brains of the rats and an electrical current flowing in the opposite direction of the rostral migration stream was applied. This stimulus caused the NSCs to march in the direction of the electrical current. Even at three and four weeks after the stimulation, the altered movement of the NSCs continued. And there was indication that the cells were specializing into various types of brain cells, an important observation for any cell therapy meant to replace diseased cells.

The Scientist interviewed Dr. Alan Trounson, of the Hudson Institute of Australia, who was not involved in study, to get his take on the results:

“This is the first study I’ve seen where stimulation is done with electrodes in the brain and has been convincing about changing the natural flow of cells so they move in the opposite direction. The technique has strong possibilities for applications because the team has shown you can move cells, and you could potentially move them into seriously affected brain areas.”

Though it’s an intriguing proof-of-concept, much works remains to show this technique is plausible in the clinic. Toward that goal, the team has plans to repeat the studies in primates using a less invasive method that transmits the electrical signals through the skull.

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.”