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.

Stem Cell Stories that Caught our Eye: CRISPRing Human Embryos, brain stem cells slow aging & BrainStorm ALS trial joins CIRM Alpha Clinics

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

Scientists claim first CRISPR editing of human embryos in the US.

Here’s the big story this week. Scientists from Portland, Oregon claim they genetically modified human embryos using the CRISPR/Cas9 gene editing technology. While their results have yet to be published in a peer review journal (though the team say they are going to be published in a prominent journal next month), if they prove true, the study will be the first successful attempt to modify human embryos in the US.

A representation of an embryo being fertilized. Scientists can inject CRISPR during fertilization to correct genetic disorders. (Getty Images).

Steve Connor from MIT Technology Review broke the story earlier this week noting that the only reports of human embryo modification were published by Chinese scientists. The China studies revealed troubling findings. CRISPR caused “off-target” effects, a situation where the CRISPR machinery randomly introduces genetic errors in a cell’s DNA, in the embryos. It also caused mosaicism, a condition where the desired DNA sequences aren’t genetically corrected in all the cells of an embryo producing an individual with cells that have different genomes. Putting aside the ethical conundrum of modifying human embryos, these studies suggested that current gene editing technologies weren’t accurate enough to safely modify human embryos.

But a new chapter in human embryo modification is beginning. Shoukhrat Mitalipov (who is a member of CIRM’s Grants Working Group, the panel of scientific experts that reviews our funding applications) and his team from the Oregon Health and Science University said that they have developed a method to successfully modify donated human embryos that avoids the problems experienced by the Chinese scientists. The team found that introducing CRISPR at the same time an embryo was being fertilized led to successful correction of disease-causing mutations while avoiding mosaicism and “off-target” effects. They grew these embryos for a few days to confirm that the genetic modifications had worked before destroying them.

The MIT piece quoted a scientist who knows of Mitalipov’s work,

“It is proof of principle that it can work. They significantly reduced mosaicism. I don’t think it’s the start of clinical trials yet, but it does take it further than anyone has before.”

Does this discovery, if it’s true, open the door further for the creation of designer babies? For discussions about the future scientific and ethical implications of this research, I recommend reading Paul Knoepfler’s blog, this piece by Megan Molteni in Wired Magazine and Jessica Berg’s article in The Conversation.

Brain stem cells slow aging in mice

The quest for eternal youth might be one step closer thanks to a new study published this week in the journal Nature. Scientists from the Albert Einstein College of Medicine in New York discovered that stem cells found in an area of the brain called the hypothalamus can slow the aging process in mice.

The hypothalamus is located smack in the center of your brain near the brain stem. It’s responsible for essential metabolic functions such as making and secreting hormones, managing body temperature and controlling feelings of hunger and thirst. Because the body’s metabolic functions decline with age, scientists have suspected that the hypothalamus plays a role in aging.

The mouse hypothalamus. (NIH, Wikimedia).

In the current study, the team found that stem cells in the hypothalamus gradually disappear as mice age. They were curious whether the disappearance of these stem cells could jump start the aging process. When they removed these stem cells, the mice showed more advanced mental and physical signs of aging compared to untreated mice.

They also conducted the opposite experiment where they transplanted hypothalamic stem cells taken from baby mice (the idea being that these stem cells would exhibit more “youthful” qualities) into the brains of middle-aged mice and saw improvements in mental and physical functions and a 10% increase in lifespan.

So what is it about these specific stem cells that slows down aging? Do they replenish the aging brain with new healthy cells or do they secrete factors that keep the brain healthy? Interestingly, the scientists found that these stem cells secreted vesicles that contained microRNAs, which are molecules that regulate gene expression by turning genes on or off.

They injected these microRNAs into the brains of middle-aged mice and found that they reversed symptoms of aging including cognitive decline and muscle degeneration. Furthermore, when they removed hypothalamic stem cells from middle-aged mice and treated them with the microRNAs, they saw the same anti-aging effects.

In an interview with Nature News, senior author on the study, Dongsheng Cai, commented that hypothalamic stem cells could have multiple ways of regulating aging and that microRNAs are just one of their tools. For this research to translate into an anti-aging therapy, “Cai suspects that anti-ageing therapies targeting the hypothalamus would need to be administered in middle age, before a person’s muscles and metabolism have degenerated beyond a point that could be reversed.”

This study and its “Fountain of Youth” implications has received ample attention from the media. You can read more coverage from The Scientist, GenBio, and the original Albert Einstein press release.

BrainStorm ALS trial joins the CIRM Alpha Clinics

Last month, the CIRM Board approved $15.9 million in funding for BrainStorm Cell Therapeutic’s Phase 3 trial that’s testing a stem cell therapy to treat patients with a devastating neurodegenerative disease called amyotrophic lateral sclerosis or ALS (also known as Lou Gehrig’s disease).

The stem cell therapy, called NurOwn®, is made of mesenchymal stem cells extracted from a patient’s bone marrow. The stem cells are genetically modified to secrete neurotrophic factors that keep neurons in the brain healthy and prevent their destruction by diseases like ALS.

BrainStorm has tested NurOwn in early stage clinical trials in Israel and in a Phase 2 study in the US. These trials revealed that the treatment was “safe and well tolerated” and that “NurOwn also achieved multiple secondary efficacy endpoints, showing clear evidence of a clinically meaningful benefit.  Notably, response rates were higher for NurOwn-treated subjects compared to placebo at all time points in the study out to 24 weeks.”

This week, BrainStorm announced that it will launch its Phase 3 CIRM-funded trial at the UC Irvine (UCI) CIRM Alpha Stem Cell Clinic. The Alpha Clinics are a network of top medical centers in California that specialize in delivering high quality stem cell clinical trials to patients. UCI is one of four medical centers including UCLA, City of Hope, and UCSD, that make up three Alpha Clinics currently supporting 38 stem cell trials in the state.

Along with UCI, BrainStorm’s Phase 3 trial will also be conducted at two other sites in the US: Mass General Hospital in Boston and California Pacific Medical Center in San Francisco. Chaim Lebovits, President and CEO, commented,

“We are privileged to have UCI and Dr. Namita Goyal join our pivotal Phase 3 study of NurOwn. Adding UCI as an enrolling center with Dr. Goyal as Principal Investigator will make the treatment more accessible to patients in California, and we welcome the opportunity to work with this prestigious institution.”

Before the Phase 3 trial can launch at UCI, it needs to be approved by our federal regulatory agency, the Food and Drug Administration (FDA), and an Institutional Review Board (IRB), which is an independent ethics committee that reviews biomedical research on human subjects. Both these steps are required to ensure that a therapy is safe to test in patients.

With promising data from their Phase 1 and 2 trials, BrainStorm’s Phase 3 trial will likely get the green light to move forward. Dr. Goyal, who will lead the trial at the UCI Alpha Clinic, concluded:

“NurOwn is a very promising treatment with compelling Phase 2 data in patients with ALS; we look forward to further advancing it in clinical development and confirming the therapeutic benefit with Brainstorm.”

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.

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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.

 

 

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.

Min_SCR full

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.

Stories that caught our eye: An antibody that could make stem cell research safer; scientists prepare for clinical trial for Parkinson’s disease; and the stem cell scientist running for Congress

Antibody to make stem cells safer:

There is an old Chinese proverb that states: ‘What seems like a blessing could be a curse’. In some ways that proverb could apply to stem cells. For example, pluripotent stem cells have the extraordinary ability to turn into many other kinds of cells, giving researchers a tool to repair damaged organs and tissues. But that same ability to turn into other kinds of cells means that a pluripotent stem cell could also turn into a cancerous one, endangering someone’s life.

A*STAR

Researchers at the A*STAR Bioprocessing Technology Institute: Photo courtesy A*STAR

Now researchers at the Agency for Science, Technology and Research (A*STAR) in Singapore may have found a way to stop that happening.

When you change, or differentiate, stem cells into other kinds of cells there will always be some of the original material that didn’t make the transformation. Those cells could turn into tumors called teratomas. Scientists have long sought for a way to identify pluripotent cells that haven’t differentiated, without harming the ones that have.

The team at A*STAR injected mice with embryonic stem cells to generate antibodies. They then tested the ability of the different antibodies to destroy pluripotent stem cells. They found one, they called A1, that did just that; killing pluripotent cells but leaving other cells unharmed.

Further study showed that A1 worked by attaching itself to specific molecules that are only found on the surface of pluripotent cells.

In an article on Phys.Org Andre Choo, the leader of the team, says this gives them a tool to get rid of the undifferentiated cells that could potentially cause problems:

“That was quite exciting because it now gives us a view of the mechanism that is responsible for the cell-killing effect.”

Reviving hope for Parkinson’s patients:

In the 1980’s and 1990’s scientists transplanted fetal tissue into the brains of people with Parkinson’s disease. They hoped the cells in the tissue would replace the dopamine-producing cells destroyed by Parkinson’s, and stop the progression of the disease.

For some patients the transplants worked well. For some they produced unwanted side effects. But for most they had little discernible effect. The disappointing results pretty much brought the field to a halt for more than a decade.

But now researchers are getting ready to try again, and a news story on NPR explained why they think things could turn out differently this time.

tabar-viviane

Viviane Tabar, MD; Photo courtesy Memorial Sloan Kettering Cancer Center

Viviane Tabar, a stem cell researcher at Memorial Sloan Kettering Cancer Center in New York, says in the past the transplanted tissue contained a mixture of cells:

“What you were placing in the patient was just a soup of brain. It did not have only the dopamine neurons, which exist in the tissue, but also several different types of cells.”

This time Tabar and her husband, Lorenz Studer, are using only cells that have been turned into the kind of cell destroyed by the disease. She says that will, hopefully, make all the difference:

“So you are confident that everything you are putting in the patient’s brain will consist of  the right type of cell.”

Tabar and Studer are now ready to apply to the Food and Drug Administration (FDA) for permission to try their approach out in a clinical trial. They hope that could start as early as next year.

Hans runs for Congress:

Keirstead

Hans Keirstead: Photo courtesy Orange County Register

Hans Keirstead is a name familiar to many in the stem cell field. Now it could become familiar to a lot of people in the political arena too, because Keirstead has announced he’s planning to run for Congress.

Keirstead is considered by some to be a pioneer in stem cell research. A CIRM grant helped him develop a treatment for spinal cord injury.  That work is now in a clinical trial being run by Asterias. We reported on encouraging results from that trial earlier this week.

Over the years the companies he has founded – focused on ovarian, skin and brain cancer – have made him millions of dollars.

Now he says it’s time to turn his sights to a different stage, Congress. Keirstead has announced he is going to challenge 18-term Orange County Republican Dana Rohrabacher.

In an article in the Los Angeles Times, Keirstead says his science and business acumen will prove important assets in his bid for the seat:

“I’ve come to realize more acutely than ever before the deficits in Congress and how my profile can actually benefit Congress. I’d like to do what I’m doing but on a larger stage — and I think Congress provides that, provides a forum for doing the greater good.”

New stem cell technique gives brain support cells a starring role

Gage et al

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.”

CIRM-funded team uncovers novel function for protein linked to autism and schizophrenia

Imagine you’ve just stopped your car at the top of the steepest street in San Francisco. Now, if want to stay at the top of the hill you’re going to need to keep your foot on the brakes. Let go and you’ll start rolling down. Fast.

Don’t step off the brake pedal! Photo: Wikipedia

Conceptually, similar decision points happen in human development. A brain cell, for instance, has the DNA instructions to become any cell in the body but must “keep the brakes on”, or repress, genes responsible for other cell types. Release the silencing of those genes and the brain cell’s properties will get pulled toward other fates.

That’s the subject of a CIRM-funded research study published today in Nature which reports on the identification of a new type of repressor protein which opens up a new understanding of how brain cells establish and keep their identity. That may not sound so exciting to our non-scientist readers but this discovery could lead to new therapy approaches for neurological disorders like autism, schizophrenia, major depression and low I.Q.

Skin cells to brain cells with just three genes
In previous experiments, this Stanford University research team led by Marius Wernig, showed it’s possible to convert a skin cell to a brain cell, or neuron, by adding just three genes to the cells, including one called Myt1l. The other two genes were known to act as master “on switches” that activate a cascade of genes responsible for making neuron-specific proteins. Myt1l also helped increase the efficiency of this direct reprogramming but it’s exact role in the process wasn’t clear.

Direct conversion of skin cell into a neuron.
Image: Wernig Lab, Stanford

A closer examination of Myt1l protein function revealed that instead of being an on switch for neuron-specific genes, it was actually an off switch for skin-specific genes. Now, there’s nothing unusual about the existence of a protein that represses gene activity to help determine cell identity. But up until now, these repressors were thought to be “lineage specific” meaning they specifically switched off genes of a specific cell type. For example, a well-studied repressor called REST affects cell fate by putting the brakes on only nerve-specific genes. The case of Myt1l was different.

Many but one
The researchers found that, in brain cells, Myt1l not only blocked the activation of skin-specific genes, it also shut down genes related to lung, cartilage, heart and other cells fates. The one set of genes that Mytl1 repressor did not appear to act on was neuron-specific genes. From these results a “many but one” pattern emerged. That is; it seems Myt1l helps drive and maintain a neuron cell fate by shutting off gene networks for many different cell identities except for neurons. It’s a novel way to regulate cell fate, as Wernig explained in a press release:

Marius Wernig
Photo: Steve Fisch

“The concept of an inverse master regulator, one that represses many different developmental programs rather than activating a single program, is a unique way to control neuronal cell identity, and a completely new paradigm as to how cells maintain their cell fate throughout an organism’s lifetime.”

To build a stronger case for Myt1l function, the team looked at the effect of blocking the protein in the developing mouse brain. Sure enough, lifting Myt1l repression lead to a decrease in the number of neurons in the brain. Wernig described the impact of also inhibiting Myt1l in mature neurons:

“When this protein is missing, neural cells get a little confused. They become less efficient at transmitting nerve signals and begin to express genes associated with other cell fates.”

Potential cures can be uncovered withfundamental lab research
It turns out that Myt1l mutations have been recently found in people with autism, schizophrenia, major depression and low I.Q. Based on their new insights, the author suggest that in adults, these disorders may be caused by a neuron’s inability to maintain its identity rather than by a more permanent abnormality that occurred during fetal brain development. This hypothesis presents the exciting possibility of developing therapies that could improve symptoms.

Using stem cells to fix bad behavior in the brain

 

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Gladstone Institutes Steven Finkbeiner and Gaia Skibinski: Photo courtesy Chris Goodfellow, Gladstone Institutes

Diseases of the brain have many different names, from Alzheimer’s and Parkinson’s to ALS and Huntington’s, but they often have similar causes. Researchers at the Gladstone Institutes in San Francisco are using that knowledge to try and find an approach that might be effective against all of these diseases. In a new CIRM-funded study, they have identified one protein that could help do just that.

Many neurodegenerative diseases are caused by faulty proteins, which start to pile up and cause damage to neurons, the brain cells that are responsible for processing and transmitting information. Ultimately, the misbehaving proteins cause those cells to die.

The researchers at the Gladstone found a way to counter this destructive process by using a protein called Nrf2. They used neurons from humans (made from induced pluripotent stem cells – iPSCs – hence the stem cell connection here) and rats. They then tested these cells in neurons that were engineered to have two different kinds of mutations found in  Parkinson’s disease (PD) plus the Nrf2 protein.

Using a unique microscope they designed especially for this study, they were able to track those transplanted neurons and monitor what happened to them over the course of a week.

The neurons that expressed Nrf2 were able to render one of those PD-causing proteins harmless, and remove the other two mutant proteins from the brain cells.

In a news release to accompany the study in The Proceedings of the National Academy of Sciences, first author Gaia Skibinski, said Nrf2 acts like a house-cleaner brought in to tidy up a mess:

“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now. Over-expressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”

Steven Finkbeiner, the senior author on the study and a Gladstone professor, said this model doesn’t just hold out hope for treating Parkinson’s disease but for treating a number of other neurodegenerative problems:

“I am very enthusiastic about this strategy for treating neurodegenerative diseases. We’ve tested Nrf2 in models of Huntington’s disease, Parkinson’s disease, and ALS, and it is the most protective thing we’ve ever found. Based on the magnitude and the breadth of the effect, we really want to understand Nrf2 and its role in protein regulation better.”

The next step is to use this deeper understanding to identify other proteins that interact with Nrf2, and potentially find ways to harness that knowledge for new therapies for neurodegenerative disorders.

Translating great stem cell ideas into effective therapies

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CIRM funds research trying to solve the Alzheimer’s puzzle

In science, there are a lot of terms that could easily mystify people without a research background; “translational” is not one of them. Translational research simply means to take findings from basic research and advance them into something that is ready to be tested in people in a clinical trial.

Yesterday our Governing Board approved $15 million in funding for four projects as part of our Translational Awards program, giving them the funding and support that we hope will ultimately result in them being tested in people.

Those projects use a variety of different approaches in tackling some very different diseases. For example, researchers at the Gladstone Institutes in San Francisco received $5.9 million to develop a new way to help the more than five million Americans battling Alzheimer’s disease. They want to generate brain cells to replace those damaged by Alzheimer’s, using induced pluripotent stem cells (iPSCs) – an adult cell that has been changed or reprogrammed so that it can then be changed into virtually any other cell in the body.

CIRM’s mission is to accelerate stem cell treatments to patients with unmet medical needs and Alzheimer’s – which has no cure and no effective long-term treatments – clearly represents an unmet medical need.

Another project approved by the Board is run by a team at Children’s Hospital Oakland Research Institute (CHORI). They got almost $4.5 million for their research helping people with sickle cell anemia, an inherited blood disorder that causes intense pain, and can result in strokes and organ damage. Sickle cell affects around 100,000 people in the US, mostly African Americans.

The CHORI team wants to use a new gene-editing tool called CRISPR-Cas9 to develop a method of editing the defective gene that causes Sickle Cell, creating a healthy, sickle-free blood supply for patients.

Right now, the only effective long-term treatment for sickle cell disease is a bone marrow transplant, but that requires a patient to have a matched donor – something that is hard to find. Even with a perfect donor the procedure can be risky, carrying with it potentially life-threatening complications. Using the patient’s own blood stem cells to create a therapy would remove those complications and even make it possible to talk about curing the disease.

While damaged cartilage isn’t life-threatening it does have huge quality of life implications for millions of people. Untreated cartilage damage can, over time lead to the degeneration of the joint, arthritis and chronic pain. Researchers at the University of Southern California (USC) were awarded $2.5 million to develop an off-the-shelf stem cell product that could be used to repair the damage.

The fourth and final award ($2.09 million) went to Ankasa Regenerative Therapeutics, which hopes to create a stem cell therapy for osteonecrosis. This is a painful, progressive disease caused by insufficient blood flow to the bones. Eventually the bones start to rot and die.

As Jonathan Thomas, Chair of the CIRM Board, said in a news release, we are hoping this is just the next step for these programs on their way to helping patients:

“These Translational Awards highlight our goal of creating a pipeline of projects, moving through different stages of research with an ultimate goal of a successful treatment. We are hopeful these projects will be able to use our newly created Stem Cell Center to speed up their progress and pave the way for approval by the FDA for a clinical trial in the next few years.”

Stem cell stories that caught our eye: glowing stem cells and new insights into Zika and SCID

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.

Glowing stem cells help scientists understand how cells work. (Karen Ring)
It’s easy to notice when something is going wrong. It’s a lot harder to notice when something is going right. The same thing can be said for biology. Scientists dedicate their careers to studying unhealthy cells, trying to understand why people get certain diseases and what’s going wrong at the cellular level to cause these problems. But there is a lot to be said for doing scientific research on healthy cells so that we can better understand what’s happening when cells start to malfunction.

A group from the Allen Institute for Cell Science is doing just this. They used a popular gene-editing technology called CRISPR/Cas9 to genetically modify human stem cell lines so that certain parts inside the cell will glow different colors when observed under a fluorescent microscope. Specifically, the scientists inserted the genetic code to produce fluorescent proteins in both the nucleus and the mitochondria of the stem cells. The final result is a tool that allows scientists to study how stem cells specialize into mature cells in various tissues and organs.

Glowing human stem cells. The edges of the cells are shown in purple while the DNA in the cell’s nucleus is in blue. (Allen Institute for Cell Science).

Glowing human stem cells. The edges of the cells are shown in purple while the DNA in the cell’s nucleus is in blue. (Allen Institute for Cell Science).

The director of stem cells and gene editing at the Allen Institute, Ruwanthi Gunawardane, explained how their technology improves upon previous methods for getting cells to glow in an interview with Forbes:

 “We’re trying to understand how the cell behaves, how it functions, but flooding it with some external protein can really mess it up. The CRISPR system allows us to go into the DNA—the blueprint—and insert a gene that allows the cell to express the protein in its normal environment. Then, through live imaging, we can watch the cell and understand how it works.”

The team has made five of these glowing stem cell lines available for use by the scientific community through the Coriell Institute for Medical Research (which also works closely with the CIRM iPSC Initiative). Each cell line is unique and has a different cellular structure that glows. You can learn more about these cell lines on the Coriell Allen Institute webpage and by watching this video:

 

Zika can take multiple routes to infect a child’s brain. (Kevin McCormack)
One of the biggest health stories of 2016 has been the rapid, indeed alarming, spread of the Zika virus. It went from an obscure virus to a global epidemic found in more than 70 countries.

The major concern about the virus is its ability to cause brain defects in the developing brain. Now researchers at Harvard have found that it can do this in more ways than previously believed.

Up till now, it was believed that Zika does its damage by grabbing onto a protein called AXL on the surface of brain cells called neural progenitor cells (NPCs). However, the study, published in the journal Cell Stem Cell, showed that even when AXL was blocked, Zika still managed to infiltrate the brain.

Using induced pluripotent stem cell technology, the researchers were able to create NPCs and then modify them so they had no AXL expression. That should, in theory, have been able to block the Zika virus. But when they exposed those cells to the virus they found they were infected just as much as ordinary brain cells exposed to the virus were.

Caption: Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image by Max Salick and Nathaniel Kirkpatrick/Novartis

Caption: Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image by Max Salick and Nathaniel Kirkpatrick/Novartis

In a story in the Harvard Gazette, Kevin Eggan, one of the lead researchers, said this shows scientists need to re-think their approach to countering the virus:

“Our finding really recalibrates this field of research because it tells us we still have to go and find out how Zika is getting into these cells.”

 

Treatment for a severe form of bubble baby disease appears on the horizon. (Todd Dubnicoff)
Without treatment, kids born with bubble baby disease typically die before reaching 12 months of age. Formally called severe combined immunodeficiency (SCID), this genetic blood disorder leaves infants without an effective immune system and unable to fight off even minor infections. A bone marrow stem cell transplant from a matched sibling can treat the disease but this is only available in less than 20 percent of cases and other types of donors carry severe risks.

In what is shaping up to be a life-changing medical breakthrough, a UCLA team has developed a stem cell/gene therapy treatment that corrects the SCID mutation. Over 40 patients have participated to date with a 100% survival rate and CIRM has just awarded the team $20 million to continue clinical trials.

There’s a catch though: other forms of SCID exist. The therapy described above treats SCID patients with a mutation in a gene responsible for producing a protein called ADA. But an inherited mutation in another gene called Artemis, leads to a more severe form of SCID. These Artemis-SCID infants have even less success with a standard bone marrow transplant compared to those with ADA-SCID. Artemis plays a role in DNA damage repair something that occurs during the chemo and radiation therapy sessions that are often necessary for blood marrow transplants. So Artemis-SCID patients are hyper-sensitive to the side of effects of standard treatments.

A recent study by UCSF scientists in Human Gene Therapy, funded in part by CIRM, brings a lot of hope to these Artemis-SCID patient. Using a similar stem cell/gene therapy method, this team collected blood stem cells from the bone marrow of mice with a form of Artemis-SCID. Then they added a good copy of the human Artemis gene to these cells. Transplanting the blood stem cells back to mice, restored their immune systems which paves the way for delivering this approach to clinic to also help the Artemis-SCID patients in desperate need of a treatment.