Stem Cell Roundup: Backup cells to repair damaged lungs; your unique bowels; and California Cures, 71 ways CIRM is changing the face of medicine

It’s good to have a backup plan

3D illustration of Lungs, medical concept.

Our lungs are amazing things. They take in the air we breathe and move it into our blood so that oxygen can be carried to every part of our body. They’re also surprisingly large. If you were to spread out a lung – and I have no idea why you would want to do that – it would be almost as large as a tennis court.

But lungs are also quite vulnerable organs, relying on a thin layer of epithelial cells to protect them from harmful materials in the air. If those materials damage the lungs our body calls in local stem cells to repair the injury.

Now researchers at the University of Iowa have identified a new group of stem cells, called glandular myoepithelial cells (MECs), that also appear to play an important role in repairing injuries in the lungs.

These MECs seem to be a kind of “reserve” stem cell, waiting around until they are needed and then able to spring into action and develop into new replacement cells in the lungs.

In a news release study author Preston Anderson, said these cells could help develop new approaches to lung regeneration:

“We demonstrated that MECs can self-renew and differentiate into seven distinct cell types in the airway. No other cell type in the lung has been identified with this much stem cell plasticity.”

The study is published in Cell Stem Cell.

Your bowels are unique

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Not to worry, that’s a plastic model of  a bowel

If you are eating as you read this, you should either put your food down or skip this item for now. A new study on bowel cancer says that every tumor is unique and every cell within that tumor is also genetically unique.

Researchers in the UK and Netherlands took samples of normal bowel tissue and cancerous bowel tissue from three people with colorectal cancer. They then grew these in the labs and turned them into mini 3D organoids, so they could study them in greater detail.

In the study, published in the journal Nature, the researchers say they found that tumor cells, not surprisingly, had many more mutations than normal cells, and that not only was each bowel cancer genetically different from each other, but that each cell they studied within that cancer was also different.

In a news release, Prof Sir Mike Stratton, joint corresponding author on the paper from the Wellcome Sanger Institute, said:

“This study gives us fundamental knowledge on the way cancers arise. By studying the patterns of mutations from individual healthy and tumour cells, we can learn what mutational processes have occurred, and then look to see what has caused them. Extending our knowledge on the origin of these processes could help us discover new risk factors to reduce the incidence of cancer and could also put us in a better position to create drugs to target cancer-specific mutational processes directly.”

California Cures: a great title for a great book about CIRM

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CIRM Board Chair Jonathan Thomas (L) and Don Reed

One of the first people I met when I started working at CIRM was Don Reed. He impressed me then with his indefatigable enthusiasm, energy and positive outlook on life. Six years later he is still impressing me.

Don has just completed his second book on stem cell research charting the work of CIRM. It’s called “California Cures: How the California Stem Cell Research Program is Fighting Your Incurable Disease”. It’s a terrific read combining stories about stem cell research with true tales about Al Jolson, Enrico Caruso and how a dolphin named Ernestine burst Don’s ear drum.

On his website, Stem Cell Battles, Don describes CIRM as a “scrappy little stage agency” – I love that – and says:

“No one can predict the pace of science, nor say when cures will come; but California is bringing the fight. Above all, “California Cures” is a call for action. Washington may argue about the expense of health care (and who will get it), but California works to bring down the mountain of medical debt: stem cell therapies to ease suffering and save lives. We have the momentum. We dare not stop short. Chronic disease threatens everyone — we are fighting for your family, and mine!”

 

New Insights into Adult Neurogenesis

To be a successful scientist, you have to expect the unexpected. No biological process or disease mechanism is ever that simple when you peel off its outer layers. Overtime, results that prove a long-believed theory can be overturned by new results that suggest an alternate theory.

UCSF scientist Arturo Alvarez-Buylla is well versed with the concept of unexpected results. His lab’s research is focused on understanding adult neurogenesis – the process of creating new nerve cells (called neurons) from neural stem cells (NSCs).

For a long time, the field of adult neurogenesis has settled on the theory that brain stem cells divide asymmetrically to create two different types of cells: neurons and neural stem cells. In this way, brain stem cells populate the brain with new neurons and they also self-renew to maintain a constant stem cell supply throughout the adult animal’s life.

New Insights into Adult Neurogenesis

Last week, Alvarez-Buylla and his colleagues published new insights on adult neurogenesis in mice in the journal Cell Stem Cell. The study overturns the original theory of asymmetrical neural stem cell division and suggests that neural stem cells divide in a symmetrical fashion that could eventually deplete their stem cell population over the lifetime of the animal.

Arturo Alvarez-Buylla explained the study’s findings in an email interview with the Stem Cellar:

Arturo Alvarez-Bulla

“Our results are not what we expected. Our work shows that postnatal NSCs are not being constantly renewed by splitting them asymmetrically, with one cell remaining as a stem cell and the other as a differentiated cell. Instead, self-renewal and differentiation are decoupled and achieved by symmetric divisions.”

In brief, the study found that neural stem cells (called B1 cells) divide symmetrically in an area of the adult mouse brain called the ventricular-subventricular zone (V-SVZ). Between 70%-80% of those symmetric divisions produced neurons while only 20%-30% created new B1 stem cells. Alvarez-Buylla said that this process would result in the gradual depletion of B1 stem cells over time and seems to be carefully choreographed for the length of the lifespan of a mouse.

What does this mean?

I asked Alvarez-Buylla how his findings in mice will impact the field and whether he expects human adult neurogenesis to follow a similar process. He explained,

“The implications are quite wide, as it changes the way we think about neural stem cell retention and aging. The cells do not seem open ended with unlimited potential to be renewed, which results in a progressive decrease in NSC number and neurogenesis with time.  Understanding the mechanisms regulating proliferation of NSCs and their self-renewal also provides new insights into how the whole process of neurogenesis is choreographed over long periods by suggesting that differentiation (generation of neurons) is regulated separately from renewal.”

He further explained that mice generate new neurons in the V-SVZ brain region throughout their lifetime while humans only appear to generate new neurons during infancy in the equivalent region of the human brain called the SVZ. In humans, he said, it remains unclear where and how many neural stem cells are retained after birth.

I also asked him how these findings will impact the development of neural stem cell-based therapies for neurological or neurodegenerative diseases. Alvarez-Buylla shared interesting insights:

“Our data also indicate that upon a self-renewing division, sibling NSCs may not be equal to each other. While one NSC might stay quiescent [non-dividing] for an extended period of time, its sister cell might become activated earlier on and either undergo another round of self-renewal or differentiate. Thus, for cell-replacement therapies it will be important to understand which kind of neuron the NSC of interest can produce, and when. The use of NSCs for brain repair requires a detailed understanding of which NSC subset will be utilized for treatment and how to induce them to produce progeny. The study also suggests that factors that control NSC renewal may be separate from those that control generation of neurons.”

Scientists developing adult NSC-based therapies will definitely need to take note of Alvarez-Buylla’s findings as some NSC populations might be more successful therapeutically than others.

Neural Stem Cells in the Wild

I’ll conclude with a beautiful image that the study’s first author, Kirsten Obernier, shared with me. It’s shows the V-SVZ of the mouse brain and a neural stem cell in red making contact with a blood vessel in green and neurons in blue.

Image of the mouse brain with a neural stem cell in red. (Credit: Kirsten Obernier, UCSF)

Kirsten described the complex morphology of B1 NSCs in the mouse brain and their dynamic behavior, which Kirsten observed by taking a time lapsed video of NSCs dividing in the mouse V-SVZ. Obernier and Alvarez-Buylla hypothesize that these NSCs could be receiving signals from their surrounding environment that tell them whether to make neurons or to self-renew.

Clearly, further research is necessary to peel back the complex layers of adult neurogenesis. If NSC differentiation is regulated separately from self-renewal, their insights could shed new light on how conditions of unregulated self-renewal like brain tumors develop.

Stem cell stories that caught our eye: How Zika may impact adult brains; Move over CRISPR there’s a new kid in town; How our bodies store fat

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.

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Zika mosquito

Zika virus could impact adult brains

It’s not just a baby’s developing brain that is vulnerable to the Zika virus, adult brains may be too. A new study shows that some stem cells that help repair damage in the adult brain can be impacted by Zika. This is the first time we’ve had any indication this could be a problem in a fully developed brain.

The study, in the journal Cell Stem Cell, looked at neural progenitors, a  stem cell that plays an important role in helping replace or repair damaged neurons, or nerve cells, in the brain. The researchers exposed the cells to the Zika virus and found that it infected the cells, causing some of the cells to die, and also limited the ability of the cells to proliferate.

In an interview in Healthday, Sujan Shresta, a researcher at the La Jolla Institute for Allergy and Immunology and one of the lead authors of the study, says although their work was done in adult mice, it may have implications for people:

“Zika can clearly enter the brains of adults and can wreak havoc. But it’s a complex disease, it’s catastrophic for early brain development, yet the majority of adults who are infected with Zika rarely show detectable symptoms. Its effect on the adult brain may be more subtle and now we know what to look for.”

Move over CRISPR, there’s a new gene-editing tool in town

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Jennifer Lopez: Photo courtesy MTV

For much of the last year the hottest topic in stem cell and gene editing research has been CRISPR and the ease with which it can be used to edit genes. It’s so hot that apparently it’s the title of an upcoming TV show starring Jeniffer Lopez.

But hold on J-Lo, a new study in Nature Communications says by the time the show is on the air it may be old hat. Researchers at Carnegie Mellon and Yale University have developed a new gene-editing system, one they claim is easier to use and more accurate than CRISPR. And to prove it, they say they have successfully cured a genetic blood disorder in mice, using a simple IV approach.

Tools like CRISPR use enzymes to cut open sections of DNA to edit a specific gene. It’s like using a pair of scissors to cut a piece of string that has a big knot in the middle; you cut out the knot then join the ends of the string together. The problem with CRISPR is that the enzymes it uses are quite large and hard to use in a living animal – let alone a human – so they have to remove the target cells from the body and do the editing in the lab. Another problem is that CRISPR sometimes cuts sections of DNA that the researchers don’t want cut and could lead to dangerous side effects.

Greater precision

The Carnegie Mellon/Yale team say their new method avoids both problems. They use nanoparticles that contain molecules made from peptide nucleic acid (PNA), a kind of artificial form of DNA. This PNA is engineered to be able to cut open DNA and bind to a specific target without cutting anything else.

The team used this approach to target the mutated gene in beta thalassemia, a blood disorder that can be fatal if left untreated. The therapy binds to the malfunctioning gene, enabling the body’s own DNA repair system to correct the problem.

In a news story in Science Daily Danith Ly, one of the lead authors on the study, says even though the technique was successful in editing the target genes just 7 percent of the time, that is way more than the 0.1 percent rate most other gene editing tools achieve.

“The effect may only be 7 percent, but that’s curative. In the case of this particular disease model, you don’t need a lot of correction. You don’t need 100 percent to see the phenotype return to normal.”

Hormone that controls if and when fat cells mature

Obesity is one of the fastest growing public health problems in the US and globally. Understanding the mechanisms behind how that happens could be key to finding ways to address it. Now researchers at Stanford University think they may have uncovered an important part of the answer.

Their findings, reported in Science Signaling, show that mature fat cells produce a hormone called Adamts1 which acts like a switch for surrounding stem cells, determining if they change into fat-storing cells.   People who eat a high-fat diet experience a change in their Adamst1 production, and that triggers the nearby stem cells to specialize and start storing fat.

There are still a lot of questions to be answered about Adamst1, including whether it acts alone or in conjunction with other as yet unknown hormones. But in an article in Health Canal, Brian Feldman, the senior author of the study, says they can now start looking at potential use of Adamst1 to fight obesity.

“That won’t be a simple answer. If you block fat formation, extra calories have to go somewhere in the body, and sending them somewhere else outside fat cells could be more detrimental to metabolism. We know from other researchers’ work that liver and muscle are both bad places to store fat, for example. We do think there are going to be opportunities for new treatments based on our discoveries, but not by simply blocking fat formation alone.”

 

The Spanish Inquisition and a tale of two stem cell agencies

Monty

Monty Python’s Spanish Inquisition sketch: Photo courtesy Daily Mail UK

It’s not often an article on stem cell research brings the old, but still much loved, British comedy series Monty Python into the discussion but a new study in the journal Cell Stem Cell does just that, comparing the impact of CIRM and the UK’s Regenerative Medicine Platform (UKRMP).

The article, written by Fiona Watt of King’s College London and Stanford’s Irv Weissman (a CIRM grantee – you can see his impressive research record here) looks at CIRM and UKRMP’s success in translating stem cell research into clinical applications in people.

It begins by saying that in research, as in real estate, location is key:

“One thing that is heavily influenced by location, however, is our source of funding. This in turn depends on the political climate of the country in which we work, as exemplified by research on stem cells.”

And, as Weissman and Watt note, political climate can have a big impact on that funding. CIRM was created by the voters of California in 2004, largely in response to President George W. Bush’s restrictions on the use of federal funds for embryonic stem cell research. UKRMP, in contrast was created by the UK government in 2013 and designed to help strengthen the UK’s translational research sector. CIRM was given $3 billion to do its work. UKRMP has approximately $38 million.

Inevitably the two agencies took very different approaches to funding, shaped in part by the circumstances of their birth – one as a largely independent state agency, the other created as a tool of national government.

CIRM, by virtue of its much larger funding was able to create world-class research facilities, attract top scientists to California and train a whole new generation of scientists. It has also been able to help some of the most promising projects get into clinical trials. UKRMP has used its more limited funding to create research hubs, focusing on areas such as cell behavior, differentiation and manufacturing, and safety and effectiveness. Those hubs are encouraged to work collaboratively, sharing their expertise and best practices.

Weissman and Watt touch on the problems both agencies ran into, including the difficulty of moving even the best research out of the lab and into clinical trials:

“Although CIRM has moved over 20 projects into clinical trials most are a long way from becoming standard therapies. This is not unexpected, as the interval between discovery and FDA approved therapeutic via clinical trials is in excess of 10 years minimum.”

 

And here is where Monty Python enters the picture. The authors quote one of the most famous lines from the series: “Nobody expects the Spanish Inquisition – because our chief weapon is surprise.”

They use that to highlight the surprises and uncertainty that stem cell research has gone through in the more than ten years since CIRM was created. They point out that a whole category of cells, induced pluripotent stem (iPS) cells, didn’t exist until 2006; and that few would have predicted the use of gene/stem cell therapy combinations. The recent development of the CRISPR/Cas9 gene-editing technology shows the field is progressing at a rate and in directions that are hard to predict; a reminder that that researchers and funding agencies should continue to expect the unexpected.

With two such different agencies the authors wisely resist the temptation to make any direct comparisons as to their success but instead conclude:

“…both CIRM and UKRMP have similar goals but different routes (and funding) to achieving them. Connecting people to work together to move regenerative medicine into the clinic is an over-arching objective and one that, we hope, will benefit patients regardless of where they live.”

Stem cell stories that caught our eye: a surprising benefit of fasting, faster way to make iPSCs, unlocking the secret of leukemia cancer cells

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.

Fasting

Is fasting the fountain of youth?

Among the many insults our bodies endure in old age is a weakened immune system which leaves the elderly more susceptible to infection. Chemotherapy patients also face the same predicament due to the immune suppressing effects of their toxic anticancer treatments. While many researchers aim to develop drugs or cell therapies to protect the immune system, a University of Southern California research report this week suggests an effective alternative intervention that’s startlingly straightforward: fasting for 72 hours.

The study published in Cell Stem Cell showed that cycles of prolonged fasting in older mice led to a decrease in white blood cells which in turn set off a regenerative burst of blood stem cells. This restart of the blood stem cells replenished the immune system with new white blood cells. In a pilot Phase 1 clinical trial, cancer patients who fasted 72 hours before receiving chemotherapy maintained normal levels of white blood cells.

A look at the molecular level of the process pointed to a decrease in the levels of a protein called PKA in stem cells during the fasting period. In a university press release carried by Science Daily, the study leader, Valter Longo, explained the significance of this finding:

“PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the ‘okay’ for stem cells to go ahead and begin proliferating and rebuild the entire system. And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”

In additional to necessary follow up studies, the team is looking into whether fasting could benefit other organ systems besides the immune system. If the data holds up, it could be that regular fasting or direct targeting of PKA could put us on the road to a much more graceful and healthier aging process.

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Faster, cheaper, safer way to use iPS cells

Science, like traffic in any major city, never moves quite as quickly as you would like, but now Japanese researchers are teaming up to develop a faster, and cheaper way of using iPSC’s , pluripotent stem cells that are reprogrammed from adult cells, for transplants.

Part of the beauty of iPSCs is that because those cells came from the patient themselves, there is less risk of rejection. But there are problems with this method. Taking adult cells and turning them into enough cells to treat someone can take a long time. It’s expensive too.

But now researchers at Kyoto University and three other institutions in Japan have announced they are teaming up to change that. They want to create a stockpile of iPSCs that are resistant to immunological rejection, and are ready to be shipped out to researchers.

Having a stockpile of ready-to-use iPSCs on hand means researchers won’t have to wait months to develop their own, so they can speed up their work.

Shinya Yamanaka, who developed the technique to create iPSCs and won the Nobel prize for his efforts, say there’s another advantage with this collaboration. In a news article on Nikkei’s Asian Review he said these cells will have been screened to make sure they don’t carry any potentially cancer-causing mutations.

“We will take all possible measures to look into the safety in each case, and we’ll give the green light once we’ve determined they are sound scientifically. If there is any concern at all, we will put a stop to it.”

CIRM is already working towards a similar goal with our iPSC Initiative.

Unlocking the secrets of leukemia stem cells

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Zombies: courtesy “The Walking Dead”

Any article that has an opening sentence that says “Cancer stem cells are like zombies” has to be worth reading. And a report in ScienceMag  that explains how pre-leukemia white blood cell precursors become leukemia cancer stem cells is definitely worth reading.

The article is about a study in the journal Cell Stem Cell by researchers at UC San Diego. The senior author is Catriona Jamieson:

“In this study, we showed that cancer stem cells co-opt an RNA editing system to clone themselves. What’s more, we found a method to dial it down.”

An enzyme called ADAR1 is known to spur cancer growth by manipulating small pieces of genetic material known as microRNA. Jamieson and her team wanted to track how that was done. They discovered it is a cascade of events, and that once the first step is taken a series of others quickly followed on.

They found that when white blood cells have a genetic mutation that is linked to leukemia, they are prone to inflammation. That inflammation then activates ADAR1, which in turn slows down a segment of microRNA called let-7 resulting in increased cell growth. The end result is that the white blood cells that began this cascade become leukemia stem cells and spread an aggressive and frequently treatment-resistant form of the blood cancer.

Having uncovered how ADAR1 works Jamieson and her team then tried to find a way to stop it. They discovered that by blocking the white blood cells susceptibility to inflammation, they could prevent the cascade from even starting. They also found that by using a compound called 8-Aza they could impede ADAR1’s ability to stimulate cell growth by around 40 percent.

Jamieson

Catriona Jamieson – definitely not a zombie

Jamieson says the findings open up all sorts of possibilities:

“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed.”

This wasn’t a CIRM-funded study but we have supported other projects by Dr. Jamieson that have led to clinical trials.

 

 

 

 

Approach that inspires DREADD could create new way to treat Parkinson’s disease

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Dopamine producing brain nerve cells, made from embryonic stem cells

Imagine having a treatment for Parkinson’s that acts like a light switch, enabling you to turn it on or off depending on your needs. Well, that’s what researchers at the University of Wisconsin-Madison have come up with. And if it works, it might help change the way we treat many other diseases.

For years researchers have been trying to come up with a way of replacing the dopamine-producing brain nerve cells, or neurons, that are attacked and destroyed by Parkinson’s. Those cells regulate movement and as they are destroyed they diminish a person’s ability to control their body, their movement and even their emotions.

Attempts to transplant dopamine-producing cells into the brains of people with Parkinson’s disease have met with mixed results. In some cases the transplanted cells have worked. In many cases the cells don’t make enough dopamine to control movement. In about 10 percent of cases the cells make too much dopamine, causing uncontrolled movements called graft-induced dyskinesia.

But now the researchers at UW Madison have found a new approach that might change that. Using the gene-editing tool CRISPR (you can read about that here) they reprogrammed embryonic stem cells to become two different types of neurons containing a kind of genetic switch called a DREADD, which stands for designer receptor exclusively activated by designer drug. When they gave mice the designer drug they created to activate DREADD, one group of cells boosted production of dopamine, the other group shut down its dopamine production.

In a news release about the study, which is published in the journal Cell Stem Cell, lead author Su-Chun Zhang says this kind of control is essential in developing safe, effective therapies:

“If we are going to use cell therapy, we need to know what the transplanted cell will do. If its activity is not right, we may want to activate it, or we may need to slow or stop it.”

Zhang says the cells developed using this approach have another big advantage:

“We can turn them on or off, up or down, using a designer drug that can only act on cells that express the designer receptor. The drug does not affect any host cell because they don’t have that specialized receptor. It’s a very clean system.”

Tests in mice showed that the cells, and the designer drug, worked as the researchers hoped they would with some cells producing more dopamine, and others halting production.

It’s an encouraging start but a lot more work needs to be done to make sure the the genetically engineered stem cells, and the designer drug, are safe and that they can get the cells to go to the part of the brain that needs increased dopamine production.

As Zhang says, having a method of remotely controlling the action of transplanted cells, one that is reversible, could create a whole new way of treating diseases.

“This is the first proof of principle, using Parkinson’s disease as the model, but it may apply to many other diseases, and not just neurological diseases.”

Family ties help drive UCLA’s search for a stem cell treatment for Duchenne muscular dystrophy

Duchenne

April Pyle, Courtney Young and Melissa Spencer: Photo courtesy UCLA Broad Stem Cell Research Center

People get into science for all sorts of different reasons. For Courtney Young the reason was easy; she has a cousin with Duchenne muscular dystrophy.

Now her work as part of a team at UCLA has led to a new approach that could eventually help many of those suffering from Duchenne, the most common fatal childhood genetic disease.

The disease, which usually affects boys, leads to progressive muscle weakness, which means children may lose their ability to walk by age 12 and eventually results in breathing difficulties and heart disease.

Duchenne is caused by a defective gene, which leads to very low levels of a protein called dystrophin – an important element in building strong, healthy muscles. There are many sections of the gene where this defect or mutation can be found, but in 60 percent of cases it occurs within one particular hot spot of DNA. That’s the area that the UCLA team focused on, helped in part by a grant from CIRM.

Skin in the game

First they obtained skin cells from people with Duchenne muscular dystrophy and turned those into iPS cells. Those cells have the ability to become any other cell in the body and, just as importantly for this research, still retain the genetic code from the person they came from. In this case it meant they still had the genetic defect that led to Duchenne muscular dystrophy.

Then the researchers used a gene editing tool called CRISPR (we’ve written about this a lot in the past, you can a couple of those articles  here and here  and here)  to remove the genetic mutations that cause Duchenne. They then turned those iPS cells into skeletal muscle cells and transplanted them into mice that had the genetic mutation that meant they couldn’t produce dystrophin.

To their delight they found that the transplanted cells produced dystrophin in the mice.

Breaking new ground

April Pyle, a co-senior author of the study, which appears in the journal Cell Stem Cell,  said, in a news release, this was the first study to use human iPS cells to correct the problem in muscle tissue caused by Duchenne:

“This work demonstrates the feasibility of using a single gene editing platform, plus the regenerative power of stem cells to correct genetic mutations and restore dystrophin production for 60 percent of Duchenne patients.”

The researchers say this is an important step towards developing a new treatment for Duchenne muscular dystrophy, but caution there are still many years of work before this approach will be ready to test in people.

For Courtney Young advancing the science is not just professionally gratifying, it’s also personally satisfying:

“I already knew I was interested in science, so after my cousin’s diagnosis, I decided to dedicate my career to finding a cure for Duchenne. It makes everything a lot more meaningful, knowing that I’m doing something to help all the boys who will come after my cousin. I feel like I’m contributing and I’m excited because the field of Duchenne research is advancing in a really positive direction.”

 

 

The key to unlocking stem cell’s potential and blocking a deadly threat

A small slice of who you are - brain cells made from embryonic stem cells.

A small slice of who you are – brain cells made from embryonic stem cells.

Our bodies are amazingly complex systems. By some estimates there are more than 37 trillion cells in our bodies.  That’s trillion with a “t”. Each of those cells engages in some form of communication and signaling with other cells which makes our bodies one heck of a busy place to be.

Yet all this activity may owe much of its splendor and complexity to a relatively small number of starting materials. Key among those may be one protein which seems to act like a “master switch” and can determine if a cell changes and multiplies, or just stays the same.

Starting out

But let’s begin at the beginning. We all start out as a single fertilized egg that develops into embryonic stem cells, which in turn become adult stem cells, which then give rise to all the different cells and tissues and structures in our body – such as our bones and brains and blood.

But how do those cells know when to change, what to change into, and when to stop? Change too little and something is undeveloped. Change too much and you risk the kind of explosive uncontrolled multiplication of cells that you see in cancer.

So, clearly, knowing what controls those changes in stem cells, and learning how to use it, could have an enormous impact on our ability to use stem cells to treat a wide range of diseases.

What’s in a name, or a number

Now researchers at Mount Sinai have identified a single protein that appears to play a major role in this control process. The protein is called zinc finger protein 217 (ZFP217) and it controls the actions of genes that in turn control whether a cell changes into another kind of cell and how often it keeps dividing and multiplying.

The study is published in Cell Stem Cell  and there is some pretty complex science involved but ultimately what it boils down to is that ZFP217 has an impact on m6A (scientists really need to start coming up with more imaginative names) which is a protein that helps determine if a gene is turned on or off. If turned on the gene performs one function. If turned off it doesn’t.

By, in effect, blocking the action of m6A, ZFP217 is able to stop the process that would allow stem cells to differentiate, or change, into other cells and also ends their ability to keep renewing themselves.

But wait, there’s more!

One other important role that ZFP217 plays is in helping spur the growth of cancerous tumors. Too much of the protein allows these cells to multiply in an unlimited and uncontrolled fashion, typical of the kind of growth we see in tumors.

The study was done in mice but in a news release  the lead study author, Martin Walsh, PhD, talked about the possible significance of the findings for people:

“The hope is that ZFP217 could be used to maintain supplies of therapeutic stem cells. At the same time, as the human ZPF217 is associated with poor survival in a variety of cancers, understanding how this protein operates in physiological conditions may help to predict cancer risk, achieve earlier diagnosis and provide novel therapeutic approaches.”

Having a deeper understanding of what makes some stem cells multiply and change into other cells could enable researchers to better use stem cells to develop new approaches to treating some of the most intractable diseases of our time.

If that happens then ZFP217 might be a name to remember after all.

Skipping a Step: Turning Brain Cells Directly into Neurons

It was once commonly believed that “what you see is what you get” with the human brain. As in, the brains cells that you are born with are the only ones you’ll have for the rest of your life because they can’t regenerate.

The discovery of brain stem cells in the late 90s disproved this notion and established that the brain can replace old cells and repair damage after injury. The brain’s regenerative capacity is limited, however. Consequently, patients suffering from neurodegenerative diseases like Alzheimer’s and Parkinson’s can’t rely on their brain stem cells to repopulate all of the sick and dying neurons in their brains.

This is where cellular reprogramming technology could come to the rescue. Induced pluripotent stem cells (iPSCs) generated from patient skin cells by cellular reprogramming can be turned into many types of brain cells to study diseases in a petri dish, as well as to test drugs and develop stem cell therapies. Eventually, the hope is to transplant iPSC-derived brain cells back into patient brains to treat or cure degenerative diseases.

Making neurons directly from other brain cells

Another form of cellular reprogramming, offers a more direct approach to generating populations of healthy brain cells. Using a similar technique to iPSCs, scientists can use specific factors to directly reprogram skin cells or other brain cells into neurons without making them go through the pluripotent stem cell state. By skipping a step in the reprogramming process, researchers save time, money, and energy – and it could result in safer cells.

The group used small molecules to directly reprogram human astrocytes into neurons that could be transplanted into mice. (Zhang et al., 2015)

The group used small molecules to directly reprogram human astrocytes into neurons that could be transplanted into mice. (Zhang et al., 2015)

While direct reprogramming of skin and non-neuronal brain cells into neurons has been published before, a study in Cell Stem Cell by a group at Penn State University last week described a new-and-improved method to make properly functioning neurons from brain astrocytes. Astrocytes are a type of glial cell that are abundant in the brain. They provide neurons with support, nutrients, and aid following injury.

Led by senior author Gong Chen, the group bathed human astrocytes in a cocktail of small molecules that turned the astrocytes into neurons in less than 10 days. These neurons survived in a dish for more than 5 months and were able to send electrical signals to each other (a sign that they were functional). Even more exciting was that the directly reprogrammed neurons survived and functioned properly when they were transplanted into the brains of mice.

When they studied the biological mechanism behind their direct reprogramming method, they found that the small molecule cocktail turned off the activity of astrocyte-specific genes in the astrocytes and turned on neuron-specific genes to convert them into neurons.

Human astrocytes (left) were directly reprogrammed into neurons (right). (Zhang et al., 2015)

Human astrocytes (left) were directly reprogrammed into neurons (right). (Zhang et al., 2015)

This discovery is great news for the reprogramming field as using small molecule reprogramming instead of the commonly used transcription-factor based reprogramming (which involves using viruses that can damage or alter the genome) is a more attractive method with broader applications­ for making neurons that can be transplanted into humans.

Direct reprogramming makes new neurons in the brain

But wait, there’s more! An article from TheScientist reported that multiple groups at the Society for Neuroscience (SFN) conference  in Chicago presented results on directly converting glial cells into neurons in mouse brains rather than in a dish.

One group from the Johannes Gutenberg University used two transcription factors, proteins that control which genes are turned on or off in the human genome, to directly reprogram mouse astrocytes into neurons. By producing more of Sox2 and Ascl1 in the cortex of the mouse brain than would normally be found there, they were able to turn 15% of the glial cells in that area into neurons.

The function of these directly reprogrammed neurons remains to be determined, but the lead scientist, Sophie Peron, told TheScientist:

“That’s the next step. Now that we have a system to get these cells converted we are currently studying their connectivity, functionality, and precise characteristics.”

Two other groups also reported similar findings when they worked with a type of glial cell called reactive astrocytes. These cells are specifically activated during injury to jumpstart the healing process. The first group from the University of Texas Southwestern used the factor Sox2 to directly reprogram reactive astrocytes into neurons in mice, while the group from Penn State University – mentioned earlier in this blog – did the same thing, but using a different factor, NeuroD1.

The Penn State group went further to test their direct reprogramming method in a mouse model of stroke and found that NeuroD1-reprogrammed neurons reduced cell death and tissue scarring after stroke.

Lead scientist Yuchen Chen said:

“These findings suggest that direct reprogramming of glial cells into functional neurons may provide a completely new approach for brain repair after stroke. Our next step is to analyze whether the glia-neuron conversion technology can facilitate functional recovery in stroke animals.”


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Happy Stem Cell Awareness Day!

SCAD_Logo_2015I woke up today extra early this morning feeling like a kid at Christmas time because it’s Stem Cell Awareness day!

This exciting day brings together organizations and people around the world working to ensure that we realize the benefits of one of the most promising fields of science in our time. The day is a unique global opportunity to foster greater understanding about stem cell research and the range of potential applications for disease and injury.

For the millions of people around the world who suffer from incurable diseases and injury, Stem Cell Awareness Day is a day to celebrate the scientific advances made to-date and be hopeful of what is yet to come.

Institutions and scientists around the world will be participating in talks and activities that celebrate and also educate the community about stem cell research. For a list of events, check out our Stem Cell Awareness Day webpage. You can also follow other events on twitter by following the hashtags #stemcellday and #astemcellscientistbecause.

In celebration of this exciting day, the Stem Cellar team would like to highlight a few videos and webpages dedicated to stem cell awareness. Enjoy!

Videos:

“A Stem Cell Story” from our friends at EuroStemCell

#AStemCellScientistBecause videos via Cell Stem Cell on twitter

 

Stem Cell Awareness Webpages: