Have your cake and eat it too: Stem cells without the risk of tumors


An unregulated stem cell treatment in 2001 led to tumor growth in the (A) brain stem and (B) spinal cord of the patient four years later. (Fig 1. PLoS Med. 2009 Feb 17;6(2):e1000029)

A real stem cell tourism story
Back in 2001, an Israeli boy suffering from Ataxia Telangiectasia, a genetic brain disease that affects movement, traveled to Russia for an unregulated stem cell treatment. His brain and spinal cord were injected with fetal stem cells though the exact composition of those cells was not known. Four years later, the boy complained of headaches and his doctors back home found tumors in his brain and spinal cord.

 Stem cells: a double-edged sword
As the BBC  and many other news outlets reported in 2009, a Plos Medicine report eventually confirmed the tumor cells originated from the donor stem cells. And here lies a double-edged sword of stem cell-based therapies. On one side, stem cells hold great promise to repair diseased or damaged tissue because they can morph, or differentiate, into a wide range of cell types.

 But on the other side, they have the capacity to remain unspecialized and continually self-renew.This is great for producing enough cells to treat many people. Researchers try to make sure only more mature cells are transplanted, but if any of these propagating, undifferentiated cells get carried along with a stem cell-based treatment, there’s a risk of introducing uncontrolled cell growth and cancers instead of remedies. Human pluripotent stem cells (hPSCs), which can form almost any cell type found in our body, are believed to be especially susceptible to this dangerous potential side effect.

Reporting this week in the journal, eLife, CIRM-funded researchers at UCSD found a way to dodge the risk of tumor growth by identifying a unique, alternate stem cell type that could be applied to kidney disease. To find this cell type, the research team focused on cells that were a bit further along a differentiation path compared to unspecialized hPSCs.

Repeat after me: endoderm, ectoderm, mesoderm

In the earliest stages of embryo development, three germ layers form. (image: Internet Science Room)

In the earliest stages of embryo development, three germ layers form. (image: Internet Science Room)

To explain, let’s take a brief detour into developmental biology. In the very early stages of specialization, the cells of the embryo form the three germ layers: ectoderm, endoderm and mesoderm. Each layer gives rise to specific set of cells and tissues. Endoderm forms, to just name a few, the lungs, intestines and pancreas; ectoderm develops into skin, the brain and spinal cord; mesoderm forms blood, muscle, bone and kidneys. Within each germ layer lie progenitor stem cells, that maintain the capacity to self-renew and can also differentiate into the adult cells formed by that germ layer.

Finding a mesoderm progenitor
While methods for growing ectoderm and endoderm progenitor stem cells from hPSCs had been previously developed, few, if any, labs had done the same for mesoderm. So the UCSD team systematically tested thousands of combinations of nutrients and chemicals for both growing and differentiating hPSCs into mesoderm. Using this approach, they successfully tracked down a recipe that gave rise to mesoderm progenitor cells with the potential to multiply and grow in population yet lacking the ability to form tumors when transplanted into mice.

Color tagged surface proteins indicate a kidney fate for activated mesodermal progenitors (Fig 7c Kumar et al. eLife 2015;4:e08413)

Color tagged surface proteins indicate a kidney fate for activated mesodermal progenitors (Fig 7c Kumar et al. eLife 2015;4:e08413)

The research team planned to work out the various conditions to specialize the progenitor cells into a wide range of mesoderm tissues. But to their surprise, when triggered to differentiate, the progenitors only gave rise to cells of the kidney. This very limited specialization is actually desired for clinical applications since purity of cell therapies is a requirement for testing in humans.

Our kidneys thank you
Putting it all together, the team has identified a cell source with unlimited self renewal capacity that can differentiate into a very specific cell type and doesn’t carry a risk of tumor formation when transplanted. These qualities make the mesoderm progenitor cell an exciting tool for developing future kidney repair or replacement treatments. And as Dr. Karl Willert, senior author and associate professor at UC San Diego, states in a UCSD press release, there is also reason to be excited about near-term applications:

“Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation. I think such a therapeutic application is still a few years in the future, but engineered kidney tissue can serve as a powerful model system to study how the human kidney interacts with and filters drugs. Such an application would be of tremendous value to the pharmaceutical industry.”

How do you know if they really know what they’re saying “yes” to?

How can you not love something titled “Money, Mischief and Science.” It just smacks of intrigue and high stakes.

And when the rest of the title is “What Have We Learned About Doing Stem Cell Research?” you have an altogether intriguing topic for a panel discussion.

Sue and Bill Gross Hall: Photo by Hoang Xuan Pham/ UC Irvine

Sue and Bill Gross Hall: Photo by Hoang Xuan Pham/ UC Irvine

That panel – featuring CIRM’s own Dr. Geoff Lomax, a regular contributor to The Stem Cellar – is just one element in a day-long event at the University of California, Irvine this Friday, November 13.

Super Symposium

The 2015 Stem Cell Symposium: “The Challenge of Informed Consent in Times of Controversy” looks at some of the problems researchers, companies, institutions and organizations face when trying to put together a clinical trial.

In many cases the individuals who want to sign up for a clinical trial involving the use of stem cells are facing life-threatening diseases or problems. Often they have tried every other option available and this trial may be their last hope. So how can you ensure that they fully understand the risks involved in signing up for a trial?

Equally important is that many of the trials now underway now are Phase 1 trials. The main goal of this kind of trial is to show that the therapy is safe and so the number of cells they use is often too small to have any obvious benefit to the patient. So how can you explain that to a patient who may chose to ignore your caveats and focus instead on the hope, distant as it may be, that this could help them?

Challenging questions

The symposium will feature experts in the fields of science, law, technology and ethics as they consider:

  • Does informed consent convey different meanings depending on who invokes the term?
  • When do we know that consent is informed?
  • What are human research subjects entitled to know before, during and after agreeing to participate in clinical trials?
  • How might the pushback on fetal tissue research impact the scientific development of vaccines, research on Alzheimer’s disease or other medical advancements?

So if you are looking for something thought provoking and engaging to do this Friday, here you are:

“The Challenge of Informed Consent in Times of Controversy,” Friday, Nov. 13, 9am – 4:30pm, at the Sue & Bill Gross Stem Cell Research Center on the University of California, Irvine campus.

The symposium will be livestreamed, and a video recording will be available on www.law.uci.edu following the event.

REGISTER: The symposium is free to UCI student, staff and faculty. There is a $20 registration fee for non-UCI attendees. Visit the event page to register.

CRISPR cluster: How the media spotlight is focusing on gene editing tool

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Illustration by Ashley Mackenzie: from New York Times Sunday Magazine

Getting in-depth stories about science in general, and regenerative medicine in particular, into the mainstream media is becoming increasingly hard these days. So when you get one major media outlet doing a really long, thoughtful piece about a potential game-changing gene-editing technology it’s good news. But when you get three major media outlets, all reporting on the same technology, all in the space of less than one week, and all devoting lots of words to the pieces, then it’s really a cause for celebration.

That’s what happened in the last few days with features on the gene editing technology CRISPR in the New York Times Sunday Magazine,  the New Yorker Magazine,  and STAT, a new online health and life-sciences publication produced by the Boston Globe.

Making the story personal

Feng Zhang: photo courtesy of the Broad Institute

Feng Zhang: photo courtesy of the Broad Institute

Each takes a similar approach, focusing on the individuals behind the new approach – Feng Zhang at Harvard/MIT and Jennifer Doudna at the University of California, Berkeley. The fact that the two are involved in a fight over patent rights for the process adds an extra element of friction to a story that already has more than its share of drama.

In the New Yorker, Michael Specter neatly summarizes why so many people are excited about this technology:

“With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system.”

Jennifer Doudna: Photo courtesy of iPSCell.com

Jennifer Doudna: Photo courtesy of iPSCell.com

Sharon Begley in STAT, writes that this discovery could bring cures to some of the deadliest health problems we face, from cancer to Alzheimer’s, but that it also comes with big ethical questions hanging over it:

“He (Zhang) has touched off a global furor over the possibility that a genetics tool he developed could usher in a dystopian age of designer babies.”

Jennifer Kahn in the New York Times Sunday Magazine follows up on that thought, writing about Doudna:

“But she also notes that the prospect of editing embryos so that they don’t carry disease-causing genes goes to the heart of CRISPR’s potential. She has received email from young women with the BRCA breast-cancer mutation, asking whether CRISPR could keep them from passing that mutation on to their children — not by selecting embryos in vitro, but by removing the mutation from the child’s genetic code altogether. ‘‘So at some point, you have to ask: What if we could rid a person’s germ line, and all their future generations, of that risk?’’ Doudna observed. ‘‘When does one risk outweigh another?’’

Each article makes for fascinating reading. Collectively they highlight why CRISPR is such a hot topic, on so many different levels, in science right now.

The topic is going to be the focus of a conference, featuring scientists from the US, Europe and China, being held at the National Academy of Sciences in Washington DC the first week of December.

CIRM is also getting involved in the debate and is holding a science-policy workshop on February 4th, 2016 in Los Angeles to consider the future use of genome editing technologies in studies sponsored by CIRM.

Gene editing in blood stem cells just got easier

Genome editing is a field of science that’s been around for awhile, but has experienced an explosion of activity and interest in recent years. Chances are that even your grandmother has heard about the recent story where for the first time, gene editing saved a one-year-old girl from dying of leukemia.

Microsoft word versus genome editing

To give you an idea of what this technique involves, think back to the last time you had to write a report. You let all your ideas flow out onto the page, but then realize that certain sentences or paragraphs need to be rearranged, removed, or added. So you copy, paste, and move stuff around with your mouse and keyboard until you’re satisfied.

Image source: Broad Institute

Image source: Broad Institute

Tools for editing the genome (which contain all of our genes) work a similar way, but they cut and paste DNA sequences in the human genome instead of words on a page. Scientists have figured out how to use these “genetic scissors” to delete genes (so they no longer have function) and to correct disease-causing mutations (by pasting in the normal DNA sequence of a gene to restore function). Both these abilities make genome editing a highly valuable tool for scientists to model diseases and to develop therapies to treat them.

There are multiple tools that researchers are currently using to modify the human genome. The main ones are fancifully named ZFNs, TALENs, and CRISPRs. All three use engineered proteins called nucleases to cut strands of DNA at specific locations in the genome. A cell’s DNA repair machinery will then either glue the DNA strands back together (this typically results in the loss of DNA and gene function), or repair the break by copying and pasting in the missing sequence of DNA from a template (you can correct disease-causing mutations this way by providing a donor template). We don’t have time to get into more details about how these tools work, but you can learn more by reading this fact sheet from Science Media Centre.

Some cells are more stubborn than others

While genome editing technologies offer many advantages for modifying human genes, it’s not a perfect science. There are still many limitations and roadblocks that need to be addressed to make sure that these tools can be safely and effectively used as therapies in humans.

Besides the obvious worry about “off-target effects” (when the genetic scissors cut random sections of DNA, which can cause big problems), another issue with genome editing tools is that some types of cells are harder to genetically modify than others.

Such is the case with blood stem cells, also known as hematopoietic stem and progenitor cells (HSPCs), that live in our bone marrow and make all the different blood cells in our body. Initial studies reported difficulty in delivering genome editing tools into human HSPCs, which is a problem if you want to use these tools to help cure patients suffering from genetic blood or immune diseases.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Have no fear, blood-stem cell editing is here

We are happy to inform you that a CIRM-funded study published today in Nature Biotechnology has developed a solution to the problem of hard-to-edit blood stem cells. Scientists from the USC Keck School of Medicine and from Sangamo BioSciences developed a new delivery method that allows for efficient genome editing of human HSPCs using zinc finger nucleases (ZFNs).

They used a viral delivery system to deliver ZFNs to distinct locations in the genome of HSPCs and successfully inserted a gene sequence that made the cells turn green under a fluorescent microscope. The virus they used was a harmless form of an adeno-associated virus (AAV), which can enter certain cells and delivery the researcher’s DNA cargo with a very low chance of altering or inserting its own DNA into the HSPC genome.

Using an AAV that was exceptionally good at entering HPSCs, they virally delivered ZFNs to specific gene locations in HSPCs that had been isolated from human blood and from fetal liver tissue. They found that delivering the ZFNs as mRNA molecules allowed the protein versions they turned into to be temporarily expressed in HSPCs. This produced a high rate of gene insertion (ranging from 15-40% of cells treated), while keeping off-target effects and cell death low. Even the most hard-to-edit HSPCs, called the primitive HSPCs, were modified. This result was really exciting because no other study has reported gene editing with this level of efficiency in this primitive population of blood stem cells.

The tools work but what about the cells?

After proving that they were able to successfully edit the genomes of HSPCs with high efficiency, they next asked whether the modified cells could grow in culture and create new blood cells when transplanted into mice.

While their method to deliver ZFNs into the HSPCs did cause some of the cells to die (around 20%), the majority that survived were able to multiply in a dish and specialize into various blood cells when grown in cultures. When the modified HSPCs were taken a step further and transplanted into immune-deficient mice (meaning their immune system is compromised and won’t attack transplanted cells), they not only survived, but they also specialized into many different types of blood cells while still retaining their genomic modifications.

Now here is where I want to give the researchers a high five. They decided that once wasn’t enough, and challenged their modified HSPCs to a second round of transplantation. They collected the bone marrow from mice that received the first transplant of modified HSPCs, and transferred it into another immune-deficient mouse. Five months later, they found that the modified cells were still there and had generated other blood cell types. Because these modified HSPCs lasted for so long and through two rounds of transplants, the authors concluded that they had successfully edited the primitive, long-term repopulating HSPCs.

Next stop, the clinic?

In summary, this study offers a new and improved method to genetically modify blood stem cells in all their forms.

So what’s next? The obvious hope is the clinic.


HIV (yellow) infecting a human immune cell. Photo credit: Seth Pincus, Elizabeth Fischer and Austin Athman, NIH.

It’s a likely future as the study was conducted in collaboration with Sangamo BioSciences. They specialize in ZFN-mediated gene therapy and have a number of preclinical therapeutic programs, many of which focus on genetic diseases that affect the blood and immune system, as well as ongoing clinical trials using ZFNs to treat patients with HIV/AIDs. (One of these trials is funded by CIRM, read more here).

In a USC press release, Dr. Michael Holmes, VP of Research at Sangamo and co-senior author on the paper hinted at future clinical applications:

Michael Holmes, Sangamo BioSciences

Michael Holmes, Sangamo BioSciences


Our results provide a strategy for broadening the application of gene editing technologies in HSPCs. This significantly advances our progress towards applying gene editing to the treatment of human diseases of the blood and immune systems.



Co-senior author and USC Professor Dr. Paula Cannon echoed Dr. Holmes:

Gene therapy using HSPCs has enormous potential for treating HIV and other diseases of the blood and immune systems.

One last question

A question that I had after reading this exciting study was whether other genome editing tools such as CRISPR could produce better results in blood stem cells using a similar viral delivery method.

CRISPR is described as a faster, cheaper, and easier gene editing technology compared to ZFNs and TALENS (for a comparison, check out this fun article by The Jackson Laboratory). And many scientists, both in academia and industry, are pushing CRISPR gene editing towards clinical applications.

When I asked Paula Cannon about which gene editing technology, ZFNs or CRISPRs, is better for therapeutic development, she said:

Paula Cannon, USC Professor

Paula Cannon, USC Professor

In terms of advantages, CRISPRs are easier to work with initially, and this makes them a great lab research tool. But when it comes to developing something for a clinical trial, its much more of a long game, so that initial advantage disappears. The ZFNs I work with have been previously optimized and are well characterized, and the CCR5 ZFNs are already in the clinic so they have a big advantage in that regard when you are trying to develop something for the next clinical application.

Related Links:

Stem cell stories that caught our eye: mini-brains in a dish, blood stem cells and state funded stem cell research

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.

Great review of brains in a dish. The veteran Associated Press science journalist Malcolm Ritter produced the most thorough overview I have seen of the recent spate of research projects that have grown “mini-brains” in lab dishes. He provides the perspective from the first report in 2013 to a recent, and as he noted, unconfirmed claim of a more complex ball of brain cells.

Alysson Muotri

Alysson Muotri

He uses CIRM grantee Alysson Muotri to discuss the value of modeling diseases with these pea-sized brains. In the case of this University of California, San Diego researcher that involves finding out how nerves in people with autism are different from those in other people. But Ritter does not leave the false impression that these very rudimentary clumps of cells—that each self-organize in slightly different ways—are functioning brains. He makes this point with great quote from Madeline Lancaster of the Medical Research Council in England:

“Lancaster compares the patchwork layout to an airplane that has one wing on top, a propeller at the back, the cockpit on the bottom and a wheel hanging off the side. ‘It can’t actually fly,’ she said. But ‘you can study each of the components individually and learn a lot about them.’”

Ritter also discusses the broader trend of creating various miniature “organoids” in the lab including a quote from CIRM grantee at the University of California, San Francisco, Arnold Kriegstein:

This overall approach “is a major change in the paradigm in terms of doing research with human tissues rather than animal tissues that are substitutes. … It’s truly spectacular.” Organoids “are poised to make a major impact on the understanding of disease, and also human development.”

Unfortunately, this AP piece did not get as broad a pick up as the wire service often achieves. But here is the version from the Seattle Times.

Throw out the textbook on blood stem cells. A new study suggests that the textbook roadmap showing blood stem cells slowly going down various paths to eventually produce specific adult blood cells may be like a faulty GPS system. In this case that voice saying “redirect” is the renown stem cell scientist John Dick of the University of Toronto.

plateletsDick’s research team showed that very early in the process the daughter cell of the stem cell is already committed to a specific adult cell, for instance a red blood cell or a platelet needed for clotting. Low cell counts for one of those cell is the most common cause for patients needing transfusions. Now, with these cell-specific progenitor cells discovered, it may be easier to generate those adult cells for therapy. The discovery will also help the research community better understand many blood disorders.

“Our discovery means we will be able to understand far better a wide variety of human blood disorders and diseases – from anemia, where there are not enough blood cells, to leukemia, where there are too many blood cells,” said Dick in a press release from the University affiliated Princess Margaret Cancer Center. “Think of it as moving from the old world of black-and-white television into the new world of high definition.”

The journal Science published the study today.

The power of states to fund stem cells. The Daily Beast published a good review of state efforts to fund stem cell research with the slightly mischievous title, “George W., Father of Stem-Cell Revolution.” It recounts how several states stepped into the breach after then President George W. Bush restricted stem cell research. The story originally ran in Kaiser Health News under a more subdued headline.


The article states that today seven states offer some level of stem cell research funding. And the author asserts that as an engine for generating economic development and local scientific prestige “stem cell research for many states appears to be worth the investment.” We have to agree.

The story does retell some of the early criticisms of CIRM, but goes on to discuss some of our reforms and quotes our new president C. Randal Mills on the “systems-based agency” he is creating:

“We’re setting up continuous paths to move basic research to clinical trials. It’s like a train moving down a track, where each grant is the link to the next step down the line.”

The piece ends with a great forward-looking quote from Jakub Tolar, head of the University of Minnesota’s Stem Cell Institute:

“We started on drugs a hundred years ago. Then we went to monoclonal antibodies—biological. We are now getting ready to use cells as a third way of doing medicine. We are at a historical sweet spot.”

Glimpse the future at a fun-filled Festival of Science

Hands-on science and fun

Hands-on science and fun

Imagine a giant circus but instead of performing animals you have a Robot Zoo; instead of scary clowns you have colorful chemicals in glass beakers. That’s what AT&T Park will look like this Saturday when the 5th Annual Discovery Day opens its doors.  It’s a hands-on, eye-opening, brain-engaging celebration of science for everyone.

It’s a lot of fun

You’ll get a chance to learn about the science of sports – an appropriate subject as you’ll be doing it at the home of the 3-time World Champions of baseball, the San Francisco Giants. You’ll also be able to experience some of the training it takes to become an astronaut, without any of that pesky going-into-space business.

All in all you’ll be able to visit more than 150 hands-on exhibits and activities spread throughout the park, put together by the top science organizations, institutions and companies from all over the Bay Area. We’re talking Stanford University, UCSF, The Tech Museum, the Exploratorium, KQED, US Geological Society and the list goes on and on.

Meet the future right now

Today's scientists inspiring tomorrow's

Today’s scientists inspiring tomorrow’s

You’ll get to meet the scientists who are exploring outer space and the depths of the ocean, who are doing cutting edge research into health and who are pushing the boundaries of scientific knowledge.

And you will get a chance to meet us, the CIRM Team. We’re going to be there all day talking about the exciting progress being made in the field of stem cell research, and about the 15 clinical trials we are currently funding in heart disease, diabetes, cancer, HIV/AIDS and blindness (to name just a few).

You can find us on the Promenade level at booth P50. We’re easy to spot. We’re the coolest ones around. And if you have kids who enjoy PlayDoh, we will give them a chance to use the fun stuff to make stem cells.

But best of all Discovery Day is a chance for kids to learn how amazing science can be, to meet the scientists who are helping shape their future, and to consider a future as scientists themselves. And for the rest of us, it’s a chance to remind ourselves why we fell in love with science to start with.

And as if that wasn’t enough, the whole shebang is FREE.

The event is this Saturday, November 7 from 10am – 4pm. For details on where it is and how to get there – go to Discovery Day

Fun on the field at AT&T Park

Fun on the field at AT&T Park

Cell survival strategy gives mesenchymal stem cells their “paramedic” properties

Electron micrograph of a human mesenchymal stem cells (Credit: Robert M. Hunt)

Electron micrograph of a human mesenchymal stem cells (Image credit: Robert M. Hunt)

A cell for all therapies
Type “mesenchymal stem cells” into the federal online database of registered clinical trials, and you’ll get a sprawling list of 527 trials testing treatments for diabetes, multiple sclerosis as well as diseases of the kidney, lung, and heart, to name just a few. Mesenchymal stem cells (MSCs) have the capacity to specialize into bone, cartilage, muscle and fat cells but their popularity as a therapeutic agent mostly comes from their ability to reduce inflammation and to help repair tissues.

MSCs may be great tools for scientists to fight disease, but what is it about their natural function that make MSCs – as UC Davis researcher Jan Nolta likes to calls them – the body’s “paramedics”? A fascinating study reported yesterday in Nature Communications by scientists at the Florida campus of The Scripps Research Institute (TSRI) and the University of Pittsburgh suggest that it’s a trait the cells gain as a result of their complex cell survival mechanisms.

The TSRI team came to this conclusion by studying how MSCs respond to oxygen-related stress. MSCs reside in the bone marrow where they help maintain and regulate blood stem cells. The bone marrow is naturally a hypoxic, or low oxygen, environment. Growing MSCs in the lab at oxygen levels found in the air we breathe are much higher than what is found in the marrow. This creates oxidative stress in which the excess oxygen leads to unwanted chemical reactions which disrupt a cell’s molecules.

One cell’s trash is another’s treasure
One result of this oxidative stress is damage to the MSCs’ mitochondria, structures responsible for generating the energy needs of a cell. The team found that MSCs package the faulty mitochondria into sacs, or vesicles, which travel to the cell surface to be dumped out of the cell. At this point, another resident of the bone marrow comes into the picture: the macrophage. Previous research has shown that macrophages and MSCs work closely together to maintain the health of the blood stem cells in the bone marrow.

Screen Shot 2015-11-04 at 9.58.48 AM

White arrow shows vesicles (red) carrying mitochondra (green) to the surface of the MSC  and being ingested by a macrophage (round shape in lower half) – (From Fig 2 Nat Commun. 2015 Oct 7;6:8472)

In a high oxygen stress environment, the team observed that MSCs can recruit macrophages to engulf the damaged mitochondria-containing vesicles and repurpose them for their own use. In fact, the researchers measured improved energy production in the macrophages after ingesting the MSCs’ mitochondria. Blocking the transfer of the damaged mitochondria from MSCs to macrophages caused the MSCs to die, confirming that this off-loading of mitochondria to macrophages is critical for MSC survival.

Evolving tricks for cell survival
Macrophages (macro=big; phages=eaters), key players of the immune system and the inflammation response, also rid the body of invading bacteria or damaged cells by devouring them. To avoid being swallowed up by the macrophage while donating its mitochondria, the stressed MSCs have another trick up their sleeve. The research team identified the release of other vesicles from the MSCs that contain molecules called microRNAs which stimulate anti-inflammatory properties in the macrophages. This prevented the macrophages from attacking and eating the MSCs.

And there you have it: as a result of relying on macrophages to survive stressful environments, MSCs appear to have evolved anti-inflammatory activities that turn out to be a handy tool for numerous ongoing and future cell therapy trials.

In a TSRI press release picked up by Newswise, professor Donald Phinney co-leader of study points out the groundbreaking aspect of the study:

Donald G. Phinney

Donald Phinney (photo: TSRI)

“This is the first time anyone has shown how mesenchymal stem cells provide for their own survival by recruiting and then suppressing normal macrophage activity.”



Could We Reverse Alzheimer’s Disease with Stem Cells?

What if you could give people whose memories have been stolen the ability to remember again? I’m talking about curing a population of more than 5 million Americans living with Alzheimer’s disease (AD) – not a small task. Unfortunately, this number is predicted to more than triple by 2050, and with it so will healthcare costs and other burdens to society. The situation is dire enough that president Barack Obama signed a law last year that increased the amount of money to fund AD research, education, outreach, and caregiver support.

This weekend, a story was picked up in the news that brings hope for AD research. South China Morning Post covered a scientific study that claims it can reverse memory loss in mice with Alzheimer’s using a cell-based therapy. The study was published in Stem Cell Reports in mid October by a group of Chinese scientists.

Although the study is still in its early stages and the results are preliminary, what I like about it is its simplicity and logic. The authors decided to generate a type of nerve cell that is typically lost (or dysfunctional) in the brains of AD patients and some mouse models of AD. It’s called a basal forebrain cholinergic neuron, and it lives in an area near the bottom of our brains that’s responsible for processing certain functions such as learning and attention. The scientists proposed that they would replace these lost nerve cells in AD mice with healthy nerve cells derived from stem cells in hopes of restoring memory function.

How they did it

The authors first devised methods to make these specific nerve cells from both mouse and human embryonic stem cells in a dish. They were successful in making nerve cells that expressed the correct markers for cholinergic neurons and functioned properly, meaning they could send the correct electrical signals to other nerve cells.

The next step was to test the functionality of the nerve cells in mouse models of AD. Instead of transplanting adult nerve cells into the brain (which don’t survive very well), the authors transplanted progenitor cells, which developmentally, are more specialized than stem cells and eventually become adult nerve cells.


Brain section from an Alzheimer’s mouse that received a transplant of progenitor cells (green) into the basal forebrain. (Yue et al., 2015)

When the mouse progenitor cells were transplanted into the basal forebrain of AD mice, most of them survived and matured into adult cholinergic nerve cells that were able to function in tandem with the original mouse nerve cells. When they transplanted human progenitor cells into the same area, a majority of the transplanted human cells did not survive (likely due to the mouse immune system rejecting them), however, the ones that did were able to turn into functioning cholinergic neurons.

Then came the final question, could the mouse and human progenitors improve the memory of these forgetful mice? The scientists compared the memories of AD mice that had received mouse or human cholinergic progenitor cells to AD mice that received no treatment and to healthy normal mice. The groups were put through a memory test where they were trained to find a hidden platform in a circular pool of water. Untreated AD mice had trouble finding the platform and couldn’t remember where it was in subsequent trials. However, the AD mice that received either mouse or human progenitor cell transplants six to eight weeks before were able to find the platform more quickly and remember where it was in multiple trials. This suggested that the transplanted nerve cells improved their ability to learn tasks and recall memories.

The water maze tests a mouse's ability to learn and recall where the hidden platform is. (Image adapted from Credit2M BioTech)

The water maze tests a mouse’s ability to learn and recall where the hidden platform is. (Image adapted from Credit2M BioTech)

Hold on: Primates before humans

So it seems from this study that replacing cholinergic nerve cells in the basal forebrain area of the brain is a potential approach to reversing memory loss in Alzheimer’s disease. However, the study’s senior author, Naihe Jing, cautioned everyone to not get ahead of themselves.

Dr. Naihe Jing, Shanghai Institutes of Biological Science

Dr. Naihe Jing

Mice are still very different from humans, so the results on mice do not guarantee the same success on human patients. Our next step is to test the method on primates. It will probably be a long time before clinical trials can be carried out on human volunteers.


But he also explained that his group is thoroughly testing the safety of their embryonic stem cell based therapy.

We used human embryonic stem cells because this method will eventually be used on humans. If the human neurons can get a footing and grow in the brain of a mouse, the chance is high the effect will be even better on a human host. The biggest concern of this development is safety. We were afraid that the transplanted cells would mutate to other types of neurons or even cause brain tumours. We have been improving the technology and making close observation of the mice for more than seven years. So far no mutation or cancerous development has been detected.

So while we might not have a cell therapy to treat Alzheimer’s in the near future, we can be comforted by the fact that groups like this one are taking all the precautions to develop safe and effective treatments.

Related Links:

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.

Stem cell stories that caught our eye: cancer fighting virus, lab-grown guts work in dogs, stem cell trial to cure HIV

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.

Cancer fighting virus approved for melanoma

(Disclaimer: While this isn’t a story about stem cells, it’s pretty cool so I had to include it.)

The term “virus” generally carries a negative connotation, but in some cases, viruses can be the good guys. This was the case on Tuesday when our drug approval agency, the US Food and Drug Administration (FDA), approved the use of a cancer fighting virus for the treatment of advanced stage melanoma (skin cancer).

The virus, called T-VEC, is a modified version of the herpesvirus, which causes a number of diseases and symptoms including painful blisters and sores in the mouth. Scientists engineered this virus to specifically infect cancer cells and not healthy cells. Once inside cancer cells, T-VEC does what a virus normally does and wreaks havoc by attacking and killing the tumor.

The beauty of this T-VEC is that in the process of killing cancer cells, it causes the release of a factor called GM-CSF from the cancer cells. This factor signals the human immune system that other cancer cells are nearby and they should be attacked and killed by the soldiers of the immune system known as T-cells. The reason why cancers are so deadly is because they can trick the immune system into not recognizing them as bad guys. T-VEC rips off their usual disguise and makes them vulnerable again to attack.

T-VEC recruits immune cells (orange) to attack cancer cells (pink) credit Dr. Andrejs Liepins/SPL

T-VEC recruits immune cells (orange) to attack cancer cells (pink). Photo credit Dr. Andrejs Liepins/SPL.

This is exciting news for cancer patients and was covered in many news outlets. Nature News wrote a great article, which included the history of how we came to use viruses as tools to attack cancer. The piece also discussed options for improving current T-VEC therapy. Currently, the virus is injected directly into the cancer tumor, but scientists hope that one day, it could be delivered intravenously, or through the bloodstream, so that it can kill hard to reach tumors or ones that have spread to other parts of the body. The article suggested combining T-VEC with other cancer immunotherapies (therapies that help the immune system recognize cancer cells) or delivering a personalized “menu” of cancer-killing viruses to treat patients with different types of cancers.

As a side note, CIRM is also interested in fighting advanced stage melanoma and recently awarded $17.7 million to Caladrius Biosciences to conduct a Phase 3 clinical trial with their melanoma killing vaccine. For more, check out our recent blog.

Lab-grown guts work in mice and dogs

If you ask what’s trending right now in stem cell research, one of the topics that surely would pop up is 3D organoids. Also known as “mini-organs”, organoids are tiny models of human organs generated from human stem cells in a dish. To make them, scientists have developed detailed protocols that sometimes involve the use of biological scaffolds (structures on which cells can attach and grow).

A study published in Regenerative Medicine and picked up by Science described the generation of “lab-grown gut” organoids using intestine-shaped scaffolds. Scientists from Johns Hopkins figured out how to grow intestinal lining that had the correct anatomy and functioned properly when transplanted into mice and dogs. Previous studies in this area used flat scaffolds or dishes to grow gut organoids, which weren’t able to form proper functional gut lining.

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

What was their secret recipe? The scientists took stem cells from the intestines of human infants or mice and poured a sticky solution of them onto a scaffold made of suture-like material. The stem cells then grew into healthy gut tissue over the next few weeks and formed tube structures that were similar to real intestines.

They tested whether their mini-guts worked by transplanting them into mice and dogs. To their excitement, the human and mouse lab-grown guts were well tolerated and worked properly in mice, and in dogs that had a portion of their intestine removed. Even more exciting was an observation made by senior author David Hackham:

“The scaffold was well tolerated and promoted healing by recruiting stem cells. [The dogs] had a perfectly normal lining after 8 weeks.”

The obvious question about this study is whether these lab-grown guts will one day help humans with debilitating intestinal diseases like Crohn’s and IBS (inflammatory bowel disorder). Hackam said that while they are still a long way from taking their technology to the clinic, “in the future, scaffolds could be custom-designed for individual human patients to replace a portion of an intestine or the entire organ.”

Clinical trial using umbilical cord stem cells to treat HIV

This week, the first clinical trial using human umbilical cord stem cells to treat HIV patients was announced in Spain. The motivation of this trial is the previous success of the Berlin Patient, Timothy Brown.

The Berlin patient can be described as the holy grail of HIV research. He is an American man who suffered from leukemia, a type of blood cancer, but was also HIV-positive. When his doctor in Berlin treated his leukemia with a stem cell transplant from a bone-marrow donor, he chose a special donor whose stem cells had an inherited mutation in their DNA that made them resistant to infection by the HIV virus. Surprisingly, after the procedure, Timothy was cured of both his cancer AND his HIV infection.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

The National Organization of Transplants (ONT) in Spain references this discovery as its impetus to conduct a stem cell clinical trial to treat patients with HIV and hopefully cure them of this deadly virus. The trial will use umbilical cord blood stem cells instead of bone-marrow stem cells from 157 blood donors that have the special HIV-resistance genetic mutation.

In coverage from Tech Times, the president of the Spanish Society of Hematology and Hemotherapy, Jose Moraleda, was quoted saying:

“This project can put us at the cutting edge of this field within the world of science. It will allow us to gain more knowledge about HIV and parallel offer us a potential option for curing a poorly diagnosed malignant hematological disease.”

The announcement for the clinical trial was made at the Haematology conference in Valencia, and ONT hopes to treat its first patient in December or January.