Stem cell stories that caught our eye: fashionable stem cells, eliminating HIV, cellular Trojan horse fights cancer

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.

Stem cell fashion for a cause. Science and art are not mutually exclusive subjects. I know plenty of scientists who are talented painters or designers. But you don’t often see science being displayed in an artistic way or art being used to help explain complex scientific topics. I think that in the future, this will change as both subjects have a lot to offer one another.

Stem cell ties are in fashion!

Stem cell ties are in fashion!

Take this story from the University of Michigan for instance. Designer Dominic Pangborn has joined forces with the Heinz C. Prechter Bipolar Research Fund at the University of Michigan (UOM) to design fashionable scarves and ties featuring beautiful pictures of stem cells. The goal of the Prechter Fund scarf and tie project is to raise awareness for mental health research.

The scarves and ties feature pictures of brain stem cells taken by UOM scientists who are studying them to understand the mechanisms behind bipolar disorder. These stem cells were generated from induced pluripotent stem cells or iPS cells that were derived from donated skin biopsies of patients with bipolar disease. Studying these diseased brain cells in a dish revealed that the nerve cells from bipolar patients were misbehaving, sending out electrical signals more frequently compared to healthy nerve cells.

Dr. Melvin McInnis, the Prechter Fund research director, explained:

“By understanding the causes of bipolar disorder, we will be able to develop new treatments for the illness and most importantly, we’ll be able to prevent destructive mood episodes. Our ultimate goal is to allow people to live happy, normal lives.”

Pangborn is passionate about using art to reflect an important cause.

“I decided to add butterflies to the design because they signify metamorphosis. Our society is finally at a point where mental illness is openly talked about and research is taking a turn for the better.”

He plans to release his collection in time for National Mental Health Awareness month in May. All proceeds will go to the Prechter bipolar research projects at UOM.

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

Dr. Melvin McInnis, left, and Dominic Pangborn in the Pangborn Design Store in Ann Arbor. (UOM)

New stem cell therapy could eliminate HIV for good

The stem cells therapies being developed to cure HIV are looking more promising every day. A few are already being tested in clinical trials, and CIRM is funding two of them (you can read more about them here). News came out this week about a new trial conducted at the City of Hope’s CIRM Alpha Stem Cell Clinic. They reported in a news release that they’ve treated their first patient. His name is Aaron Kim, and he’s had HIV since he was born. In 1983, he and his twin sister were born prematurely and due to a complication, Aaron had to get a blood transfusion that unfortunately gave him HIV.

Aaron Kim with nurse. (City of Hope)

Aaron Kim with nurse. (City of Hope)

Aaron thought he would live with this disease the rest of his life, but now he has a chance at being cured. In March, Aaron received a transplant of his own bone marrow stem cells that were genetically engineered to have a modified version of the CCR5 gene that makes his cells resistant to HIV infection. CCR5 is a is a protein receptor on the surface of blood cells that acts as a gateway for HIV entry. The hope is that his reengineered stem cells will populate his immune system with HIV-resistant cells that can eliminate the virus completely.

Dr. John Zaia who is the director the the City of Hope Alpha Clinic explained,

“The stem cell therapy Aaron received is one of more than 20 cure strategies for HIV. It may not cure him, but our goal is to reduce or even halt Aaron’s reliance on HIV drugs, potentially eliminating the virus completely.”

My favorite part of this story was that it acknowledged how importance it is for patients to participate in clinical trials testing promising new stem cell therapies where the outcomes aren’t always known. Brave patients such as Aaron make it possible for scientists to make progress and develop better and safer treatments for patients in the future.

Dr. Zaia commented, “It’s a wonderful and generous humanitarian gesture on Aaron’s part to participate in this trial.”

Stem cell Trojan horse fights cancer

Chemotherapy is great at killing cancer cells, but unfortunately, it’s also great at killing healthy cells too. To combat this issue, scientists are developing new delivery methods that can bring high doses of chemotherapy drugs to the cancer tumors and minimize exposure of healthy tissues.

Mesenchymal stem cells loaded with drug-containing microparticles. Credit: Jeff Karp and Oren Levy, Brigham and Women's Hospital

Mesenchymal stem cells loaded with drug-containing microparticles.
Credit: Jeff Karp and Oren Levy, Brigham and Women’s Hospital

A study published this week in Biomaterials, describes a new drug delivery method that has the potential to be an effective treatment for prostate cancer. Researchers from the Brigham and Women’s Hospital and Johns Hopkins University developed a drug delivery platform using mesenchymal stem cells. They packaged a non-active, prodrug version of a potent prostate cancer chemotherapy drug into microparticles that they loaded into MSCs. When the MSCs and prostate cancer cells were cultured together in a dish, the MSCs released their prodrug cargo, which was then internalized by the prostate cancer cells. The prodrug was then metabolized into its active, cancer-killing form and was very effective at killing the cancer cells.

In a news release picked up by Science Daily, one of the lead scientists on the study, Dr. Oren Levy, further explained the stem cell Trojan horse concept:

“Mesenchymal stem cells represent a potential vehicle that can be engineered to seek out tumors. Loading those cells with a potent chemotherapeutic drug is a promising cell-based Trojan horse approach to deliver drugs to sites of cancer.”

If all goes well, the teams plan to develop different versions of their stem cell-based drug delivery method that target different cancers and other diseases.

Scientists tackle aging by stabilizing defective blood stem cells in mice

Aging is an inevitable process that effects every cell, tissue, and organ in your body. You can live longer by maintaining a healthy, active lifestyle, but there is no magic pill that can prevent your body’s natural processes from slowly breaking down and becoming less efficient. As author Chinua Achebe would say, “Things Fall Apart”.

Adult stem cells are an unfortunate victim of the aging process. They have the important job of replenishing the cells in your body throughout your lifetime. However, as you grow older, adult stem cells lose their regenerative ability and fail to maintain the integrity and function of their tissues and organs. This can happen for a number of reasons, but no matter the cause, dysfunctional stem cells can accelerate aging and contribute to a shortened lifespan.

So to put it simply, aging adult stem cells = decline in stem cell function = shortened lifespan.

Dysfunctional blood stem cells make an unhappy immune system

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.

A good example of this process is hematopoietic stem cells (HSCs), which are adult stem cells found in bone marrow that make all the cells in our blood and immune system. When HSCs get old, they lose their edge and fail to generate some of the important blood cell types that are crucial for a healthy immune system. This can be life-threatening for elderly people who are at higher risk for infections and disease.

So how can we improve the function of aging HSCs to boost the immune system in older people and potentially extend their healthy years of life? A team of researchers from Germany might have an answer. They’ve identified a genetic switch that revitalizes aged, defective HSCs in mice and prolongs their lifespan. They published their findings this week in Nature Cell Biology.

Identifying the Per-petrator for aging HSCs

The perpetrator in this story is a gene called Per2. The team identified Per2 through a genetic screen of hundreds of potential tumor suppressor genes that could potentially impair the regenerative abilities of HSCs in response to DNA damage caused by aging.

It turns out that the Per2 gene is turned on in a subset of HSCs, called lymphoid-HSCs, that preferentially generate blood cells in the lymphatic system. These include B and T cells, both important parts of our immune system. When Per2 is turned on in lymphoid-HSCs, it activates the DNA damage response pathway. While responding to DNA damage may sound like a good thing, it also slows down the cell division process and prevents lymphoid-HSCs from producing their normal amount of lymphoid cells. Adding insult to injury, Per2 also activates the p53-dependent apoptosis pathway, which causes programmed cell death and further reduces the number of HSCs in reserve.

To address these problems, the team decided to delete the Per2 gene in mice and study the function of their HSCs as they aged. They found that removing Per2 stabilized lymphoid-HSCs and rescued their ability to generate the appropriate number of lymphoid cells. Per2 deletion also boosted their immune system, making the mice less susceptible to infection, and extended their lifespan by as much as 15 percent.

A key finding was that deleting Per2 did not increase the incidence of tumors in the aging mice – a logical concern as Per2 mutations in humans are link to increased cancer risk.

Per2 might not be a Per-fect solution for healthy aging

In summary, getting rid of Per2 in the HSCs of older mice improves their function and the function of their immune system while also extending their lifespan.

Senior author on the study, Karl Lenhard Rudolph, commented about their findings in a news release:

Karl Lenhard Rudolph. Photo: Anne Günther/FSU

Karl Lenhard Rudolph.

“All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly.”

 

 

So Per2 may be a good healthy aging target in mice, but the real question is whether these results will translate to humans. Per2 is a circadian rhythm gene and is important for regulating the sleep-wake cycle. Deleting this gene in humans could cause sleep disorders and other unwanted side effects.

Rudolph acknowledges that his team needs to move their focus from mouse to humans.

“It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging — it is of great interest for us to further investigate this question.”

Rare disease underdogs come out on top at CIRM Board meeting

 

It seems like an oxymoron but one in ten Americans has a rare disease. With more than 7,000 known rare diseases it’s easy to see how each one could affect thousands of individuals and still be considered a rare or orphan condition.

Only 5% of rare diseases have FDA approved therapies

rare disease

(Source: Sermo)

People with rare diseases, and their families, consider themselves the underdogs of the medical world because they often have difficulty getting a proper diagnosis (most physicians have never come across many of these diseases and so don’t know how to identify them), and even when they do get a diagnosis they have limited treatment options, and those options they do have are often very expensive.  It’s no wonder these patients and their families feel isolated and alone.

Rare diseases affect more people than HIV and Cancer combined

Hopefully some will feel less isolated after yesterday’s CIRM Board meeting when several rare diseases were among the big winners, getting funding to tackle conditions such as ALS or Lou Gehrig’s disease, Severe Combined Immunodeficiency or SCID, Canavan disease, Tay-Sachs and Sandhoff disease. These all won awards under our Translation Research Program except for the SCID program which is a pre-clinical stage project.

As CIRM Board Chair Jonathan Thomas said in our news release, these awards have one purpose:

“The goal of our Translation program is to support the most promising stem cell-based projects and to help them accelerate that research out of the lab and into the real world, such as a clinical trial where they can be tested in people. The projects that our Board approved today are a great example of work that takes innovative approaches to developing new therapies for a wide variety of diseases.”

These awards are all for early-stage research projects, ones we hope will be successful and eventually move into clinical trials. One project approved yesterday is already in a clinical trial. Capricor Therapeutics was awarded $3.4 million to complete a combined Phase 1/2 clinical trial treating heart failure associated with Duchenne muscular dystrophy with its cardiosphere stem cell technology.  This same Capricor technology is being used in an ongoing CIRM-funded trial which aims to heal the scarring that occurs after a heart attack.

Duchenne muscular dystrophy (DMD) is a genetic disorder that is marked by progressive muscle degeneration and weakness. The symptoms usually start in early childhood, between ages 3 and 5, and the vast majority of cases are in boys. As the disease progresses it leads to heart failure, which typically leads to death before age 40.

The Capricor clinical trial hopes to treat that aspect of DMD, one that currently has no effective treatment.

As our President and CEO Randy Mills said in our news release:

Randy Mills, Stem Cell Agency President & CEO

Randy Mills, Stem Cell Agency President & CEO

“There can be nothing worse than for a parent to watch their child slowly lose a fight against a deadly disease. Many of the programs we are funding today are focused on helping find treatments for diseases that affect children, often in infancy. Because many of these diseases are rare there are limited treatment options for them, which makes it all the more important for CIRM to focus on targeting these unmet medical needs.”

Speaking on Rare Disease Day (you can read our blog about that here) Massachusetts Senator Karen Spilka said that “Rare diseases impact over 30 Million patients and caregivers in the United States alone.”

Hopefully the steps that the CIRM Board took yesterday will ultimately help ease the struggles of some of those families.

Five Cool Stem Cell Technologies to Tell Your Friends

As a former stem cell scientist turned science communicator, I love answering science questions no matter how complicated or bizarre. The other day my friend asked me about what CRISPR was and how scientists were using it on stem cells to help people. This got me thinking that it would be cool to do a blog on some of the latest stem cell technologies that are changing the way we do science and ultimately how we treat patients.

So in the spirit of sharing knowledge and also giving you some interesting conversation points at your next dinner party, here are five stem cell technologies that I think are pretty awesome. (As a disclaimer: this isn’t a top 5 list. I picked a few recently published studies that I thought were worth mentioning.)

1) Need a body part? Let me print that for you.

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3D printed ear. (Wake Forest University)

Scientists from Wake Forest University have developed technology to make custom-made living body parts by 3D-printing stem cells onto biodegradable scaffolds. The stem cells are printed in a hydrogel solution using a special 3D printer they call ITOP. This printer makes it possible for the printed stem cells to develop into life-sized tissues and organs that have built-in microchannels that allow blood, oxygen and other nutrients to flow through. Using the ITOP technology, the team was able to generate segments of jawbone, an ear, and muscle tissue. We wrote a blog about this fascinating technology, so check it out if you’re thirsty for more details.

 2) Bio-bots controlled by light

When you think robots, you think machines and metal. But what if the robot was made out of human cells? Crazy? Not even. Scientists from the University of Illinois have made what they called “bio-bots” or tiny machines “powered by biological components.” They printed muscle cells onto flexible skeletons in the shape of rings (see GIF). The muscle cells are engineered to have light sensitive switches, so when they are exposed to light, they contract like normal muscles do. The beauty of bio-bots is that they “can sense, process, and respond to dynamic environmental signals in real time, enabling a variety of applications.” Some of these applications could include bio-bots made up of other types of tissue (brain, heart, etc.) and general use for disease research. Story credit goes to Megan Thielking’s Morning Rounds for STATnews.

Bio-bots composed of muscle cells are powered by light. (University of Illinois)

Bio-bots composed of muscle cells are powered by light. (University of Illinois)

3) New way to track stem cells using MRI

Scientists from the UC San Diego School of Medicine have developed a new way to track cells in the body using magnetic resonance imaging (MRI). In a CIRM-funded study, the scientists made a new Fluorine-based chemical tracer that is taken in by the cells of interest. When these cells are imaged with MRI, the tracer gives off a bright and easily detectable signal. According to MNT news who covered the story, “the work is expected to enhance the progress of treatments involving stem cells and immune cells, as it will give researchers a clear picture of how cells behave after being introduced to the body.”

 4) Engineering cells to fight cancer

Genomic modification of human stem cells by gene editing methods such as CRISPR is not a novel concept, but the technology continues to evolve at record pace and is worth mentioning. You can think of CRISPR as molecular scissors that can remove disease-causing mutations in a person’s DNA. Scientists can repair genetic mutations in human stem cells and other cell types and then use these repaired cells to replace diseased or damaged tissue or to perform therapeutic functions in patients. An article by Antonio Regalado at MIT Technology Review nicely summarizes how genetically engineered immune cells are saving the lives of cancer patients. These immune cells are engineered to recognize cancer cells (which are normally expert at evading the immune system) and when they are transplanted into cancer patients, they attack and kill off the cancer pretty effectively.

5) One day, stem cells will help the blind see

Artistic representation of the human eye. (Dr. Kang Zhang, Dr. Yizhi Liu)

Artistic representation of the human eye. (Dr. Kang Zhang, Dr. Yizhi Liu)

Blindness is a big problem and stem cells are considered a promising therapeutic strategy for restoring sight in patients suffering from diseases of blindness. We covered two recent discoveries in last week’s round-up, but it never hurts to mention them again. One study from UC San Diego Health treated children suffering from cataracts. They removed the cataracts and stimulated the native stem cells in their eyes to produce new lens tissue that was able to improve their vision. The other study generated different eye parts in a dish using reprogrammed human induced pluripotent stem cells or iPS cells. They generated corneas from iPS cells and transplanted them into blind rabbits and were successful in restoring their vision. Hopefully soon stem cell technologies will advance through the clinic and provide new treatments to cure patients who’ve lost their sight.

Stem cell stories that caught our eye: fighting cancer, a cell’s neighborhood matters, funding next generation scientists

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.

Reprogramming skin to fight cancer. Earlier CIRM-funded research showed that adult nerve stem cells can home to the residual brain cancer left behind after surgery and deliver a cancer killing agent directly to where it is most needed. Now a team at the University of North Carolina has shown it can use reprogramming techniques similar to the Nobel-prize winning iPS cell reprogramming method to turn a patient’s own skin cells directly into adult nerve stem cells. They then used those stem cells to deliver a cancer-fighting protein to mice with brain cancer and extended their lives.

“We wanted to find out if these induced neural stem cells would home in on cancer cells and whether they could be used to deliver a therapeutic agent. This is the first time this direct reprogramming technology has been used to treat cancer,” said the leader of the study, Shawn Hingtgen, in a UNC press release.

Cancer cells. (iStockPhoto)

Cancer cells. (iStockPhoto)

Many outlets picked up the release, including FoxNews, which overstated the lack of progress in the field.  Their piece suggests there had been no improvements “in more than 30 years,” which ignores several advances, but you can not argue with the quote they use from Hingtgen: “Patients desperately need a better standard of care.”

More evidence the neighborhood matters. Cells excrete substances that become the structure, known as the extracellular matrix (ECM), that holds them in place. Many regenerative medicine strategies count on using donor ECM to attract and hold stem cells, or use a synthetic material that mimics ECM. A team at the Institute for Research in Biomedicine in Barcelona has documented a strong feedback loop in which the ECM also directs which cells populate an area.

The work builds on a growing body of research we have written about that shows the neighborhood a stem cell finds itself in helps dictate what it will become. The study, published in eLife, focused on the tracheal tube in fruit flies.

“The biological context of these cells modifies not only their behavior but also their internal structure,” said the head of the project Jordi Casanova in a press release picked up by NewsMedical.net. “When we modify only the extracellular matrix, the cytoskeleton is also altered.”

The research team suggested that this form of intracellular communication has been preserved in evolution and has an important role in humans, including in inflammatory diseases and cancer.

Cancer therapys major step toward patients. We frequently point out that our mission is not to do research; it is to deliver therapies to patients. And that requires commercial partners that can do all the late stage work needed to bring a therapy to market. So, we are thrilled when the developers of a therapy we have fostered from the very earliest days in the lab announces they have complete the first half of a $75 million round of venture financing, and with major names from Silicon Valley, Lightspeed, Sutter Hill and Google Ventures.

The therapy, from the Stanford Lab of Irv Weissman, now being taken forward by the company he and colleagues founded, Forty Seven, has been shown to be effective against several types of cancer in animals and is now in an early phase human clinical trial funded by CIRM. We also funded the pre-clinical work for a total investment of more than $30 million in the therapy, which has promise to work synergistically with other therapies to wipe out notoriously difficult cancers. The company name comes from the therapy’s target on cancer stem cells, CD47.

Irv Weissman

Irv Weissman

“Targeting CD47 integrates the adaptive and innate immune systems, creating synergy with existing cancer-specific antibodies like rituximab, cetuximab and trastuzumab through ADCP, and potentially with T-cell checkpoint inhibitors through cross-presentation,” said Weissman in a company press release.

The online publication Xconomy wrote a longer piece providing more perspective on how the therapy could fit into the market and on CIRM’s role in its development.

The next generation in the lab.  The Guardsman, the student newspaper of City College, San Francisco, did a nice write up on our recent renewal of the colleges grant for one of our 17 current Bridges programs that train undergraduate and masters level students the ins-and-outs of working in a stem cell laboratory.

Rosa Canchari works with cell cultures in City College’s biotech laboratory. (Photo by Amanda Aceves/Special to The Guardsman)

Rosa Canchari works with cell cultures in City College’s biotech laboratory. (Photo by Amanda Aceves/Special to The Guardsman)

The current renewal has redirected the programs to have the students better understand the end user, the patient, and to get a firmer grasp on the regulatory and process development pathways needed to bring a new therapy to market. As program officer for this initiative, I will be meeting with all the program directors next week to discuss how best to implement these changes.

But, as the CCSF director Dr. Carin Zimmerman told the Guardsman, the program continues to generate highly valued skilled workers. Like many of our programs, CCSF offers its basic courses to students at the school beyond those enrolled in the CIRM internships, and even that more limited exposure to stem cell science often lands jobs.

“One of the reasons we have a hard time filling all these classes is because people take one or two classes and get hired,” said Carin Zimmerman.

New stem cell approach targeting deadly blood cancers

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Every four minutes someone in the US is diagnosed with a blood cancer. It might be lymphoma or leukemia, myeloma or myelodysplastic syndromes (MDS). While we have made great strides in treating some of these over the years, we still have a long way to go. Need proof? Well, every nine minutes someone in the US dies from a blood cancer.

Because of that need, the CIRM Board last week approved $3.5 million to help fund the search for a more effective, more efficient way to treat people suffering from blood cancer.

The Board funded a program by Angiocrine Biosciences, a San Diego-based company that is developing a new method for transplanting cord blood into patients.

Now cord blood transplants have been around for decades and they can be very effective. But they can also cause serious, even life-threatening complications. And they have limitations. For example some cord blood units are small and don’t have as many stem cells as the doctors would like. As a result, patients may need to spend longer in the hospital recovering from the procedure, putting them at increased risk of viral infections or pneumonia. Alternatively, doctors could use more than one cord blood unit for each transplant and while that seems to be an effective alternative, some studies suggest it can also carry an increased risk for serious complications such as Graft-versus-host disease (GVHD) where the newly transplanted cells attack the patient’s body.

To get around these issues, Angiocrine is developing a product called AB-110. This takes stem cells from cord blood, uses a specialized manufacturing facility to expand their numbers and then mixes them with genetically modified endothelial cells, the kind of cell that forms the lining of blood vessels.

It’s hoped that AB-110 will reduce the complications and increase the chances the transplanted cells will successfully engraft, meaning they start growing and creating new, healthy, blood cells.

In a news release CIRM’s President and CEO, C. Randal Mills, PhD, says this program fits in perfectly with our mission of accelerating stem cell treatments to patients with unmet medical needs:

“This project aims to do precisely that, speeding up the body’s ability to create new white blood cells and platelets – both essential qualities when treating deadly diseases like leukemia and lymphoma. Under CIRM 2.0, we are trying to create a pipeline of products that move out of the lab and into clinical trials in people, and we’re hopeful this program will demonstrate it’s potential and get approval from the Food and Drug Administration (FDA) to begin a clinical trial.”

Everyone at Angiocrine and CIRM will work as hard as we can to move this research toward a clinical trial as fast as we can. But in the meantime there are tens of thousands of critically ill people in desperate need of a life-saving transplant.

One way of helping those in need is for new parents to donate their child’s umbilical cord blood to the state’s umbilical cord blood collection program. This is a safe procedure that doesn’t harm the baby but could save someone’s life.

The cord blood program is housed at the UC Davis Institute for Regenerative Cures – a facility CIRM helped build and where we fund many great projects. This program is particularly important because it collects and stores cord blood units that reflect the state’s diverse communities, and that are available to all those in need of a transplant.

The bank also is a rich source of cord blood units for research, particularly for stem cell research, which will hopefully lead to even more effective therapies in the future.

CIRM-funded study suggests methods to make pluripotent stem cells are safe

We live in an era where stem cell treatments are already being tested in human clinical trials for eye disease, spinal cord injury, and type 1 diabetes. The hope is that transplanting stem cells or their cell derivatives will replace diseased tissue, restore function, and cure patients – all while being safe and without causing negative side effects.

Safety will be the key to the future success of stem cell replacement therapies. We’ve learned our lesson from early failed gene therapy experiments where genetically altered stem cells that were supposed to help patients actually caused them to get cancer. Science has since developed methods of gene therapy that appear safe, but new concerns have cropped up around the safety of the methods used to generate pluripotent stem cells, which are considered a potential starting material for cell replacement therapies.

Stem cell reprogramming can cause problems

Induced pluripotent stem cells (iPS cells) cultured in a dish.

Induced pluripotent stem cells (iPS cells) cultured in a dish.

Induced pluripotent stem cells, or iPS cells, are a potential source of pluripotent stem cells for cell therapy. These cells are equivalent to embryonic stem cells but can be generated from adult tissue (such as skin or even blood) by reprogramming cells back to a pluripotent state. During cellular reprogramming, one set of genes is turned off and another set is turned on through a process called epigenetic remodeling. We don’t have time to explain epigenetics in this blog, but to be brief, it involves chromatin remodeling (chromatin is the complex of DNA and protein that make up chromosomes) and is essential for controlling gene expression.

To make healthy iPS cells, the intricate steps involved in cellular reprogramming and epigenetic remodeling have to be coordinated perfectly. Scientists worry that these processes aren’t always perfect and that cancer-causing mutations could be introduced that could cause tumors when transplanted into patients.

A CIRM-funded study published Friday in Nature Communications offers some relief to this potential roadblock to using reprogrammed iPS cells for cell therapy. Scientists from The Scripps Research Institute (TSRI) and the J. Craig Venter Institute (JCVI) collaborated on a study that assessed the safety of three common methods for generating iPS cells. Their findings suggest that these reprogramming methods are relatively safe and unlikely to give cancer-causing mutations to patients.

Comparing three reprogramming methods

In case you didn’t know, iPS cells are typically made by turning on expression of four genes – OCT4, SOX2, KLF4, and c-MYC – that maintain stem cells in a pluripotent state. Scientists can force an adult cell to express these genes by delivering extra copies into the cell. In this study, the scientists conducted a comparative genomic analysis of three commonly used iPS cell reprogramming methods (integrating retroviral vectors, non-integrating Sendai virus, and synthetic mRNAs) to search for potential cancer-causing mutations in the DNA of the iPS cells.

Unlike previous studies that focused on finding a single type of genetic mutation in reprogrammed iPS cells, the group looked at multiple types of genetic mutations – from single nucleotide changes in DNA to large structural variations – by comparing whole-genome sequencing data of the starting parental cells (skin cells) to iPS cells.

They concluded that the three reprogramming methods generally do not cause serious problems and hypothesized that cancer-causing mutations likely happen at a later step after the iPS cells are already made, an issue the team is addressing in ongoing work.

They explained in their publication:

“We detected subtle differences in the numbers of [genetic] variants depending on the method, but rarely found mutations in genes that have any known association with increased cancer risk. We conclude that mutations that have been reported in iPS cell cultures are unlikely to be caused by their reprogramming, but instead are probably due to the well-known selective pressures that occur when hPSCs [human pluripotent stem cells] are expanded in culture.”

The safety of patients comes first

Senior authors on the study, Dr. Jeanne Loring from TSRI and Dr. Nicholas Schork from JCVI, explained in a TSRI News Release that the goal of this study was to make sure that the reprogramming methods used to make iPS cells were safe for patients.

4fb4e-jeanne_loring_headshot_web

Jeanne Loring

“We wanted to know whether reprogramming cells would make the cells prone to mutations,” said Jeanne Loring, “The answer is ‘no.’ The methods we’re using to make pluripotent stem cells are safe.”

 

Nicholas Schork added:

Nicholas Schork

Nicholas Schork

“The safety of patients comes first, and our study is one of the first to address the safety concerns about iPSC-based cell replacement strategies and hopefully will spark further interest.”

 

 

Moving from bench to clinic

It’s good news that reprogramming methods are relatively safe, but the fact that maintaining and expanding iPS cells in culture causes cancerous mutations is still a major issue that scientists need to address.

Jeanne Loring recognizes this important issue and says that the next steps are to use similar genomic analyses to assess the safety of reprogrammed iPS cells before they are used in patients.

“We need to move on to developing these cells for clinical applications,” said Loring. “The quality control we’re recommending is to use genomic methods to thoroughly characterize the cells before you put them into people.”

Stem cell stories that caught our eye: watching tumors grow, faster creation of stem cells, reducing spinal cord damage, mini organs

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.

Video shows tumors growing. A team at the University of Iowa used video to capture breast cancer cells recruiting normal cells to the dark side where they help tumors grow.

Led by David Soll, the team reports that cancer cells secrete a cable that can reach out and actively grab other cells. Once the cable reaches another cell, it pulls it in forming a larger tumor.

 “There’s nothing but tumorigenic cells in the bridge (between cells),” Soll said in a story in SciCasts, “and that’s the discovery. The tumorigenic cells know what they’re doing. They make tumors.”

They published their work in the American Journal of Cancer Research, and in a press release they suggested the results could provide an alternative to the theory that cancer stem cells are the engine of tumor growth.  I would guess that before too long, someone will find a way to merge the two theories into one, more cohesive story of how cancer grows.

 

3-D home creates stem cells quicker. Using a 3-D gel to grow the cells, a Swiss team reprogrammed skin cells into iPS-type stem cells in half the time that it takes in a flat petri dish. Since these induced Pluripotent Stem cells have tremendous value now in research and potentially in the future treating of patients, this major improvement in a process that has been notoriously slow and inefficient is great news.

The senior researcher Matthias Lutoff from Polytechnique Federale explained that the 3-D environment gave the cells a home closer to the environment where they would grow in someone’s body. In an article in Healthline, he described the common method used today:

 “What we currently have available is this two dimensional plastic surface that many, many stem cells really don’t like at all.”

At CIRM our goal is to get this research done as quickly as possible and to find ways to scale up any therapy so that it becomes practical to make it available to all patients who need it. Healthline quoted our CIRM scientist colleague Kevin Whittlesey on how the work would be a boon for stem cells scientists with its ability to shave months off the process of creating iPS cells.

 

Help for recent spinal cord injury.  A team at Case Western Reserve University in Cleveland used the offspring of stem cells that they are calling multi-potent adult progenitor cells (MAPCs) to modulate the immune response after spinal cord injury. They wanted to preserve some of the role of the immune system in clearing debris after an injury but prevent any overly rambunctious activity that would result in additional damage to healthy tissue and scarring.

a6353-spinalcord

They published their work in Scientific Reports and at the web portal MD the senior researcher Jerry Silver described the project as targeting a specific immune cell, the macrophage, in the early days following stroke in mice:

 

 “These were kinder, gentler macrophages. They do the job, but they pick and choose what they consume. The end result is spared tissue.”

The team injected the MAPCs into the mice one day after injury. Those cells were observed to go mostly to the spleen, which is know to be a reservoir for macrophages, and from their the MAPCs seemed to modulate the immune response.

 “There was this remarkable neuroprotection with the friendlier macrophages,” Silver explained. “The spinal cord was just bigger, healthier, with much less tissue damage.”

 

Rundown on all the mini-organs.  Regular readers of The Stem Cellar know researchers have made tremendous strides toward growing replacement organs from stem cells. You also know that with a few exceptions, like bladders and the esophagus, these are not ready for transplant into people.

Live Science web site does a fun rundown of progress with 11 different organs. They hit the more advanced esophagus and cover the early work on the reproductive tract, with items on fallopian tubes, vaginas and the penis. But most of the piece covers the early stage research that results in mini-organs, or as some have dubbed them, organoids. The author includes brain, heart, kidney, lung, stomach and liver. They also throw it the recent full ear grown on a scaffold.

Each short item comes with a photograph, mostly beautiful fluorescent microscopic images of cells forming the complex structures that become rudimentary organs.

3D printed human ear.

3D printed human ear.

Mini-stomachs.

Mini-stomachs.

This past summer we wrote about an article on work at the University of Wisconsin on the many hurdles that have to be leapt to get actual replacement organs. Progress is happening faster that most of us expected, but we still have a quite a way to go.

New drug kicks the cancer stem cell addiction

Did you know that cancer stem cells have an addiction problem? This might sound bizarre, but the science checks out.

Cancer stem cells are found in many different types of cancer tumors. They have the uncanny ability to survive even the most aggressive forms of treatment. After weathering the storm, cancer stem cells are able to divide and repopulate an entire tumor and even take road trips to create tumors in other areas of the body.

How cancer stem cells are able to survive and thrive is a question that is being actively pursued by scientists who aim to develop new strategies that target these cells.

Cancer stem cells have a Wnt addiction

To understand why a cancer stem cell is so good at staying alive and creating new tumors, you need to get down to the protein signaling level, which is basically a cascade of protein interactions that begin at the cell surface and instruct certain activities inside the cell. During embryonic development, one of the signaling pathways that’s activated is the Wnt pathway. It’s responsible for keeping embryonic stem cells in a pluripotent state where they maintain the ability to become any cell type.

As embryonic stem cells mature into adult cells, Wnt signaling plays different roles. It helps stem cells differentiate or change into cells of various tissues and helps maintain the health and integrity of those tissues. Because Wnt signaling has varying functions depending on the developmental stage of the cells, it’s important for cells to properly regulate this pathway.

It turns out that cancer stem cells don’t do this. Typically cells need to receive certain biochemical signals to activate the Wnt pathway, but cancer stem cells acquire genetic mutations and evolve such that this pathway is constantly activated. They ramp up their Wnt signaling and never turn it off. This “Wnt addiction” allows them to stay alive and flourish in a cancerous stem cell state.

Kicking the Wnt Addiction

A team at the Max Delbruck Center (MDC) in Germany decided to kick this Wnt addiction and make cancer stem cells go cold turkey. They published their results in the journal Cancer Research this week.

Their strategy involved targeting proteins called transcription factors, the activators of genes, that are turned on during aberrant Wnt signaling in cancer stem cells. The transcription factor they focused on is called TCF4. In normal cells, biochemical signals are required to activate the Wnt cascade and a protein called beta-catenin, which transmits signals to transcription factors like TCF4 that then turn on genes. In cancer stem cells, this signal isn’t required because the Wnt pathway is permanently switched on leaving TCF4 free to activate genes that promote tumor cell survival and growth.

The researchers thought that if they could break up the partnership between beta-catenin and TCF4, that they might be able to block Wnt signaling and kill the life-line of the cancer stem cells. They screened a library of drugs and identified a small molecule called LF3 that was able to block the interaction between beta-catenin and TCF4.

A new drug kills that cancer stem cells. The image on the left shows beta catenin (red) in cell nuclei indicating that these are cancer stem cells. The image on the right shows that the new substance sucessfully removed beta catenin from the nuclei. Picture by Liang Fang for the MDC

Cancer stem cells express beta-catenin shown in red on the left. On the right, drug treatment blocks Wnt signaling and removes beta-catenin from the cancer stem cells. (Image: Liang Fang for the MDC)

The scientists tested the LF3 molecule in mice with tumors derived from human colon cancer stem cells. Senior author on the study, Walter Birchmeier, explained in an MDC press release:

Walter

Walter Birchmeier

“We observed a strong reduction of tumor growth. What remained of the tumors seemed to be devoid of cancer stem cells – LF3 seemed to be powerfully triggering these cells to differentiate into benign tissue. At the same time, no signaling systems other than Wnt were disturbed. All of these factors make LF3 very promising to further develop as a lead compound, aiming for therapies that target human tumors whose growth and survival depend on Wnt signaling.”

Upon further analysis, they found that LF3 prevented cancer stem cells from dividing into more stem cells and migrating to other tissues. Instead, they differentiated into non-cancerous tissues. Importantly, the drug did not negatively affect the function of healthy cells nearby. This is a logical concern as Wnt signaling is activated in healthy adult tissue, just in a different way than in stem cells.

This study offers a new angle for cancer treatment. Not only does LF3 force cancer stem cells to kick their “Wnt addiction”, it also spares healthy cells and tissues. This drug sounds like a promising option for patients who suffer from aggressive, recurring tumors caused by cancer stem cells.


 

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A New Vaccine Could Make Stem Cell Transplants Safer

Stem cell transplants offer a lot of promise for treating or curing patients who’ve exhausted their therapeutic options. However, there are some potential risks associated with putting stem cells into the human body such as cancer and infection. But scientists and clinicians are working hard to reduce the risk of stem cell therapies by testing them in animals and in early stage clinical trials.

There was good news recently when scientists at the City of Hope reported that they’ve developed a vaccine that could make stem cell transplants safer.

Cytomegalovirus. Image credit (https://scienceforscientists.wordpress.com/tag/cytomegalovirus-cmv/)

Cytomegalovirus. Image credit scienceforscientists

The vaccine helps the immune system fight cytomegalovirus (CMV), which affects 50-80% of adults in the US. CMV typically lies dormant in the human body, but it can be activated in immunocompromised people, pregnant women, and patients receiving stem cell transplants. Once activated, CMV can cause nasty infections and even hepatitis (liver inflammation). There are anti-viral drugs that patients suffering from CMV flare-ups can take, but these drugs are very toxic and can sometimes do more harm than good.

CMVPepVax to the rescue!

In a report published in the Lancet Haematology, the group at City of Hope described a CMV vaccine called CMVPepVax that’s both safe and effective in protecting patients receiving stem cell transplants from CMV flare-ups. They tested the vaccine in a phase 1 clinical trial in 36 patients receiving stem cell treatments for cancer or other diseases. Half of the group received two doses of the vaccine at different time points (28 and 56 days), and the other half didn’t get the vaccine.

After three months, the researchers compared the group that received the vaccine to the control group and saw striking differences. Patients who got CMVPepVax had a boosted immune response against CMV, lower occurrence of CMV flare-ups, and reduced need for anti-viral drugs.

First author on the study, Ryotaro Nakamura, commented:

Ryotaro Nakamura

Ryotaro Nakamura

“Overall, people who received the vaccine had more robust immune recovery than those in the observation group. I was surprised because I didn’t expect to see such a dramatic difference between the two groups in such a small sample study.”

 

But wait, there’s more good news!

Even more exciting was the observation that patients receiving the vaccine were less likely to experience a relapse of their disease (leukemia was given as an example) and had a lower risk of death.

Senior author on the paper Don Diamond explained,

Don Diamond

Don Diamond

“We didn’t anticipate this to happen. Yet we found this striking signal from the data, which told us that those in the vaccine arm of the trial were less likely to relapse of their disease and less likely to develop problems that would lead to non-relapse mortality. In the future, the CMVPepVax vaccine may prove useful not only for patients receiving stem cell transplants, but also for recipients of solid organ transplants or other immunodeficiency diseases.”

Hold your horses

Of course, with any exciting breakthrough such as this, it’s wise to not count your chickens too early. In a City of Hope press release, both Nakamura and Diamond said that these results need to be replicated in a larger phase 2 trial before they can conclude that the vaccine works.

The trial is currently underway. It’s a larger, double-blind study that will compare patients receiving CMVPepVax to a placebo group. It’s the authors’ hope that the results from this trial will support their earlier phase 1 results and also shed light on why the vaccine protects against leukemia relapse.

Diamond concluded:

“We want to get confirmation to see whether lightning strikes twice with these effects. The current phase 2 trial, funded by the National Cancer Institute, will tell us whether the protective effects are really valid. If they are, it would be quite exciting.”

 

The results of this phase 2 trial will be especially important given the recent news about the failure of Chimerix Inc.’s antiviral CMV drug. The company’s stock took a huge hit today after they reported that their oral antiviral CMV drug didn’t reduce infection in stem cell transplant patients in a late-stage study.

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