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Cancer, Research, Science, Stanford News, Stem Cells

Making iPS cells safer for use in humans through the study of a cellular odd fellow

Making iPS cells safer for use in humans through the study of a cellular odd fellow

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Induced pluripotent stem cells, or iPS cells, are a hot commodity right now in biology. The cells, which are created when non-stem cells are reprogrammed to resemble embryonic stem cells, have many potential uses in therapy and drug development. They’re usually created by using a virus to add just four genes (identified because they are highly expressed in embryonic stem cells) to the cell to be reprogrammed.

However, the molecular minutiae of the transformation are not well understood, and the expression of one of the  genes, called c-Myc, is frequently elevated in human cancers. This has given researchers and clinicians pause when considering the use of iPS cells in humans.

Now researchers in the laboratory of Helen Blau, PhD, Stanford’s Donald E. and Delia B. Baxter Professor, have found that fusing a mouse embryonic stem cell with a human skin cell, or fibroblast, to create two-nuclei, bi-species mongrel called a heterokaryon is an excellent way to study the earliest steps of reprogramming. That’s because factors in the developmentally flexible stem cell nucleus reprogram the more-staid skin cell nucleus — quickly and efficiently — giving researchers a ring-side seat to the intricate transformation.

In contrast, only about one in every one thousand would-be iPS cells ever complete their transformation to pluripotency: a pretty boring, uninformative show if you pick the wrong cell to follow. As Blau explained in an e-mail:

Studying these heterokaryons gives us a molecular snapshot of pluripotency that would otherwise have been missed and allows us to capture reprogramming in action. For the first time we’re able to identify critically important transient regulators that would be totally missed by current methods of study.

Blau is the senior author of the research, which was published Sunday in Nature Cell Biology (subscription required). Postdoctoral scholar Jennifer Brady, PhD, is the lead author.

As Blau predicted, the study of the heterokaryons paid off. The researchers found that a signaling molecule called IL-6 is highly expressed in the human fibroblast nucleus during the first few hours of reprogramming in the fused cells. They were then able to show that temporary exposure to IL-6 during the creation of iPS cells can replace c-Myc.

The hope is that the findings will lead to iPS cells that will be safer to use in human therapies. But there’s still much to be learned from the heterokaryon model, said Blau:

This method provides insights into the logic and timing of the reprogramming process that would not be possible by any other means. Really understanding this process is vital to getting better and more efficient reprogramming to make iPS cells.

Previously: Nobel Prize-netting iPS-cell discovery was initially a tough sell (for me, anyway), Making induced pluripotent stem cells a loopy process, say Stanford/VA researchers and Nature summarizes iPS challenges

Medical Education, Science, Stanford News, Stem Cells

The “transformative experience” of working in a Stanford stem-cell lab

The "transformative experience" of working in a Stanford stem-cell lab

Jeffrey Yu - smallThis summer we’ve been sharing the experiences of high-school students in the Stanford Institutes of Medicine Summer Research Program. Yesterday, the California Institute for Regenerative Medicine, which helps fund the program, published on its blog the thoughts of Jeffrey Lu, who has been working in the lab of Michael Clarke, MD. Lu writes of his foray into the world of stem cells:

Coming into this internship, my idea of science was rote memorization and doing “experiments”, which were always pre-made and no different from following an instruction manual. I had an even shallower knowledge of stem cells. Apart from a vague understanding of the controversial embryonic stem cells and it’s regenerative potential, I knew close to nothing. Little did I know… that I was in for a transformative experience.

Expecting to pipette clear liquids into tubes monotonously for eight hours a day, I did just that. That is, until I realized why I was doing the things I did, [and] it all started to make sense. From reading lengthy papers that made my brain hurt, to filling 92 wells in one sitting, this combination of high speed learning and AP biology lab on steroids gave me a heaping plate of what science truly was. I came to realized the methods, purpose, and direction behind every experiment done, the trial and error, the expected and actual outcomes. It was a revelation. Before this experience, science had been nothing but memorizing plant physiology and biological processes. Science to me now… is a persistent yet methodical and intelligently constructed game plan to answering questions about the natural world around us, and this self-discovery was worth the entire experience.

Previously: Image of the Week: CIRM intern Brian Woo’s summer project, Image of the Week: CIRM intern Christina Bui’s summer project, A look at one high-school student’s summer internship experience at Stanford, I know what you did this summer: High-school interns share their experiences at Stanford, Stanford’s med school training programs in full swing and Stanford summer research intern named finalist in national science competition
Photo from the #CIRMStemCellLab Instagram

Cardiovascular Medicine, Immunology, Research, Stanford News, Stem Cells

Shushing T cells promotes acceptance of stem cell therapies, say Stanford researchers

Shushing T cells promotes acceptance of stem cell therapies, say Stanford researchers

Embryonic stem cells are full of promise. But they’re also peppered with red flags for the body’s immune system, which recognizes them as foreign tissue and tries to destroy them. Unless the body can be coaxed to accept the cells it will be difficult to use them as therapy.

Now Stanford cardiologist Joseph Wu, MD, PhD, along with medical student Julia Ransohoff and postdoctoral scholar Bruno Huber, PhD, have outlined a novel new therapy to block the body’s attack on the cells. The research was recently published (subscription required) in Stem Cells.

As Wu, director of the Stanford Cardiovascular Institute, explained to me in an e-mail:

Regenerative therapies hold great clinical promise, particularly for patients with damaged hearts and end-stage heart failure. But, surprisingly, promoting long-term stem cell graft acceptance is a much more formidable task than is supporting host acceptance of a vascularized solid organ such as a heart.

The researchers found that a course of treatment with two antibodies that block a pathway necessary for optimal T cell activation helps a laboratory mouse accept transplanted human stem cells. This new, dual-agent approach was more effective than a combination of prednisone and cyclosporin A - two more-broadly acting drugs that are currently used to suppress the immune systems of patients who have received organ transplants. Promoting the acceptance and engraftment of the human stem cells in a mouse model of myocardial infarction, or heart attack, also improved the animals’ heart function, the researchers found.

But there’s another important potential advantage. As Ransohoff explains:

In marked contrast to the life-long immunosuppressive regimens that transplant patients face, which leave them immunocompromised and susceptible to infection, our regimen is not only significantly more effective, but also requires only minimal dosage limited to the first week following transplantation.

Superior acceptance of stem cells with a single, short-course of treatment? Yes, please. There’s still much work to be done to determine whether this approach would work in human patients. But it’s tantalizing to imagine we’re marching ever closer to a future in which therapies derived from human embryonic stem cells are routinely used to help people with heart problems.

Previously: Overcoming immune response to stem cells essential for therapies, say Stanford researchers and New technique prevents immune-system rejection of embryonic stem cells

Stem Cells, Technology

3D printer in China makes tiny ears

On the heels of the world’s smallest Mona Lisa, created by scientists at Georgia Tech using a novel nanotechnique, a 3D printer of living tissue that replicates body parts could disrupt another of art history’s greats this week. New Scientist reports:

It’s way too late for Vincent van Gogh, but cutting off your ear is a much less impressive gesture now you can get a new one printed.

Scientists from China’s Hangzhou Dianzi University made little ears from their Regenovo 3D printer, according to the post, following other news of ear-, liver-, and human embryonic stem cell-printing strides across the globe.

Previously: Creating organ models using 3D printing“Grow your own” organs and other life-changing innovations and 3D printer uses living cells to produce a human kidney

Cancer, Health Disparities, In the News, Stem Cells, Transplants

Closing the racial gap for life-saving transplants

Closing the racial gap for life-saving transplants

The already-tricky process of finding a match for a stem cell or bone marrow transplant proves more elusive for people with a diverse heritage. A Washington Post article today puts the numbers in perspective: “When all of humankind’s relevant genes are considered, there are 10 billion possible combinations.”

With a focus on the genetic, cultural and religious issues surrounding transplantation, the piece spotlights two Stanford affiliates who have struggled to find life-saving donors. A match for psychology professor Nalini Ambady, PhD, was recently discovered after a difficult search. Meanwhile, Nina Louie, a former Stanford undergraduate of Chinese and Thai descent, still needs a bone marrow and peripheral blood stem cell transplant to treat her advanced lymphoma.

Read more from the Post about Louie’s friends’ campaign to save her life in the face of 1-in-20,000 odds of success, and how they and organizations such as Be The Match raise awareness about the importance of registering to donate, especially among people of minority-group backgrounds.

Previously: Study highlights social media’s potential as a public-health tool, Stanford faculty and students launch social media campaign to expand bone marrow donor registry and Valuing bone marrow

Aging, Genetics, Neuroscience, Research, Stanford News, Stem Cells

Longevity gene tied to nerve stem cell regeneration, say Stanford researchers

Longevity gene tied to nerve stem cell regeneration, say Stanford researchers

Geneticist Anne Brunet, PhD, thinks a lot about aging. Much of her research focuses on understanding why some people and animals live much longer than their peers. She’s characterized some proteins, including one called FOXO3, that play a role in this process. Today, in a study published in Cell Reports, she and her colleagues outline one of the ways that FOXO3 accomplishes this feat. As Brunet, who recently received a NIH Director’s Pioneer Award to conduct her longevity research, explained to me in an e-mail:

This work is exciting because it reveals for the first time how the pro-longevity factor FOXO3 works in stem cells from the adult brain. FOXO3 belongs to a family of genes that promotes longevity from worms to humans. In fact, humans with variation in the FOXO3 genes have increased chances of becoming centenarians. But how FOXO3 extends lifespan had remained elusive.

Brunet and the study’s lead author, postdoctoral scholar Ashley Webb, PhD, were interested in a previous finding from Brunet’s lab – the ability of FOXO3 to maintain neural stem cells in the adult brain. These cells give rise to neurons that contribute to learning and memory. Preserving these cells, Brunet explains, is likely critical to maintain cognitive function during aging. But until now it wasn’t known exactly how FOXO3 regulated this process.

Webb discovered that FOXO3, which is a transcription factor that binds to DNA and regulates gene expression, latches on to the control regions of genes that are also bound by a protein called ASCL1. According to Brunet:

This was really exciting to us, because ASCL1 has been widely studied, in particular by Marius Wernig, MD, at Stanford, for its ability to convert or ‘reprogram’ cells into neurons. Ashley found that FOXO3 could inhibit the ability of ASCL1 to promote the expression of pro-neuronal genes and the formation of new neurons. This could explain how FOXO3 maintains the pool of adult neural stem cells: by preventing them from undergoing premature differentiation into neurons and by keeping them as “stem cells”.

The researchers are now homing in on the signals that control FOXO3′s activities, and trying to understand how these signals may be affected by aging or age-related brain diseases like Alzheimer’s.

Previously: Brain, health thyself? Stanford research describes delayed onset of multiple sclerosis in mice and NIH awards nine faculty funding for innovative research

Stanford News, Stem Cells

State stem cell agency installs Dean Lloyd Minor, honors Philip Pizzo

State stem cell agency installs Dean Lloyd Minor, honors Philip Pizzo

Pizzo_CIRMThe California Institute for Regenerative Medicine yesterday installed Lloyd Minor, MD, dean of Stanford’s School of Medicine, as a member of its governing board. The agency also honored former Stanford medical school dean Philip Pizzo, MD, for his years of service on the same board. Pizzo joined the board in 2004 as its first member and served until 2012.  

According to a press release from the agency:

Jonathan Thomas, PhD, JD, Chairman of the ICOC, praised Dr. Pizzo, saying: “Phil has left an indelible mark on CIRM and has been an invaluable force for advancing stem cell science in California. We shall miss him but wish him well in his future endeavors.”

After listening to several Board members praise his wisdom, intellect and leadership, Dr. Pizzo responded with characteristic humility and humor saying: “I am deeply humbled to be here and feel I’m almost at the point of listening to an obituary. But this has been very meaningful  and the honor has been mine to serve with you. I thank you for everything and know that this will continue to bring to the citizens of California the true benefits of the research and the science we have funded.”

Previously: A closer look at Stanford medical school’s new dean and A farewell to Dean Philip Pizzo
Photo by Christopher Vaughan

Clinical Trials, Medicine and Society, Research, Science Policy, Stanford News, Stem Cells

Very small embryonic like stem cells may not exist, say Stanford researchers

Very small embryonic like stem cells may not exist, say Stanford researchers

There’s a shake-up happening today in the world of stem cell research. Very small embryonic-like stem cells, or VSEL cells, have been proposed by some researchers as an alternative to human embryonic stem cells. Because they’re said to exist in the bone marrow of adult humans and mice, they could obviate the ethical issues surrounding the use of human embryos.

The research has sounded promising enough that a New York-based company, NeoStem, was awarded a grant from the National Institute of Dental and Craniofacial Research to investigate the use of the cells to stimulate bone growth after tooth extraction.

But in a study published today in Stem Cell Reports, Stanford stem cell scientist Irving Weissman, MD, casts doubt on the existence of the cells. From our release:

“It has become important to know to what extent and where these VSEL cells exist to understand how they may affect the field of stem cell research,” said Weissman, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. “We tried as hard as we could to replicate the original published results using the methods described and were unable to detect these cells in either the bone marrow or the blood of laboratory mice.”

Although other groups have seemingly confirmed the existence of these cells as defined by size and the expression of key cell-surface molecules, Weissman’s study is the first to evaluate the biological potency of the cells.

An article in today’s Nature magazine summarizes the controversy surrounding the cells, and calls Weissman’s study a “major blow to the field.” Alison Abbott writes:

Led by Irving Weissman, a prominent stem-cell researcher at Stanford University in California, the study is the fourth to refute the cells’ existence — and the most thorough yet.

“Weissman’s evidence is a clincher — it is the end of the road for VSELs,” believes Rüdiger Alt, head of research at Vita 34, a private bank for umbilical cord blood in Leipzig, Germany, who last year published the first failure to replicate claims for the cells2.

Robin Smith, chief executive at Neostem, disagrees. She compares the attacks on VSELs to those suffered by Charles Darwin and Nicolaus Copernicus when they proposed their world-changing scientific theories.

It will likely take some time for the controversy to end. In the meantime, Weissman and his colleagues have concluded that “the existence of adult mouse VSELs in the bone marrow remains dubious.”

Previously: Stanford’s Irving Weissman on the (lost?) promise of stem cells

Image of the Week, Stem Cells

Image of the Week: CIRM intern Christina Bui’s summer project

Image of the Week: CIRM intern Christina Bui's summer project

CIRM_Stanford_Christina_Bui

For high-school senior Christina Bui, summer is more than a welcome reprieve - it’s time to pursue her passion for science. Bui, a student Piedmont Hills High School in San Jose, explained that her high-school science courses sparked her interest in the field of biological sciences.

She applied to the Stanford Institutes of Medicine Summer Research Program (SIMR) because she wanted to learn more about a specific area of science in more detail. SIMR is an eight-week summer program that helps high-schoolers get an early start in university-caliber research by pairing them with mentors in Stanford’s School of Medicine.

When I asked Bui which area of science interested her most, she laughed. “All of the topics were interesting; I couldn’t choose between them,” she said. But she admits that stem cell research was her first choice. So, the SIMR program placed Bui in the stem cell institute with Stanford mentor Nathan DeCarolis, PhD, a postdoctoral student in the lab of Theo Palmer, PhD. She is working under the SIMR program, with an additional grant from the California Institute for Regenerative Medicine (CIRM), an organization that provides grants for stem cell research.

Bui is studying neural stem cell behavior. “There’s something special about the environment of the stem cell,” said Bui. The surroundings of stem cells influence what the stem cells develop into, she explained.

The image shown here is a photo of the first gel electrophoresis test – a process that uses an electric current to sort fragments of negatively-charged DNA based on their size.

Bui will present the findings of her summer SIMR project at a poster presentation at Stanford on August 8, and as a part of the CIRM grant, she will present at the University of California, San Francisco on August 12.

Holly MacCormick is a writing intern in the medical school’s Office of Communication & Public Affairs. She is a graduate student in ecology and evolutionary biology at University of California-Santa Cruz.

Previously: A look at one high-school student’s summer internship experience at StanfordVitamins may help stem cells in the brain survive inflammatory damage and Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they’re making new knees.
Photo from Christina Bui

Aging, Orthopedics, Stanford News, Stem Cells, Surgery

Stanford study shows protein bath may rev up sluggish bone-forming cells

Stanford study shows protein bath may rev up sluggish bone-forming cells

Fractures that are complex, pose a significant health risk, or don’t heal properly are repaired using bone grafts. The surgical process involves transplanting whole marrow, which is rich in stem cells that form bone, blood and the cells of the immune system, into a fracture site.

Although it’s preferable to use a patient’s own tissue to avoid rejection, elderly patients (whose older marrow forms bone less robustly), often require the use of donor bone marrow from younger people or the use of drugs to stimulate bone growth.

Now researchers at Stanford have identified a simple way to stimulate old marrow to form bone, which could allow the use a patient’s own cells without medications. My colleague explains the findings in a release:

In studies involving mice and rabbits, the researchers found that a quick dip in a bath of a signaling protein called Wnt3a can rev up sluggish bone-forming cells in older animals that would normally be unable to heal a fracture. If the simple treatment is eventually found to be effective in humans, it may significantly improve the success of bone grafts, which are performed more than 500,000 times every year in the United States.

“We’re very focused on designing a treatment that could be easily employed by orthopaedic surgeons in the normal course of bone grafting,” said professor of surgery Jill Helms, DDS, PhD. “We’ve shown that when we temporarily treat bone marrow from aged animals with Wnt before transplanting the cells into a fracture site, we see really robust bone formation.”

“Hip fractures in elderly people nearly triple the risk of dying within a year of the injury, and a rapidly aging population demands more effective treatments for this type of trauma,” said Helms.

Previously: Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they’re making new knees and Biomarker can predict graft-versus-host disease in men after transplants from women donors

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