Published by
Stanford Medicine


Stem Cells

Cancer, Research, Stanford News, Stem Cells, Videos

The latest on stem-cell therapies for leukemia

The latest on stem-cell therapies for leukemia

Leukemia research was the focus of a recent Google Hangout hosted by the California Institute for Regenerative Medicine; included in the conversation were Stanford’s Ravi Majeti, MD, PhD; Catriona Jamieson, MD, PhD, with the University of California San Diego; and Karen Berry, PhD, DVM, a CIRM science officer. In the words of CIRM blogger Kevin McCormack, “Between the three of them they painted an optimistic look at the state of stem cell research into leukemia, the progress we are making, and the obstacles we still have to overcome.”

Majeti, whose works focuses on a potential leukemia treatment using an antibody to a protein called CD47, begins talking around the 10-minute mark.

Previously: Blood cancers shown to arise from mutations that accumulate in stem cells and Leukemia prognosis and cancer stem cells
Related: Cancer roundhouse

Cardiovascular Medicine, Genetics, Research, Stanford News, Stem Cells, Transplants

Stem cell medicine for hearts? Yes, please, says one amazing family

Stem cell medicine for hearts? Yes, please, says one amazing family

SM image of bird and heartRecently, a medical situation with one of my children had me gnawing my fingernails and laying awake at night waiting for scary-sounding test results. Thankfully, my growing anxiety was relieved after several days by a reassuring phone call from our doctor. Unfortunately, the health concerns of the stars of my most recent magazine story - the Bingham family of eastern Oregon – are not so easily dismissed.

Three of the five Bingham children have a heart condition called dilated cardiomyopathy; two of the three (14-year-old Sierra and 10-year-old Lindsey) have already had heart transplants at Lucile Packard Children’s Hospital Stanford. Their parents, Jason and Stacy, were gracious enough to share their family’s story with me for my article in our most recent issue of Stanford Medicine magazine.

Heart transplants are life-saving, but they come with a lifetime of medication and monitoring. Many physicians feel that cardiac medicine is on the cusp of a revolution – one in which the power of stem cells will be harnessed to help hearts heal themselves, or perhaps even to grow new, perfectly matched organs for transplant. The California Institute for Regenerative Medicine has awarded more than $120 million to pursue potential therapies. No matter how fast any advances occur, however, they can’t come soon enough for the Bingham parents, who are now anxiously monitoring 5-year-old Gage’s battle with the same disease that led to his sisters’ transplants.

At the same time, physicians at the Stanford Center for Inherited Cardiovascular Disease are searching to find the (presumably) genetic cause for the Bingham family’s heart problems through gene sequencing while researchers in the laboratory of Stanford cardiologist and director of the Stanford Cardiovascular Institute Joseph Wu, MD, PhD, work to create induced pluripotent stem cells from the family to better understand the molecular basis of their illnesses.

I’ve been thinking a lot about Jason and Stacy this past week while I faced my own fears for my daughter. I cannot comprehend how strong they have to be for their children. And, although I work daily with many amazing doctors and researchers, I have to say that Jason and Stacy (and other parents like them) are my true heroes.

Previously: Mysteries of the heart: Stanford Medicine magazine answers cardiovascular questions, At new Stanford center, revealing dangerous secrets of the heart and Packard Children’s heart transplant family featured tonight on Dateline and
Illustration, which originally appeared in Stanford Medicine, courtesy of Jason Holley

Aging, Stanford News, Stem Cells

Elderly muscle stem cells from mice rejuvenated by Stanford scientists

Elderly muscle stem cells from mice rejuvenated by Stanford scientists

dumbbellsI’ve been pretty good about my gym workouts lately. But I’ve realized that it’s a lot more difficult to build muscle mass now than it was during my 20s. That’s because, as we age, muscle stem cells become less able to repair injury and generate new muscle fibers.

Now a report in Nature Medicine outlines some interesting findings from the laboratory of Stanford microbiologist and immunologist Helen Blau, PhD, suggesting it may be possible to perk up a population of elderly stem cells through a combination of biophysical and biochemical cues.

As I describe in our release:

Blau and her colleagues also identified for the first time a process by which the older muscle stem cell populations can be rejuvenated to function like younger cells. “Our findings identify a defect inherent to old muscle stem cells,” she said. “Most exciting is that we also discovered a way to overcome the defect. As a result, we have a new therapeutic target that could one day be used to help elderly human patients repair muscle damage.”

Blau, who directs Stanford’s Baxter Laboratory for Stem Cell Biology, and postdoctoral scholar Ben Cosgrove, PhD, found that growing muscle stem cells from elderly laboratory mice (a 24-month-old mouse is roughly equivalent to an 80-year-old human, based on average lifespans) in a specialized matrix called hydrogel, coupled with a drug treatment to block an inhibitory pathway, caused the cells to divide rapidly. When implanted into elderly mice with a muscle injury, the cultured cells sprang to work.

“We were able to show that transplantation of the old treated muscle stem cell population repaired the damage and restored strength to injured muscles of old mice,” Cosgrove said. “Two months after transplantation, these muscles exhibited forces equivalent to young, uninjured muscles. This was the most encouraging finding of all.”
The researchers plan to continue their research to learn whether this technique could be used in humans. “If we could isolate the stem cells from an elderly person, expose them in culture to the proper conditions to rejuvenate them and transfer them back into a site of muscle injury, we may be able to use the person’s own cells to aid recovery from trauma or to prevent localized muscle atrophy and weakness due to broken bones,” Blau said. “This really opens a whole new avenue to enhance the repair of specific muscles in the elderly, especially after an injury. Our data pave the way for such a stem cell therapy.”

Previously: Making iPS cells safer for use in human through the study of a cellular odd fellow, New mouse model of muscular dystrophy provides clues to cardiac failure and Mouse model of muscular dystrophy points finger at stem cells
Photo by Positively Fit

otolaryngology, Research, Stanford News, Stem Cells

Understanding hearing loss at the molecular level

Understanding hearing loss at the molecular level

baby earDeep inside the ear, specialized cells that are confusingly called “hair cells” – they have nothing to do those hairs protruding from your Uncle Fred’s ears – detect vibrations in the air and translate them into sound. Without them, you can’t hear. Unlike non-mammalian species, in humans, there are a limited number of these cells, and if enough of them get damaged or killed off, hearing loss occurs.

Hair cells are the key to understanding the process of hearing. By figuring out how these cells work at a molecular level, scientists believe they can eventually develop better treatments and possible cures for deafness. Key to this goal is figuring out how to regenerate these cells if they get damaged or die off.

A new Stanford study published in the journal Development takes one more step along this pathway by showing that these early hair cells can be grown back in newborn mice.

“The study builds on the hypothesis that younger cochlea – that portion of the inner ear where the hair cells are located – can regenerate,” said Alan Cheng, MD, one of the senior authors of the study, which was done in collaboration with St. Jude Children’s Research Hospital.

“No spontaneous auditory hair cell regeneration has been observed in postnatal mammals prior to this study,” Cheng, an assistant professor of otolaryngology and pediatrics, told me. “Extensive efforts from laboratories around the world have focused on understanding mechanisms that can drive mammalian hair cell regeneration.”

In their study, the scientists induced hair cell loss in their mouse models at birth and then observed there was “spontaneous regeneration of hair cells.” One week after birth, there was no much regeneration.

The research also showed, interestingly, that most of these regenerated hair cells in the young cochlea didn’t ultimately survive. “This lack of survival posits a new challenge to regenerating hearing,” Cheng said.

Previously: Battling hearing loss on and off the battlefield, Stanford researchers gain new insights into how auditory neurons develop in animal study, Stanford hearing study upends 30-year-old belief on how humans perceive sound and Stanford chair of otolaryngology discusses future regenerative therapies for hearing loss
Photo by boltron-

Cancer, Stanford News, Stem Cells

Stanford among the beneficiaries of major gift from Ludwig Cancer Research

Stanford among the beneficiaries of major gift from Ludwig Cancer Research

Daniel K. Ludwig was a reclusive, self-made billionaire and a friend of President Richard Nixon who took the president’s “War on Cancer” to heart. In his will, Ludwig left his entire fortune to cancer research. Now, the New York-based Ludwig Cancer Research is announcing one of the largest gifts ever made to cancer by an individual donor: $540 million to be shared by six leading cancer centers nationwide.

The beneficiaries include the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, which will receive $90 million to spur its innovative work on cancer stem cells, which are believed to drive the growth of many cancers. The center, founded in 2006, has received $150 million from Ludwig Cancer Research to date.

Irving Weissman, MD, the center’s director, said Ludwig was willing to invest in cancer stem cells at a time when there was great controversy in the medical community about the role of these cells – and whether they existed at all.

“The Ludwig was absolutely critical to taking this very high-risk research into a real and rapid understanding of cancer cells,” said Weissman, the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research at Stanford. As a result of the Ludwig support, he said, “We have taken many of our understandings of cancer stem cells into potential therapeutics.”

Weissman and his colleagues at the Ludwig center have discovered that virtually all human cancers express a protein known as CD47, which functions as a “don’t-eat-me-signal” to fend off potential attacks from the immune system. They have developed an antibody against CD47 which has been shown to attack a wide range of solid tumors. The scientists plan to begin a clinical trial in early 2014. They also plan to test it in combination with other antibodies to see if there is a synergy that will make it even more effective, Weissman said.

With Ludwig support, Weissman is also moving forward with clinical trials with a therapy that could dramatically improve survival rates for women with metastatic breast cancer. The innovative approach was tested more than 15 years ago in a small group of women, 33 percent of whom are still alive and well. With the standard treatment, the survival rate after 15 years is just 7 percent, Weissman said. The trial was discontinued by the sponsoring company but with Ludwig support, Weissman and his colleague, Judith Shizuru, MD, an associate professor of medicine, have obtained the rights to the process and plan a larger trial in 2014. “We need urgently to take this forward,” he said.

Previously: Single antibody shrinks or eliminates human tumors in mice at Stanford and Cancer stem cell researchers are feeling the need for speed
Photo of Irving Weissman in featured entry box by Flynn Larsen

Cardiovascular Medicine, Research, Stanford News, Stem Cells

Stanford cardiologist joins CIRM Google+ Hangout today

Stanford cardiologist joins CIRM Google+ Hangout today

Have lunch plans yet? Join a California Institute for Regenerative Medicine Google+ Hangout discussing the latest developments in stem cell therapies for heart disease. Stanford cardiologist Joseph Wu, MD, a CIRM grantee, joins CIRM science officer Cathy Priest, and stem cell clinical trial participant Fred Lesikar in conversation.

The hangout happens from noon ’til 1 PM Pacific time today. Use the hashtag #AskCIRM_Heart to ask questions on Twitter.

Previously: Shushing T cells promotes acceptance of stem cell therapies, say Stanford researchers“Clinical trial in a dish” may make common medicines safer, say Stanford scientistsSudden cardiac death has cellular cause, say Stanford researchers and Overcoming immune response to stem cells essential for therapies, say Stanford researchers

Applied Biotechnology, Bioengineering, Immunology, Research, Stanford News, Stem Cells

Alchemy: From liposuction fluid to new liver cells

Alchemy: From liposuction fluid to new liver cells

alchemyHow’s this for modern-day medical alchemy: A team led by Stanford’s Gary Peltz, MD, PhD, has found a fast, cheap, efficient way for regenerating liver tissue from a patient’s own fat cells. Let it be immediately said that the “patients” in this endeavor (described in a just-published study in Cell Transplantation) were mice. But the fat cells that Peltz’s team used as starter materials and the liver tissue that grew inside the mice (replacing their own organs, which had experienced severe poisoning not unlike that caused by a Tylenol overdose) were completely human.

The liver – the body’s chemistry set – builds complex biomolecules we need and filters and breaks down waste products and toxic substances we need to get rid of. Unlike most organs, a healthy liver can regenerate itself to a significant extent. But this ability is no match for acute liver poisoning or damage from chronic alcoholism or viral hepatitis. Acute liver failure from acetaminophen (Tylenol) alone takes a toll of about 500 lives every year and accounts for upwards of 60,000 emergency-room visits annually.

That begets an ongoing, life-threatening liver shortage. From my release on the study:

Some 6,300 liver transplants are performed annually in the United States, with another 16,000 patients on the waiting list. Every year, more than 1,400 people die before a suitable liver can be found for them. While it can save lives, liver transplantation is complicated, risky and, even when successful, fraught with aftereffects. Typically, the recipient is consigned to a lifetime of taking immunosuppressant drugs to prevent organ rejection.

Making new livers out of a patient’s own readily retrieved fat tissue could help plug the gap between the number of available donor livers for transplantation and the number of people in dire need of that procedure. It might also go a long way to alleviating the requirement for lifelong immunosuppressant therapy afterward.

Peltz’s team obtained adipose stem cells, which ordinarily grow up to be fat cells, from fat-filled fluid removed during routine liposuction procedures. The team then put these cells through a series of biochemical hoops that caused them to change their minds and decide to be liver cells instead.

That’s not easy. (“We had to work hard to convert them to liver cells,” Peltz told me.) But it’s been done before. The problem was that previous fat-to-liver methods took longer than a patient with acute liver failure can survive, and were inefficient and expensive to boot. Using a new technique, Peltz’s group was able to get enough good liver cells for the next regenerative step – injecting the cells into mice’s liver cavities – within seven or eight days. A month later the mice exhibited healthy human liver formation and activity. Importantly, inspection at two months out showed no signs of tumor formation, which is a big obstacle to the alternative use of human embryonic stem cells or induced pluripotent stem cells for this purpose.

Peltz hopes to see the new technology enter clinical trials within a couple of years.

Previously: Fortune teller: Mice with ‘humanized’ livers predict HCV drug candidate’s behavior in humans, Free database of drugs associated with liver injury available from NIH and Hepatitis C virus’s Achilles heel
Photo by Abode of Chaos

Research, Science, Stanford News, Stem Cells

Researchers celebrate 25th anniversary of major stem cell discovery

Researchers celebrate 25th anniversary of major stem cell discovery

A new era of stem cell science began 25 years ago. At that time, Stanford researcher Irving Weissman, MD, and his colleagues announced in Science that they had purified hematopoietic stem cells from a mouse. This was the first “adult” (tissue specific) stem cell isolated in purified form from any species. In order to isolate the stem cells, the researchers had to identify the key cell-surface proteins that differentiated the stem cells from closely related cells and separate them from each other. They also had to develop new transplant models to show that the stem cells could produce every single type of blood an immune cell needed by the body.

Since then, researchers at Stanford and elsewhere have learned to identify and purify blood stem cells and other types of stem cells in humans, opening the door to creating stem cell therapies that researchers hope will be able to cure many intractable diseases. Today, we’re honoring this achievement as part of the observation of World Stem Cell Awareness Day.

Previously: Very small embryonic like stem cells may not exist, say Stanford researchers, Stanford’s Irving Weissman on the (lost?) promise of stem cells and Stanford study shows stem cell treatment improves survival of patients with metastatic breast cancer

Aging, Cancer, Neuroscience, Research, Science, Stanford News, Stem Cells

Down syndrome due to faulty stem cell regulation?

Down syndrome due to faulty stem cell regulation?

neuronsDown syndrome as a stem cell disease? It sounds like an unlikely mash-up of two hot-button research topics. But a study from the laboratory of cancer stem cell biologist Michael Clarke, MD, published today in Nature suggests that some of the learning and memory problems suffered by people with Down syndrome could be due in part to defective regulation of nerve stem cells. Furthermore, one gene could be the primary culprit. As described in our press release:

The finding marks the first time Down syndrome has been linked to stem cells, and addresses some long-standing mysteries about the disorder. Although the gene, called Usp16, is unlikely to be the only contributor to the disease, the finding raises the possibility of an eventual therapy based on reducing its expression.

Most people know that people with Down syndrome have three, rather than the normal two, copies of chromosome 21. It’s not clear, however, which of the hundreds of excess genes are involved in the learning disabilities and unique craniofacial structure that are the hallmarks of the condition.

Now Clarke and postdoctoral scholar Maddalena Adorno, PhD, have shown that nerve stem cells from mice and people with Down syndrome are less able to grow and renew themselves than their unaffected peers. Furthermore, lowering the expression of Usp16 to more normal levels restores the ability of the cells to grow normally. As Clarke, who is also the associate director of Stanford’s stem cell institute, described in the release, “There appear to be defects in the stem cells in all the tissues that we tested, including the brain. We believe Usp16 overexpression is a major contributor to the neurological deficits seen in Down syndrome.”

The new study’s findings suggest answers to many long-standing mysteries about the condition, including why people with Down syndrome appear to age faster and exhibit early Alzheimer’s disease. More from the release:

“This study is the first to provide a possible explanation for these tendencies,” said [Craig Garner, PhD, the co-director of Stanford’s Center for Research and Treatment of Down Syndrome and study co-author]. The fact that people with Down syndrome have three copies of chromosome 21 and the Usp16 gene “accelerates the rate at which stem cells are used during early development, which likely exhausts stem cell pools and impairs tissue regeneration in adults with Down syndrome. As a result, their brains age faster and are susceptible to early onset neurodegenerative disorders.”

There’s still lots to be learned about whether and how this finding could be applied to people with Down syndrome:

“We are really interested in learning how other genes in this chromosomal region may be affecting stem cell renewal,” said Clarke. “We also want to understand how much we’re able to rescue the neurological defect by normalizing the expression of Usp16 in this mouse model. How does this compare to what is happening in humans? We’re sure it plays some significant role.”

Previously: Progress on drug treatments for cognitive aspects of Down syndrome, Moving toward a Down syndrome drug and More on the debate over “curing” Down syndrome
Photo of neurons provided by the California Institute for Regenerative Medicine, taken in the lab of Xianmin Zeng, PhD, at the Buck Institute for Age Research

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

Blau banner

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

Stanford Medicine Resources: