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Cancer, Research, Science, Stanford News, Stem Cells

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Radiation therapy may attract circulating cancer cells, according to new Stanford study

Localized radiation therapy for breast cancer kills cancer cells at the tumor site. But, in a cruel irony, Stanford radiation oncologist Edward Graves, PhD, and research associate Marta Vilalta, PhD, have found that the dying cells in the breast may send out a signal that recruits other cancer cells back to the site of the initial tumor. Their work was published today in Cell Reports. As Graves explained in an e-mail to me:

Cancer spreads by shedding tumor cells into the circulation, where they can travel to distant organs and form secondary lesions.  We’ve demonstrated with this study that cancer radiation therapy may actually attract these circulating tumor cells, or CTCs, back to the primary tumor, which may lead to the regrowth of the tumor after radiation therapy.

The researchers studied mouse and human breast cancer cells growing in a laboratory dish, as well as human breast cancer cells implanted into mice. They found that irradiated cells secreted a molecule called granulocyte macrophage colony stimulating factor, or GM-CSF. Blocking the expression of GM-CSF by the cells inhibited (but didn’t completely block) their ability to recruit other cells to the cancer site. The finding is particularly interesting, since physicians sometimes give cancer patients injections of GM-CSF to enhance the growth of infection-fighting white blood cells that can be damaged during chemotherapy. As Graves explained, “This work has important implications for clinical radiotherapy, and for the use of GM-CSF in treating neutropenia in cancer patients during therapy.”

The researchers say, however, that cancer patients shouldn’t eschew radiation therapy. Rather, the finding may help clinicians devise better ways to fight the disease – perhaps by blocking GM-CSF signaling. Graves concluded:

It should be emphasized that radiation therapy remains one of the most effective treatments for cancer. Our findings will help us to further optimize patient outcomes following this already potent therapy.

Previously: Using 3-D technology to screen for breast cancer, Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers and Common drug class targets breast cancer stem cells, may benefit more patients, says study

Cancer, FDA, Genetics, Research, Science, Stanford News

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers

6825694281_dfb79615d6_zIf you’re a regular reader of this blog, or follow cancer literature, you’ll have heard of a signaling pathway called Hedgehog that is activated in many cancers, including brain, skin and even bladder. It’s a cute name for cellular cascade that can kill when inappropriately activated.

Neurologist Yoon-Jae Cho, MD, treats children with brain tumors called medulloblastomas. He and postdoctoral fellow in his lab, Yujie Tang, PhD, published a study yesterday in Nature Medicine that could one day help some patients whose Hedgehog-driven tumors have become resistant to available therapies.

As Cho explained in an e-mail to me:

Medulloblastomas are the most common malignant brain tumors in children. They are comprised of various subgroups, including one with activation of a strong oncogenic signal called the Hedgehog pathway. Notably, the Hedgehog pathway is also activated in several other cancers including basal cell carcinoma, the most common cancer worldwide. Therefore, pharmaceutical companies and several research groups have developed drugs to target this pathway.

The most common of these drugs targets a downstream protein component of the pathway called Smoothened, including one currently marketed by Genentechcalled vismodegib (trade name Erivedge) and an investigational drug produced by Novartis called LDE225. Blocking the activity of Smoothened stops the chain reaction leading to division of the cancer cells. You can think of it (in simplified terms) as a line of dominoes standing on end, waiting for an eager finger to begin the chain reaction. Removing one domino (nixing Smoothened activity) can sometimes stop the rest of the row from falling and block the cancerous cell from dividing. But, as Cho explained:

Unfortunately, many cancers activate the Hedgehog pathway downstream of Smoothened and are inherently resistant to these therapies. Other cancers that are initially responsive to these drugs develop resistance through activation of downstream Hedgehog pathway components.

Cho and his colleagues have now described a new, novel way to interfere with the Hedgehog pathway. They’ve found that compounds that inhibit a protein called BRD4 can stop the growth of human Hedgehog-driven cancers – even when they’re resistant to drugs blocking Smoothened activity. This is particularly interesting because the BRD family of proteins recognizes and binds to particular chemical tags on chromatin that control whether (and when) a gene is made into a protein. It’s the first time such an epigenetic regulator has been implicated as a target in the Hedgehog pathway. Additionally, it’s a new avenue to explore for patients with Hedgehog-driven medulloblastomas – as many as half of whom will be resistant to Smoothened inhibition, according to a previous study co-authored by Cho and members of the International Cancer Genome Consortium’s Pediatric Brain Tumor Project. Cho concludes, “Our study offers a promising new treatment strategy for patients with Hedgehog-driven cancers that are resistant to the currently used Smoothened antagonists.”

Previously: New skin cancer target identified by Stanford researchers, Humble anti-fungal pill appears to have noble side-effect: treating skin cancer and Studies show new drug may treat and prevent basal cell carcinoma
Photo by Phillip Taylor

Cardiovascular Medicine, Genetics, Patient Care, Pediatrics, Research, Stanford News

When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn

When ten days = a lifetime: Rapid whole-genome sequencing helps critically ill newborn

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It’s an ‘edge-of-your-seat’ story: The newborn’s heart had stopped multiple times in the hours since her birth. Her doctors at Lucile Packard Children’s Hospital Stanford had tried everything to help her, but her situation was dire.

The baby had an unusually severe form of an inherited cardiac condition called long QT syndrome. The syndrome, which is most often diagnosed in older children or adults, can be caused by a mutation in any of several genes; until the doctors knew exactly which genetic mutation was causing the condition they wouldn’t know what drug would be most likely to help. The stakes were high: by her second day of life she’d received an implantable defibrillator and several intravenous drug infusions.

As cardiologist Euan Ashley, MD, PhD, explained to me:

The team literally tried everything we could think of to help this child, including trying every drug that could possibly make a difference. It was a heroic effort by a very diverse group of professionals.

The clinicians and researchers, including pediatric cardiologist Scott Ceresnak, MD, who managed the baby’s clinical care, realized it was critically important to identify the baby’s disease-causing mutation to learn which drug would be best for her. To do so, they dropped everything else they were doing and sequenced her entire genome to pinpoint the culprit within just ten days – an unprecedented feat. Ashley, who directs Stanford’s new Clinical Genomics Service as well as its  Center for Inherited Cardiovascular Disease, and pediatric cardiology fellow James Priest, MD, recently published the case study in the journal Heart Rhythm.

This is the future of genetic testing and we hope, the future of medicine.

Using customized commercial software and tools developed at Stanford, the researchers were able to zero in on a mutation in a gene called KCNH2 known to be associated with long QT. They also found another, novel mutation in a gene involved in determining the structure of the heart during development.

As Priest explained in an e-mail to me:

Whether it is a CT scan, x-ray, or genetic test, we work hard to make a diagnosis as quickly as possible when there is a critically-ill baby under our care. Whole genome sequencing returned this diagnosis in days instead of weeks. We were able to turn the raw sequence data into a diagnosis in about 12 hours.

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Cardiovascular Medicine, Genetics, In the News, Research, Science, Stanford News

A simple blood test may unearth the earliest signs of heart transplant rejection

A simple blood test may unearth the earliest signs of heart transplant rejection

2123984831_b7d09079a4_oIs there an organ more precious than a donated heart? Heart transplant recipients would likely say no. But, in order to keep their new heart healthy, they have to identify any signs of rejection as early as possible. Unfortunately (and ironically), the gold standard procedure to detect rejection – repeated heart biopsies – involves snipping away and analyzing tiny bits of tissue from the very organ they waited so long to receive. The procedure is also uncomfortable, and can cause complications.

Now, Stanford bioengineer Stephen Quake, PhD, and his colleagues have found that a simple blood test that detects donor DNA in the bloodstream of the recipient can detect signs of rejection far earlier than biopsy. Their results were published today in Science Translational Medicine.

From our release:

The study of 65 patients (21 children and 44 adults) extends and confirms the results of a small pilot study completed in 2011 by the Stanford researchers. Whereas the earlier study used stored blood samples and medical histories from seven people, the new study followed patients in real time before and after transplant. The researchers directly compared the results of simultaneously collected biopsies and blood samples, and tracked how the values changed during the rejection process.

The blood test takes advantage of the fact that dying heart cells release genetic material into the recipient’s blood. Any increase beyond a normal baseline level indicates a possible attack by the immune system on the donated organ. As described in our release:

In the pilot study of 2011, the researchers first used the presence of the Y chromosome to track the donor DNA when a woman received a heart from a male donor. Then they hit upon using differences in SNPs instead; this method doesn’t require a gender mismatch between donor and recipient. They found that, in transplant recipients not experiencing rejection, the donor DNA accounted for less than 1 percent of all cell-free DNA in the recipient’s blood. During rejection episodes, however, the percentage of donor DNA increased to about 3 or 4 percent.

In the new study, the researchers monitored 565 samples from the 65 patients to assess the assay under real-time clinical conditions. They found they were able to accurately detect the two main types of rejection (antibody-mediated rejection and acute cellular rejection) in 24 patients who suffered moderate to severe rejection episodes, one of whom required a second transplant. They were also able to detect signs of rejection up to five months before the biopsies indicated anything troubling.

The test will still need to be optimized for regular clinical use. However, cardiologist Kiran Khush, MD, a co-senior author of the study, explained what the advance could mean to heart transplant recipients:

This test has the potential to revolutionize the care of our patients… It may also allow us to conduct several diagnostic tests simultaneously. For example, we could also look for microbial sequences in the blood sample to rule out infection or other complications sometimes experienced by transplant recipients. It could allow us to determine whether shortness of breath experienced by a patient is due to an infection or the start of a rejection episode. It could be a one-stop shop for multiple potential problems.

Full disclosure: Stanford has applied for a patent relating to the test described in this study. Quake is a consultant for and holds equity in CareDX Inc., a molecular diagnostics company that has licensed a patent from Stanford related to a method used in the study and is developing it for clinical use.

Previously: ‘Genome transplant’ concept helps Stanford scientists predict organ rejection, Stanford study in transplant patients could lead to better treatment and New techniques to diagnose disease in a fetus
Photo by Desi

Research, Science, Stanford News, Stem Cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

A new era for stem cells in cardiac medicine? A simple, effective way to generate patient-specific heart muscle cells

Ford assembly lineIn the early 1900s, Henry Ford was lauded for his use of the assembly line, which allowed the rapid, reliable and uniform production of over 15 million Model T automobiles. By codifying each step of production and using identical, interchangeable parts, he brought car ownership within reach of the average American and changed the face of our country.

Now Stanford cardiologist Joseph Wu, MD, PhD, and instructor Paul Burridge, PhD, have done something similar with stem cells. They’ve devised a way to create large numbers of heart muscle cells called cardiomyocytes from stem cells without using human or animal-derived products, which can vary in composition and concentration among batches. Their technique was published Sunday in Nature Methods. Wu, who is the director of the Stanford Cardiovascular Institute explained to me in an e-mail:

This technique solves an important hurdle for the use of iPS-derived heart cells. In order to fully realize the potential of these cells in drug screening and cell therapy, it’s necessary to be able to reliably generate large numbers at low cost. Due to their chemically defined nature, this system is highly reproducible, massively scalable and substantially reduces costs to allow the production of billions of cardiomyocytes matching a specific patient’s heart phenotype.

Chemically defined cell culture means that scientists know exactly what (and how much) is in the liquid in which the cells are grown. In contrast, many common cell culture methods involve the use of nutrient-rich broth derived from animal or human sources. These liquids are teaming with proteins, some known and some unknown, that can promote stem cell growth. They get the job done, but their components can vary among batches and the outcome isn’t always reproducible.

In the new method, Wu and his colleagues collected cells from the skin or blood of an individual. They used a virus called the Sendai virus encoding four reprogramming genes to create induced pluripotent stem cells. These cells were then grown in a liquid in which everything needed for growth was precisely defined. As Wu explained, “This approach gives us an opportunity to fully understand the molecular and macromolecular requirements for cardiac differentiation and eliminates any animal-derived components that were previously used.”

The researchers found they were able to produce about 100 cardiomyocytes for every one stem cell by following a systematic series of steps and using a growing medium that contained just three well-defined components. They showed the technique worked on 11 different batches of induced pluripotent stem cells. The cardiomyocytes were more than 95 percent pure, making it easier to get large numbers of cells to study disease processes or to test the effects of compounds during drug development. According to Wu:

We can use this approach to assess the effect of a particular medication on a specific patient’s heart cells, to discover new drugs, to better understand the process of heart development and to generate cardiomyocytes for use in regenerative medicine approaches, such as for injection into the heart to aid recovery after a heart attack. The system also serves as a platform to study cardiomyocyte subtype specification and maturation.

Of course, stem cells are nothing like automobiles, and regular people aren’t lining up clamoring for a fresh vial of heart muscle cells. But it’s possible that the ability to reliably generate large numbers of cardiomyocytes for study and therapy could be as transformative to cardiac medicine as the Model T was to our grandparents and great grandparents.

Previously: Oh grow up! “Specialized” stem cells tolerated by the immune system, say Stanford researchers, Stem cell medicine for hearts? Yes, please, says one amazing family and “Clinical trial in a dish” may make common medicines safer, say Stanford scientists
Photo by Kyle Harris

Evolution, Genetics, Global Health, Public Health, Research, Stanford News

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

Melting pot or mosaic? International collaboration studies genomic diversity in Mexico

6626429111_df791cbb8d_zMexico is a vast country with a storied past. Indigenous Native American groups across the country maintain their own languages and culture, while its cosmopolitan residents of large cities are as globally connected as anywhere on Earth. But Mexicans and Mexican Americans are usually lumped together as “Latinos” for the purposes of genetic or medical studies.

Now an international collaboration headed by Stanford geneticist Carlos Bustamante, PhD, and the University of California, San Francisco pulmonologist and public-health expert Esteban Burchard, MD, MPH, has assessed the breadth and depth of genomic diversity in Mexico for the first time. Their work was published today in Science. As I explain in our release:

The researchers compared variation in more than 1 million single nucleotide polymorphisms, or SNPs, among 511 people representing 20 indigenous populations from all over Mexico. They compared these findings with SNP variation among 500 people of mixed Mexican, European and African descent (a category called mestizos) from 10 Mexican states, a region of Guadalajara and Los Angeles, as well as with SNP variation among individuals from 16 European populations and the Yoruba people of West Africa.

The researchers found that Mexico’s indigenous populations diverge genetically along a diagonal northwest-to-southeast axis, with differences becoming more pronounced as the ethnic groups become more geographically distant from one another. In particular, the Seri people along the northern mainland coast of the Gulf of California and a Mayan people known as the Lacandon found near the country’s southern border with Guatemala are as genetically different from one another as Europeans are from Chinese.

Surprisingly, this pattern of diversity is mirrored in the genomes of Mexican individuals with mixed heritage (usually a combination of European, Native American and African):

Consistent with the history of the Spanish occupation and colonization of Mexico, the researchers found that the European portion of the mixed-individuals’ genomes broadly corresponded to that of modern-day inhabitants of the Iberian Peninsula. The Native American portion of their genomes, however, was more likely to correspond to that of local indigenous people. A person in the Mexican state of Sonora, for example, was likely to have ancestors from indigenous groups in the northern part of the country, whereas someone from Yucatan was more likely to have a southern native component in their genome, namely Mayan.

“We were really fascinated by these results because we had expected that 500 years of population movements, immigration and mixing would have swamped the signal of pre-Columbian population structure,” said Bustamante

Finally, the researchers found that the origin of the Native America portion of an individual’s genome affected a clinical measure of lung function abbreviated FEV1:

The researchers drew on data that calculated the predicted normal FEV1 for each subject based on age, gender, height and ethnicity (in this case, the reference was a standard used for all people of Mexican descent). To understand implications of these results within Mexico, they modeled the predicted lung function across Mexico, accounting for differences in local Native American ancestry for a large cohort of mestizos from eight states. The model predicts a marked difference across the country, with the average predicted FEV1 for a person from the northern state of Sonora and another from the state of Yucatan differing by about 7.3 percent. (That is, the population from Sonora has predicted values that were slightly higher than the average for the country, and those from the Yucatan were slightly lower.)

“There’s a definite predicted difference that’s due only to an individual’s Native American ancestry,” said Gignoux. “Variations in genetic composition clearly give a different physiological response.”

The researchers emphasize that a lower FEV1 does not necessarily mean a particular ethnic group has impaired lung function. Disease analysis takes place in the context of standardized values of matched populations, and the study points out how it is necessary to match people correctly to their ethnic backgrounds before making clinical decisions.

Stanford’s Andres Moreno Estrada, MD, PhD, and Christopher Gignoux, PhD, share first authorship of the study with Juan Carlos Fernandez Lopez, a researcher at Mexico’s National Institute of Genomic Medicine.

Previously: Roots of disease may vary with ancestry, according to Stanford geneticist, Recent shared ancestry between southern Europe and North Africa identified by Stanford researchers, and Caribbean genetic diversity explored by Stanford/University of Miami researchers
Photo by DL

Cancer, Research, Science, Stanford News

Smoking gun or hit-and-run? How oncogenes make good cells go bad

Smoking gun or hit-and-run? How oncogenes make good cells go bad

Smoking gun

It can be tough to find the mutations responsible for turning a normal cell cancerous. By the time a tumor has been diagnosed and analyzed, its cells have undergone many, many rounds of DNA replication and division – likely accumulating mutations all the while. But oncogenes (mutated versions of normal genes often associated with cell division) have been identified as the smoking gun in many cancers, some are viewed as attractive targets for cancer therapies because their effects on cell growth appear so pervasive.

Now new research is beginning to suggest a cancer cell’s reliance on oncogenes and other mutations may be much more nuanced than originally believed. Stanford oncologists Ash Alizadeh, MD, PhD, and Michael Green, PhD, study diffuse B-cell lymphoma, which is the most-common aggressive lymphoma in this country. About half of all people diagnosed with the condition will die from the disease. (Stanford’s Lymphoma and Hodgkin’s Disease Research Program treats many patients with this and other blood cancers.)

In 2000, Alizadeh showed that cancer cells from patients with diffuse B-cell lymphoma fall into two subsets when categorized by their gene expression profiles. One, the germinal center B-cell like (or GCB-like) subset has a much better prognosis than the other, which more closely resembles the gene profile seen in activated B-cells (ABC-like). But the basis of the prognostic differences between the two groups has not been known.

In the new study, which was published this week in Nature Communications (subscription required), Alizadeh and Green investigate the role of an oncogene called Bcl6 in diffuse B cell lymphoma. Their research suggests that, in at least one of the subcategories of this type of lymphoma, the reliance on the Bcl6 oncogene is limited to very early stages of development, before the cells themselves had completely matured.

As Green explained in an e-mail to me:

This work adds to growing evidence that the two subtypes of diffuse large B-cell lymphoma, which have very different clinical outcomes, may in fact be two genetically distinct diseases. There were also a number of surprises in this project. In particular, the notion that expression of an oncogene for a limited period in a stem cell is capable of reprogramming those cells towards becoming cancer at a later stage of development is a completely new paradigm. Now we have to ask ourselves whether we should be thinking differently about how lymphoma, and maybe cancer in general, evolves.

This type of hit-and-run hypothesis is different from the traditional view of how oncogenes work, Alizadeh explained in an e-mail:

 The results from this study clearly illustrate that, if cancers can result via ”hit-and-run” oncogenesis, oncogenes that initiate tumor formation might be dispensable for tumor cell survival and/or tumor progression. In this context, mutations that activate oncogenes would have a driving role in the tumorigenic process, but may act as passenger mutations thereafter, or may have a secondary role in evolved tumor cell clones. This may provide an explanation for the failure of some modern targeted therapies to clear tumor progenitor cells, despite being effective agents against evolved tumor cells. As a consequence, targeted treatment strategies may need to be altered to accommodate combinations of agents that target oncogenic pathways that are active at both the early and late stages of tumor development.

Their research was conducted in collaboration with researchers in the laboratory of Isidro Sanchez-Garcia, MD, PhD at the Institute of Biomedical Research of Salamanca in Spain.

Previously: Cellular culprit identified for invasive bladder cancer, according to Stanford study,  Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers, and Leukemia prognosis and cancer stem cells
Photo by brett jordan

Evolution, Genetics, Research, Science, Stanford News, Stem Cells

It’s a blond thing: Stanford researchers suss out molecular basis of hair color

It's a blond thing: Stanford researchers suss out molecular basis of hair color

blond hair, brighter

It’s all over the news today: Blonds aren’t stupid.

Well, that’s what most of the media would have you believe is the take-home message of the latest research by developmental biologist David Kingsley, PhD. And although I’m happy to see such great coverage, I’m hoping that readers realize that Kingley’s study on human hair color, which was published yesterday in Nature Genetics (subscription required), describes something much more subtle, and less superficial. From our release:

The study describes for the first time the molecular basis for one of our most noticeable traits. It also outlines how tiny DNA changes can reverberate through our genome in ways that may affect evolution, migration and even human history.

Kingsley, who is known for his study of a tiny fish called the threespine stickleback, is interested in learning how organism adapt to new environments by developing new traits. He’s found that this type of adaptation is most-often accomplished by changes in DNA regulatory regions that affect when, where and how a gene is expressed, rather than through (possibly disruptive) changes in the genes themselves.

In this case, he and his colleagues turned his attention to the blond hair common to many northern European and Icelanders. A previous study had shown that a single nucleotide change on human chromosome 12 was a major driver in hair color. As explained in the release:

The researchers found that the blond hair commonly seen in Northern Europeans is caused by a single change in the DNA that regulates the expression of a gene that encodes a protein called KITLG, also known as stem cell factor. This change affects how much KITLG is expressed in the hair follicles without changing how it’s expressed in the rest of the body. Introducing the change into normally brown-haired laboratory mice yields an animal with a decidedly lighter coat — not quite Norma Jeane to Marilyn Monroe, but significant nonetheless.

The involvement of KITLG, with its critical role in stem cell biology, is certainly interesting. But there’s also a more global lesson about the specificity of gene expression their effect on phenotype:

The study shows that even small, tissue-specific changes in the expression of genes can have noticeable morphological effects. It also emphasizes how difficult it can be to clearly connect specific DNA changes with particular clinical or phenotypic outcomes. In this case, the change is subtle: A single nucleotide called an adenine is replaced by another called a guanine on human chromosome 12. The change occurs over 350,000 nucleotides away from the KITLG gene and only alters the amount of gene expression about 20 percent — a relatively tiny blip on a biological scale more often assessed in terms of gene expression being 100 percent “on” or “off.”

“What we’re seeing is that this regulatory region exercises exquisite control over where, and how much, KITLG expression occurs,” said Kingsley. “In this case, it controls hair color. In another situation — perhaps under the influence of a different regulatory region — it probably controls stem cell division. Dialing up and down the expression of an essential growth factor in this manner could be a common mechanism that underlies many different traits.”

And now, the hook that excited most of the news media:

[Kingsley] added: “It’s clear that this hair color change is occurring through a regulatory mechanism that operates only in the hair. This isn’t something that also affects other traits, like intelligence or personality. The change that causes blond hair is, literally, only skin deep.”

Previously: Something fishy: Threespine stickleback genome published by Stanford researchers, Hey guys, sometimes less really is more , Tickled by stickle(backs) and Blond hair evolved more than once, and why it matters
Photo by Traci Lawson

Research, Science, Stanford News, Stem Cells

“Alert” stem cells speed damage response, say Stanford researchers

"Alert" stem cells speed damage response, say Stanford researchers

191855419_350c4827a2_zStanford neurologist and longevity researcher Thomas Rando, MD, PhD and his colleagues have found that adult stem cells (those that hang around in mature tissues to facilitate tissue repair) have a surprising ability to notice, and respond, to damage in distant parts of the body. The researchers termed the response an  “alert” state; the cells are no longer resting deeply, but are also not yet committed to possibly unnecessary action. (As I was writing our release, I kept envisioning the stem cells like dogs frozen in a point, waiting for further movement or instructions.)

Their study was published last week in Nature. As I explained:

The researchers were studying the response of mouse muscle stem cells, or satellite cells, to muscle injury. Conventional wisdom holds that adult stem cells are by nature quiescent — a term that indicates a profound resting state characterized by small size and no cell division. It’s a kind of cellular deep freeze. In contrast, most other cells cycle through rounds of DNA replication and cell division in discrete, well-defined phases. A quiescent stem cell can “wake up” and enter the cell cycle in response to local signals of damage or other regeneration needs.

Rando and his colleagues were studying this activation process in laboratory mice by watching how muscle stem cells in one leg respond to a nearby muscle injury in the same leg. (Mice were anesthetized prior to a local injection of muscle-damaging toxin; they were given pain relief and antibiotics during the recovery period.) The researchers had planned to observe the quiescent muscle stem cells in the uninjured leg as a control for their experiment. However, they instead saw something unexpected.

“The muscle stem cells in the uninjured leg had definitely changed,” said Rando, who is director of the Rehabilitation Research & Development Center of Excellence at the Veterans Affairs Palo Alto Health Care System. “They were very clearly biochemically different from completely dormant, quiescent cells, and from fully activated stem cells. We termed this state an ‘alert’ state of quiescence.”

These alert stem cells were able to respond to subsequent, nearby damage much more quickly and efficiently than completely quiescent cells, the researchers found. They also learned that the stem cells’ response encompasses several tissue types in addition to the one in which the injury occurred. More from the release:

Surprisingly, the muscle stem cells also became alert in response to bone or minor skin injuries — injuries in which the cells are not known to play any regenerative role.

Conversely, other non-muscle adult stem cells, including hematopoietic stem cells in the bone marrow and mesenchymal stem cells in the muscle, became alert in response to muscle damage.

“It is clear that this alert state is a systemic response,” said Rando.

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

Oh, grow up! “Specialized” stem cells tolerated by immune system, say Stanford researchers

Oh, grow up! "Specialized" stem cells tolerated by immune system, say Stanford researchers

3075268200_419b9e73b7_zMany of us know by now that stem cells are remarkably fluid in the types of cells they can become. But this fluidity, or pluripotency, comes with a price. Several studies have shown that the body’s immune system will attack and reject even genetically identical transplanted stem cells, making it difficult to envision their usefulness for long-term therapies.

Now Stanford cardiologist Joseph Wu, MD, PhD, and his colleagues have shown that coaxing the stem cells to become more-specialized (a process known as differentiation) before transplantation allows the body to recognize and tolerate the cells. Their research was published today in Nature Communications (subscription required).

From our release:

In a world teeming with microbial threats, the immune system is a necessary watchdog. Immune cells patrol the body looking not just for foreign invaders, but also for diseased or cancerous cells to eradicate. The researchers speculate that the act of reprogramming adult cells to pluripotency may induce the expression of cell-surface molecules the immune system has not seen since the animal (or person) was an early embryo. These molecules, or antigens, could look foreign to the immune system of a mature organism.

Previous studies have suggested that differentiation of iPS cells could reduce their tendency to inflame the immune system after transplantation, but this study is the first to closely examine, at the molecular and cellular level, why that might be the case.

Postdoctoral scholars Patricia Almeida, PhD, and Nigel Kooreman, MD, and assistant professor of medicine Everett Meyer, MD, PhD, share lead authorship of the study. They found that laboratory mice accepted grafts of endothelial cells made from stem cells much more readily than they did the stem cells themselves. As Wu, who also directs the Stanford Cardiovascular Institute said in our release:

This study certainly makes us optimistic that differentiation — into any nonpluripotent cell type — will render iPS cells less recognizable to the immune system. We have more confidence that we can move toward clinical use of these cells in humans with less concern than we’ve previously had.

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

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