Monthly Archives: October 2012

ScienceDaily (Oct. 11, 2012) The generation of functional thyroid tissue from stem cells could allow the treatment of patients, which suffer from thyroid hormone deficiency due to defective function, or abnormal development of the thyroid gland. The team of Sabine Costagliola at the IRIBHM (Universit Libre de Bruxelles) recently developed a protocol that allowed for the first time the efficient generation of functional thyroid tissue from stem cells in mice and published the results of their studies in the scientific journal Nature.

Thyroid hormones are a class of iodide-containing molecules that play a critical role in the regulation of various body function including growth, metabolism and heart function and that are crucial for normal brain development. The thyroid gland, an endocrine organ that has been specialized in trapping iodide, is the only organ where these hormones are produced. It is, however, of note that one out of 3000 human newborns is born with congenital hypothyroidism, a condition characterized by insufficient production of thyroid hormones. In the absence of a medical treatment with thyroid hormones -- initiated during the first days after birth -- the child will be affected by an irreversible mental retardation. Moreover, a life-long hormonal treatment is necessary in order to maintain proper regulation of growth and general metabolism.

By employing a protocol in which two important genes can be transiently induced in undifferentiated stem cells, the researchers at IRIBHM were able to efficiently push the differentiation of stem cells into thyrocytes, the primary cell type responsible for thyroid hormone production in the thyroid gland.

A first exciting finding of these studies was the development of functional thyroid tissue already within the culture dishes. As a next step, the team of Sabine Costagliola transplanted the stem-cell-derived thyrocytes into mice lacking a functional thyroid gland. Four weeks after transplantation, the researchers observed that transplanted mice had re-established normal levels of thyroid hormones in their blood and were rescued from the symptoms associated with thyroid hormone deficiency. These findings have several important implications. First, the cell system employed by the IRIBHM group provides a vital tool to better characterize the molecular processes associated with embryonic thyroid development. Second, the results of the transplantation studies open new avenues for the treatment of thyroid hormone deficiency but also for the replacement of thyroid tissue in patients suffering from thyroid cancer.

The researchers are currently developing a similar protocol based on human stem cells and explore ways to generate functional human thyroid tissue by reprogramming pluripotent stem cells (iPS) derived from skin cells.

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The above story is reprinted from materials provided by Universit Libre de Bruxelles, via AlphaGalileo.

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Generation of functional thyroid tissue from stem cells

ScienceDaily (Oct. 11, 2012) In recent years investigators have discovered that breast tumors are influenced by more than just the cancer cells within them. A variety of noncancerous cells, which in many cases constitute the majority of the tumor mass, form what is known as the "tumor microenvironment." This sea of noncancerous cells and the products they deposit appear to play key roles in tumor pathogenesis.

Among the key accomplices in the tumor microenvironment are mesenchymal stem cells (MSCs), a group of adult progenitor cells which have been shown to help breast cancers maneuver and spread to other parts of the body.

Now, new research sheds further light on how this is happening. Led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the findings demonstrate that the lysyl oxidase (LOX) gene is spurred to production in cancer cells as a result of their contact with MSCs, and once produced, can help ensure the spread of otherwise weakly metastatic cancer cells from primary tumors to the lung and bones. Described on-line in the Proceedings of the National Academy of Sciences (PNAS), this discovery not only provides key insights into the basic biology of tumor formation, but also offers a potential new direction in the pursuit of therapies for the treatment of bone metastasis.

"We don't have a lot of therapies that can target breast cancer once it has metastasized, particularly once cancer cells have lodged in the bone," says senior author Antoine Karnoub, PhD, an investigator in the Department of Pathology at BIDMC and Assistant Professor of Pathology at Harvard Medical School. "When breast cancer cells reach the skeleton, one way in which they cause damage is by breaking down bone tissue, which results in the bone's rich matrix releasing numerous factors. These factors, in turn, feed the cancer cells, setting in motion a vicious cycle that leaves patients susceptible to fractures, pain, and further metastasis."

MSCs are non-hematopoietic progenitor cells predominantly produced in the bone marrow that generate bone, cartilage, fat, and fibrous connective tissue. They additionally support immune cell development and are recruited to inflammatory sites throughout the body to help shut down immune responses and regenerate damaged tissues, as might occur during wound healing. Several years ago, as a postdoctoral researcher at the Whitehead Institute of the Massachusetts Institute of Technology, Karnoub began exploring the idea that MSCs were migrating to tumors after mistaking the cancer sites for inflammatory lesions in need of healing.

"We discovered that once MSCs had reached the tumor sites, they were actually helping in cancer metastasis, causing primary cancer cells to spread to other sites in the body," he explains. In this new paper, Karnoub wanted to find out, in greater molecular detail, how breast cancer cells respond to the influences of MSCs in order to better understand how cancer cells cross-talk with recruited cells in the microenvironment.

His scientific team first embarked on a straightforward experiment. "We took two dishes of cells, cancer cells and MSCs, and mixed them together," explains Karnoub. After three days, they removed the cancer cells and studied them to see how they had changed.

"We found that the lysyl oxidase [LOX] gene was highly upregulated in the cancer cells," he says. "It turns out that when a cancer cell comes in contact with an MSC, it flips on this LOX gene, turning it up by a factor of about 100. So our next question was, 'What happens to the cancer cells when they encounter this boost of LOX that they themselves have produced?'"

The answer, as revealed in subsequent experiments, was that LOX was setting in motion a cell program called epithelial-to-mesenchymal transition (EMT). During EMT, cancer cells that usually clump together undergo a transformation into cells that exhibit decreased adhesion to their neighbors and go their own way. As a result, these cancerous cells are able to migrate, significantly enhancing their ability to metastasize.

"When we put these cells back into mice, they not only formed tumors that metastasized to the lung, but also to the bone," says Karnoub. "This makes you wonder whether the cancer cells in primary tumors have become so acclimated to interacting with bone-derived MSCs that they can now grow more easily in the bone once they leave the tumor."

Original post:
Clues to cancer metastasis: Discovery points to potential therapies for bone metastasis

Public release date: 11-Oct-2012 [ | E-mail | Share ]

Contact: Bonnie Prescott bprescot@bidmc.harvard.edu 617-667-7306 Beth Israel Deaconess Medical Center

BOSTON In recent years investigators have discovered that breast tumors are influenced by more than just the cancer cells within them. A variety of noncancerous cells, which in many cases constitute the majority of the tumor mass, form what is known as the "tumor microenvironment." This sea of noncancerous cells and the products they deposit appear to play key roles in tumor pathogenesis.

Among the key accomplices in the tumor microenvironment are mesenchymal stem cells (MSCs), a group of adult progenitor cells which have been shown to help breast cancers maneuver and spread to other parts of the body.

Now, new research sheds further light on how this is happening. Led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the findings demonstrate that the lysyl oxidase (LOX) gene is spurred to production in cancer cells as a result of their contact with MSCs, and once produced, can help ensure the spread of otherwise weakly metastatic cancer cells from primary tumors to the lung and bones. Described on-line in the Proceedings of the National Academy of Sciences (PNAS), this discovery not only provides key insights into the basic biology of tumor formation, but also offers a potential new direction in the pursuit of therapies for the treatment of bone metastasis.

"We don't have a lot of therapies that can target breast cancer once it has metastasized, particularly once cancer cells have lodged in the bone," says senior author Antoine Karnoub, PhD, an investigator in the Department of Pathology at BIDMC and Assistant Professor of Pathology at Harvard Medical School. "When breast cancer cells reach the skeleton, one way in which they cause damage is by breaking down bone tissue, which results in the bone's rich matrix releasing numerous factors. These factors, in turn, feed the cancer cells, setting in motion a vicious cycle that leaves patients susceptible to fractures, pain, and further metastasis."

MSCs are non-hematopoietic progenitor cells predominantly produced in the bone marrow that generate bone, cartilage, fat, and fibrous connective tissue. They additionally support immune cell development and are recruited to inflammatory sites throughout the body to help shut down immune responses and regenerate damaged tissues, as might occur during wound healing. Several years ago, as a postdoctoral researcher at the Whitehead Institute of the Massachusetts Institute of Technology, Karnoub began exploring the idea that MSCs were migrating to tumors after mistaking the cancer sites for inflammatory lesions in need of healing.

"We discovered that once MSCs had reached the tumor sites, they were actually helping in cancer metastasis, causing primary cancer cells to spread to other sites in the body," he explains. In this new paper, Karnoub wanted to find out, in greater molecular detail, how breast cancer cells respond to the influences of MSCs in order to better understand how cancer cells cross-talk with recruited cells in the microenvironment.

His scientific team first embarked on a straightforward experiment. "We took two dishes of cells, cancer cells and MSCs, and mixed them together," explains Karnoub. After three days, they removed the cancer cells and studied them to see how they had changed.

"We found that the lysyl oxidase [LOX] gene was highly upregulated in the cancer cells," he says. "It turns out that when a cancer cell comes in contact with an MSC, it flips on this LOX gene, turning it up by a factor of about 100. So our next question was, 'What happens to the cancer cells when they encounter this boost of LOX that they themselves have produced?'"

Link:
Discovery reveals important clues to cancer metastasis

The achievement is the latest success in the relatively new field of regenerative medicine

By Dan Jones and Nature magazine

WE CAN REBUILD HIM: Regenerative successes in mice are adding up. Image: Nature News

Showcasing more than fifty of the most provocative, original, and significant online essays from 2011, The Best Science Writing Online 2012 will change the way...

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From Nature magazine

A series of achievements have stoked excitement about the potential of regenerative medicine, which aims to tackle diseases by replacing or regenerating damaged cells, tissues and organs. A paper in Nature today reports another step towards this goal: the generation of working thyroid cells from stem cells.

Sabine Costagliola, a molecular embryologist at the Free University of Brussels, and her team study the development of the thyroid gland, which regulates how the body uses energy and affects sensitivity to other hormones. Their research shows that thyroid function can be re-established even after the gland has been destroyed at least in mice. If the same technique could be applied to humans, it would help the roughly 1 in 3,000 babies born with deficient thyroid activity, or hypothyroidism, which can result in stunted physical and mental development.

The thyroid is the latest in a growing list of body parts that can now be fixed in mice, with the potential to treat diseases from diabetes to Parkinsons (see 'We can rebuild him'). Progress has been very rapid over the past decade, says Charles ffrench-Constant, director of the MRC Centre for Regenerative Medicine at the University of Edinburgh, UK. In recent years weve seen a number of very important studies in which mouse stem cells have been converted to a desired cell type that has then been shown to be functional in vivo, and to confer benefits in mouse models of human diseases.

Key ingredient Costagliola and her colleagues first genetically engineered embryonic stem cells to express two proteins NKX2-1 and PAX8 that are expressed together only in the thyroid. When these cells were grown in Petri dishes in the presence of thyroid-stimulating hormone, they turned into thyroid cells.

Read more here:
Hormone-Producing Thyroid Grown from Embryonic Stem Cells

An oligodendrocytethe type of cell that manufactures myelin.

At first, the infants seem to be progressing normally. But it soon turns out they may have vision or hearing problems, and when the time comes to lift their heads, the milestone comes and goes. It often gets worse from there. Children with the rare PelizaeusMerzbacher disease, like others who lack the usual insulating sheaths on their neurons, have trouble controlling their muscles, and often develop serious neurological and motor problems early in life. There is no cure for the genetic disorder. Nor is there a standardized treatment.

PMD, as its called, and related diseases are some of the leading candidates for potential treatment with stem cells. The idea is that if stem cells that produce the missing insulator, the fatty substance called myelin, can be successfully implanted in the brains of patients, perhaps they will pitch in what the patients native cells cannot.

This week saw two incremental but encouraging advances toward such treatments, both published inScience Translational Medicine.In one study, mice without the ability to make myelin were implanted with human neural stem cells that, within weeks, developed into myelin-making cells 60-70% of the time and produced the substance in the brain. In the other study, four young boys with early onset PMD underwent an experimental treatment: the same type of stem cells were implanted into their brains, and, after 9 months of drugs to surpress the childrens immune systems so the cells could take hold, MRI exams, psychological tests, and motor tests are consistent with more myelin having formed.

Since there was no control group in the human study, the scientists have no way of knowing whether the new myelin formation is actually due to the implanted cells (for that, they would need a group of boys who received every step of the treatment except getting the cells, to compare). And there are, of course, only four subjects. But the fact that there have been no major side effectsespecially tumors, which not unheard-of after stem cell treatmentsis in and of itself heartening. It indicates that future studies using these cells can tentatively proceed. Image courtesy of Methoxyroxy / Wikimedia Commons

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Stem Cells Safely Implanted in Brains of Boys with Neurological Disorder | 80beats

By Emily Underwood, ScienceNOW

Four young boys with a rare, fatal brain condition have made it through a dangerous ordeal. Scientists have safely transplanted human neural stem cells into their brains. Twelve months after the surgeries, the boys have more myelin a fatty insulating protein that coats nerve fibers and speeds up electric signals between neurons and show improved brain function, a new study in Science Translational Medicine reports. The preliminary trial paves the way for future research into potential stem cell treatments for the disorder, which overlaps with more common diseases such as Parkinsons disease and multiple sclerosis.

This is very exciting, says Douglas Fields, a neuroscientist at the National Institutes of Health in Bethesda, Maryland, who was not involved in the work. From these early studies one sees the promise of cell transplant therapy in overcoming disease and relieving suffering.

Without myelin, electrical impulses traveling along nerve fibers in the brain cant travel from neuron to neuron says Nalin Gupta, lead author of the study and a neurosurgeon at the University of California, San Francisco (UCSF). Signals in the brain become scattered and disorganized, he says, comparing them to a pile of lumber. You wouldnt expect lumber to assemble itself into a house, he notes, yet neurons in a newborn babys brain perform a similar feat with the help of myelin-producing cells called oligodendrocytes. Most infants are born with very little myelin and develop it over time. In children with early-onset Pelizaeus-Merzbacher disease, he says, a genetic mutation prevents oligodendrocytes from producing myelin, causing electrical signals to die out before they reach their destinations. This results in serious developmental setbacks, such as the inability to talk, walk, or breathe independently, and ultimately causes premature death.

Although researchers have long dreamed of implanting human neural stem cells to generate healthy oligodendrocytes and replace myelin, it has taken years of research in animals to develop a stem cell that can do the job, says Stephen Huhn, vice president of Newark, California-based StemCells Inc., the biotechnology company that created the cells used in the study and that funded the research. However, he says, a separate study by researchers at Oregon Health & Science University, Portland, found that the StemCell Inc. cells specialized into oligodendrocytes 60 percent to 70 percent of the time in mice, producing myelin and improved survival rates in myelin-deficient animals. So the team was able to test the cells safety and efficacy in the boys.

Led by Gupta, the researchers drilled four small holes in each childs skull and then used a fine needle to insert millions of stem cells into white matter deep in their frontal lobes. The scientists administered a drug that suppressed the boys immune systems for 9 months to keep them from rejecting the cells and checked their progress with magnetic resonance imaging and a variety of psychological and motor tests. After a year, each of the boys showed brain changes consistent with increased myelination and no serious side effects such as tumors, says David Rowitch, one of the neuroscientists on the UCSF team. In addition, three of the four boys showed modest improvements in their development. For example, the 5-year-old boy the oldest child in the study had begun for the first time to feed himself and walk with minimal assistance.

Although these signs are encouraging, Gupta and Rowitch say, a cure for Pelizaeus-Merzbacher disease is not near. Animal studies strongly support the idea that the stem cells are producing myelin-making oligodendrocytes in the boys, but its possible that the myelination didnt result from the transplant but from a bout of normal growth. Rowitch adds that although such behavioral improvements are unusual for the disease, they could be a fluke. Huhn acknowledges that the study is small and has no control, but hes is still excited. We are for the first time seeing a biological effect of a neural stem cells transplantation into the brain [in humans]. The most important thing, he says, is that the transplants appear safe. This gives the researchers a green light to pursue larger, controlled studies, he says.

It isnt the flashiest thing, but demonstrating that its feasible to transplant these stem cells into childrens brains without negative consequences at least so far is extremely hopeful, says Timothy Kennedy, a neuroscientist at McGill University in Montreal, Canada.

Although hes concerned that myelination seen in mouse models might not scale up to a disease as severe as Pelizaeus-Merzbacher in humans, Ian Duncan, a neuroscientist at the University of Wisconsin, Madison, describes the study as setting a precedent for translating animal research in stem cells to humans. If you could improve quality of life by targeting key areas of the brain with these cells, he says, that would be a huge advance.

See more here:
Stem Cells Show Early Promise for Rare Brain Disorder