Heart and Blood Cells from iPS Cells

UCLA stem cell researchers create heart and blood cells from reprogrammed skin cells Wednesday, 30 April 2008 Stem cell researchers at UCLA were able to grow functioning cardiac cells using mouse skin cells that had been reprogrammed into cells with the same unlimited properties as embryonic stem cells. The finding is the first to show that induced pluripotent stem cells or iPS cells, which don’t involve the use of embryos or eggs, can be differentiated into the three types of cardiovascular cells needed to repair the heart and blood vessels. The discovery could one day lead to clinical trials of new treatments for people who suffer heart attacks, have atherosclerosis or are in heart failure, said Dr. Robb MacLellan, an associate professor of cardiology and physiology at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and senior author of the study. Researchers also were able to differentiate the iPS cells into several types of blood cells, which may one day aid in treating blood diseases and in bone marrow transplantation. “I believe iPS cells address many of the shortcomings of human embryonic stem cells and are the future of regenerative medicine,” said MacLellan. “I’m hoping that these scientific findings are the first step towards one day developing new therapies that I can offer my patients. There are still many limitations with using iPS cells in clinical studies that we must overcome, but there are scientists in labs across the country working to address these issues right now.” The study, which brought together stem cell and cardiology researchers at UCLA, appears online May 1, 2008 in the journal Stem Cells. Last June, UCLA stem cell researchers were among several scientific teams that were the first to reprogram mouse skin cells into cells resembling embryonic stem cells, which have the ability to become every cell type found in the body. MacLellan and his team used UCLA’s iPS cells in their study. Although iPS cells are believed to be very similar to embryonic stem cells, further study needs to be done to confirm their differentiation potential. MacLellan’s study proved that iPS cells can be induced into becoming cardiovascular cells, an important step in the confirmation process. “Theoretically, iPS cells are able to differentiate into 220 different cells types,” said Dr. Miodrag Stojkovic, co-editor of Stem Cells. “For the first time, scientists from UCLA were able to induce the differentiation of mouse iPS cells into functional heart cells.” In MacLellan’s study, the iPS cells were cultured on a protein matrix known to direct embryonic stem cells into differentiating into cardiovascular progenitor cells, immature heart cells that can give rise to mature cardiac cells that perform different functions. The progenitor cells were then isolated from the other iPS cells that did not differentiate using a protein marker called KDR, a growth factor receptor expressed on the surface of the progenitor cells. Once isolated, the cardiovascular progenitor cells were coaxed into becoming cardiomyocytes, or mature heart muscle cells that control heartbeat, endothelial cells, which form rudimentary blood vessels, and vascular smooth muscle cells, the specialized cells that line blood vessel walls. Once mature, the cardiomyocytes beat in the Petri dish. Studies are under way now at UCLA to determine if human iPS cells behave the same way as the mouse cells behave. If they do, the time may come when a person could use their own skin cells to create individualized iPS cell lines to provide cells for cardiac repair and regeneration, MacLellan said. It is vital to be able to grow and isolate progenitor, or partially differentiated, cells that can create the three types of cardiac cells for potential clinical use. When embryonic stem cells are injected directly into the heart in animal models, they create tumours because the cells differentiate not only into cardiac cells but into other cells found in the human body as well. Likewise, using embryonic stem cells garnered from other sources than the patient could result in rejection of the injected cells. The use of iPS cells may solve those problems. If the iPS cells come from the patient, rejection should not be an issue. Additionally, the use of cells that are already partially transformed into specific cardiac cell types may prevent tumour growth. The use of iPS cells also sidesteps the controversy some associate with deriving pluripotent stem cells from embryos or eggs, MacLellan said. “Our hope is that, based on this work in mice, we can show that similar cardiovascular progenitor cells can be found in human iPS cells and, using a similar strategy, that we can isolate the progenitor cells and differentiate them into the cells types found in the human heart,” MacLellan said. About Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research: The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. ......... ZenMaster

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Stem Cells in the Pituitary

Scientists Find Stem Cells for the First Time in the Pituitary Their presence in the hormone-secreting gland of mice suggests a means of adapting to stress and life changes Tuesday, 29 April 2008 A team of researchers led by scientists at Cold Spring Harbor Laboratory have for the first time identified stem cells that allow the pituitary glands of mice to grow even after birth. They found that, in contrast to most adult stem cells, these cells are distinct from those that fuel the initial growth of this important organ. The results suggest a novel way that the hormone-secreting gland may adapt, even in adolescents and adults, to traumatic stress or to normal life changes like pregnancy. Seeking Adult Stem Cells Maturity, in some respects, brings diminished possibilities. As a fertilized egg cell repeatedly divides to grow into a mature animal, most of the resulting cells become ever more specialized. But a small number of cells, known as stem cells, remain uncommitted even as they spawn more specialized progeny. The most versatile stem cells, taken from days-old embryos, are able to form any cell type — but studying them in people is controversial. Even in adults, however, other types of stem cell persist that have a more limited repertoire. Some replace specific cells as they wear out; others help to rebuild damaged tissues. Still other stem cells are suspected by some scientists of starting or maintaining cancers. In spite of their importance, stem cells are hard to spot among the multitude of cells in complex tissue. Several years ago, neuroscientist Grigori Enikolopov, Ph.D., an associate professor at Cold Spring Harbor Laboratory (CSHL), and his colleagues developed a tool to look for stem cells that give rise to new adult brain cells. Researchers had known that a gene called Nestin was active in these neural stem cells. The CSHL team genetically engineered mice so that the same conditions that activate Nestin in a particular cell also make it glow green under ultraviolet light. Using these mice gives researchers an important pointer to cells that may be adult stem cells. Almost 100 research teams around the world have now used these special mice to help find adult stem cells in hair follicles, liver, muscle, and other tissues. Looking at the pituitary One place where stem cells had been suspected — but never found — is the pituitary gland. This organ, which in people is about the size of a pea, sits at the base of the brain, where it secretes hormones that regulate various processes throughout the body. In mice, the gland develops in the embryo, but then has a second growth spurt. “A few weeks after they are born the pituitary undergoes massive expansion” says Dr. Enikolopov, which suggests a role for adult stem cells. Anatoli Gleiberman, Ph.D., a researcher in the lab of pituitary expert M. Geoff Rosenfeld at the University of California, San Diego, initiated collaboration between the two labs to look for pituitary stem cells. The researchers used the Nestin-tracking mice to identify candidate cells in the anterior pituitary, the section of the organ that secretes hormones. They then used other techniques to show that these are true stem cells. “There are six main lineages in the adult pituitary and we can demonstrate that one adult stem cell can generate all six lineages...” with each cell type secreting a different hormone, says Dr. Enikolopov. A distinct kind of stem cell These cells differ from most adult stem cells, however. “In most cases that we know, cells that become stem cells of the adult have been also contributing to embryonic development and continue to serve as stem cells in the adult,” says Dr. Enikolopov. The research team demonstrated that adult stem cells in the pituitary did not help construct the embryonic organ. Their research, the scientists suggest, indicates that the adult mouse pituitary includes two similar — but not identical — types of hormone-producing cells: some that grew in the developing embryo, and some that appeared later. They speculate that having two sets of cells may let the organ respond differently to changing body conditions. Dr. Enikolopov notes that hormones strongly influence human neuropsychiatric phenomena, including stress and depression that are his main research focus. “All are mediated through the pituitary,” he said, so changes that happen during the later growth of the gland could have lasting effects. Reference: Genetic approaches identify adult pituitary stem cells Anatoli S. Gleiberman , Tatyana Michurina, Juan M. Encinas, Jose L. Roig, Peter Krasnov, Francesca Balordi, Gord Fishell, Michael G. Rosenfeld,, and Grigori Enikolopov Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0801644105 About CSHL: Cold Spring Harbor Laboratory is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases and other causes of human suffering. ......... ZenMaster

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Genes for Heart and Kidney Problems Identified

Genes for Common Heart Condition and Kidney Problem Identified Tuesday, 29 April 2008 A gene that can cause the heart to become enlarged, greatly increasing the risk of heart attacks and heart failure, is identified today in a new study. A gene that can cause the kidney to become inflamed, which can lead to kidney failure, is also revealed in a parallel discovery. The heart research, published in the journal Nature Genetics, reveals how a gene called osteoglycin (Ogn), which had not previously been linked with heart function, plays a key role in regulating heart growth. The study suggests that the gene can behave abnormally in some people, and that this can lead to the heart becoming abnormally enlarged. The researchers hope that through understanding how enlarged hearts are linked to the workings of genes like Ogn, they will be able to develop new treatments for the condition, which affects a large proportion of those with high blood pressure, obesity and diabetes. Scientists believe that enlarged hearts are caused by a combination of genetic factors and external stimuli such as high blood pressure and obesity. However, the role played by genes has remained largely unknown. The researchers, from Imperial College London, the Medical Research Council (MRC), and other international institutions, hope that their findings will provide new avenues for treating people who either have an enlarged heart or are at risk of developing one. At present enlarged hearts can only be treated by lowering blood pressure. The study shows that Ogn regulates the growth of the heart's main pumping chamber, its left ventricle. If the left ventricle thickens, this creates a condition known as elevated Left Ventricular Mass (LVM), a major contributing factor for common heart diseases. When the heart is enlarged it needs more oxygen and becomes stiff. This can cause shortness of breath or lead to a heart attack. The researchers found that higher than normal levels of Ogn were associated with the heart becoming enlarged in rats and mice and in humans. Dr Stuart Cook, one of the corresponding authors of the study from the MRC Clinical Sciences Centre and the National Heart and Lung Institute at Imperial College London, said: "Enlarged hearts are very common. A person whose heart is enlarged is more likely to suffer a heart attack or heart failure than someone whose heart is a normal size. We can't currently treat the condition directly, so lowering a patient's blood pressure is the only option we have. Now that we are unravelling how genes control heart growth, we can gain a better understanding of common forms of heart disease. This should lead to new and more effective ways of treating people." The study was primarily funded by the British Heart Foundation and the UK Department of Health. The researchers first linked the Ogn gene with elevated LVM by looking at rat models and analysing how LVM related to the genetic makeup of rats with both elevated and normal LVM. They then carried out the same analyses on samples from the human heart, volunteered by patients who had undergone cardiac surgery at Hammersmith Hospital, part of Imperial College Healthcare NHS Trust, and from a second group of patients from the Netherlands. These analyses showed that out of 22,000 possible genes, Ogn was the gene most strongly correlated with elevated LVM in humans. Professor Tim Aitman, also a corresponding author of the study from the MRC Clinical Sciences Centre and Imperial College London, added: "This study shows how we can use the wealth of new genome technologies for analysing people's genes to gain a much greater understanding of common human disorders. We already knew that enlarged hearts were linked with conditions such as high blood pressure and obesity but figuring out the genetic causes as well could be key to working out how to treat the condition." In a parallel development today, Professor Aitman, working with colleagues including Professor Terry Cook from Imperial College London, has identified a gene which controls the activity of a group of cells thought to be responsible for potentially severe inflammation of the kidney. The gene, also revealed in a study in Nature Genetics, is known as Jund and it could offer a route for tackling the auto-immune destruction of kidney tissue which can occur in lupus patients, causing renal failure. Jund regulates the activity of macrophages, cells which help us fight infection by eating up cellular debris and pathogens, and stimulating immune cells. The new research showed that when these cells are overactive, they can destroy healthy kidney tissue. Professor Aitman, who led the Medical Research Council team, said: "We are hoping that this discovery will allow us to find a new and effective way of treating this potentially fatal form of kidney failure. By reducing the activity of the Jund gene, we were able to reduce activity of inflammatory cells that can become overactive in certain diseases of the kidney. Such a therapy would be of obvious benefit to patients suffering from auto-immune diseases such as lupus. This would allow them to avoid dialysis and maintain their quality of life." ......... ZenMaster

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Cell-based Therapy for Parkinson's disease

Cell-based Therapy Shows Promise in Patients with Parkinson's disease Tuesday, 29 April 2008 A novel cell therapy using retinal pigment epithelial (RPE) cells attached to tiny gelatine bead micro-carriers implanted in the brain can improve the symptoms of patients with moderate to advanced Parkinson’s disease (PD). Rush University Medical Center neurosurgeon Dr. Roy A. E. Bakay and colleagues from Emory University, Atlanta found the therapy Spheramine was well-tolerated and patients experienced improvement in Parkinsonian symptoms (tremor, rigidity, slowness of movements, and impaired balance and coordination.) These findings were presented at the Annual Meeting of the American Association of Neurological Surgeons in Chicago on April 28, 2008. The pilot study was initiated at Emory University Hospital and followed six patients with moderate to advanced PD to investigate the safety, tolerability, and efficacy of the Spheramine implantation. The full patient group has been evaluated for four years, and several have been monitored for six years. Bakay and colleagues report long-term improvement or stabilization of symptoms, maintained for a minimum of two years after Spheramine implantation. They note no Spheramine-related serious adverse events were reported and that the most frequent adverse event was postsurgical headache, which spontaneously resolved within one to two weeks. “The results of this study are very encouraging – Spheramine is well tolerated through several years of follow-up and improvement in parkinsonian symptoms is sustained,” stated Bakay. The cellular product Spheramine consists of RPE cells attached to micro-carriers. RPE cells produce levodopa, the precursor of dopamine. Dopamine is a neurotransmitter produced by nerve cells in the brain that progressively declines as the disease progresses. The RPE cells, which are normally found in the back of the eye, are cultured under standardized conditions and attached to the microscopic beads prior to implantation. The micro-carriers are necessary for the cells to survive in the brain. The implanted cells serve as a new potential source of levodopa to enhance dopamine production where it is most needed. The patients were selected based on disease stage, levodopa responsiveness, and severity of PD symptoms while off medication. An even distribution of Spheramine was surgically implanted into the more affected side of the brain, and patients left the hospital a few days later. The primary efficacy measure in this trial is the motor score of the Unified Parkinson’s Disease Rating Scale (UPDRS) when the patient has been OFF anti-parkinsonian medication for at least 12 hours. The researchers report clinical improvements were noted in both UPDRS motor scores off medication (44 percent improvement from baseline at 48 months) and patient-reported quality of life scores (23 percent improvement from baseline of total PDQ-39 score at 48 months). Several of these patients have been monitored for 6 years and the trial has been extended to 10 years of follow-up. Bakay said positive results in the pilot study prompted the initiation of a Phase IIb, multicenter, double-blind, randomized, sham surgery-controlled study (STEPS) to further evaluate the safety, tolerability and efficacy of Spheramine. Changes from the pilot study included implantation in both sides of the brain and the addition of a sham surgery group. To date, 71 patients have been randomized for either Spheramine or sham surgery and results from the study will become available later this year. About Parkinson’s Disease Parkinson’s disease is a progressive brain disorder that affects a person’s motor skills which worsen as the disease advances. Early in the disease, there is a loss of brain cells that produce the chemical dopamine. Normally, dopamine operates in a delicate balance with other neurotransmitters to help coordinate the millions of nerve and muscle cells involved in movement. Without enough dopamine, this balance is disrupted, resulting in tremor (trembling in the hands, arms, legs and jaw); rigidity (stiffness of the limbs); slowness of movement; and impaired balance and coordination – the hallmark symptoms of PD. PD affects one in every 100 people over the age of 65. The latest epidemiology studies indicate that worldwide numbers will increase from an estimated 4.1 million in 2005 to 8.7 million people with PD by 2030. There were an estimated 19,500 PD-related deaths in the United States in 2005, an increase of 1,500 deaths from 2004. It is estimated to cost $23 billion a year in direct and indirect costs and lost productivity. Despite therapeutic advancements, oral medications provide insufficient symptom control after the disease has progressed and new approaches are needed. ......... ZenMaster

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ESCs Made to Blood Stem Cells

Tissue-specific Blood Stem Cells Established From Embryonic Stem Cells Monday, 28 April 2008 A research team at the Umeå Center for Molecular Medicine (UCMM) in Sweden, led by Professor Leif Carlsson, has managed to specifically establish and isolate the tissue-specific stem cell that produces blood cells (blood stem cell) by using genetically modified embryonic stem cells. A deeper understanding of the regulation of blood stem cells is important if we are to be able to further develop treatments for diseases that require bone marrow transplants, such as leukaemia, immune deficiencies, and anaemia disorders. Blood stem cells are unique in that they can both continually generate all types of blood cells and also produce new stem cells, so-called self-regeneration. These two properties are the basic reason why we have a functioning blood system throughout our lives and why bone marrow transplants are a functional treatment method. An understanding of how tissue-specific stem cells are produced and regulated is absolutely essential for us to be able to develop forms of treatment in so-called regenerative medicine, that is, where damaged tissue needs to be replaced by new tissue. On source of transplantable cells for this purpose are embryonic stem cells, since they have a unique capacity to generate different types of tissues. But one of the major problems with embryonic stem cells is to be able to establish and isolate tissue-specific stem cells, such as blood stem cells, from these cells in a reproducible manner. Even though the process of self-regeneration is well known, the molecular mechanisms that underlie it are largely unknown. The fact that it is now possible to establish and isolate blood stem cells from embryonic stem cells in a reproducible way will yield key insights into the molecular mechanisms that regulate the function of blood stem cells and will thereby lead to enhanced methods of treatment for patients who need bone marrow transplants, such as leukaemia patients. Reference: Lhx2 expression promotes self-renewal of a distinct multipotential hematopoietic progenitor cell in embryonic stem cell-derived embryoid bodies. Dahl, L., Richter, K., Hägglund, A-C. and Carlsson, L. PLoS ONE (2008) 3(4):e2025 ......... ZenMaster

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To Good To Be True?

Paralyzed man back on his feet after embryonic stem cell therapy Monday, 28 April 2008 The Grand Junction Sentinel in Colorado today report about a man receiving embryonic stem cell treatment in India, after a spinal cord accident several years ago. In December, he went to Dr. Geeta Shroff’s clinic at the Nu Tech Mediworld medical center in New Delhi. She is originally an infertility expert, that say’s she have developed the embryonic stem cell therapy offered there. For the next two months, Rusty Leech received stem cell therapy in several ways: twice-daily injections into his upper arms, three weeks of intravenous stem cell fluids, and five large injections near his spinal cord at the point of his initial injury — the thoracic 10 vertebrae. The treatment also included intense and daily physical therapy designed to help rebuild the muscles that atrophied during the many years of paralysis. He was never told how many stem cells he received, and he doesn’t know exactly how and why Shroff’s treatments work. Shroff’s treatment has been much criticised and questioned, because she has never publicized any details of her procedures. The reason for this, she maintain, is that she is seeking a patent for her therapy in many countries across the globe, including the United States. Is this a miracle cure, or is the improvements seen by Rusty coming from the intense physical therapy only? No-one can really say, before detailed scrutiny of the procedure is disclosed. That this happens, not only at this clinic in New Delhi but at several other locations around the world, is very unfortunate for the medical world, and especially for all suffering patients waiting for some new procedures to alleviate their sufferings. All scientists and medical researchers should, as soon as possible, describe their results in detail, so that the effectiveness can be assessed by others too. It is not moral to wait for patents or any other monetary benefits. Read more at: 'Unbelievable': Paralyzed man back on his feet after embryonic stem cell therapy Grand Junction Sentinel, CO, Monday, April 28, 2008 Watch a Video of Rusty. ......... ZenMaster

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Dinosaurs and Birds Are Close Relatives

Genetic sequencing of protein from T. rex bone confirms dinosaurs' link to birds Study also shows mastodon link to modern elephants Thursday, 24 April 2008 Scientists have put more meat on the theory that dinosaurs' closest living relatives are modern-day birds. Molecular analysis, or genetic sequencing, of a 68-million-year-old Tyrannosaurus rex protein from the dinosaur's femur confirms that T. rex shares a common ancestry with chickens, ostriches, and to a lesser extent, alligators. The dinosaur protein was wrested from a fossil T. rex femur discovered in 2003 by palaeontologist John Horner of the Museum of the Rockies; the bone was found in a fossil-rich stretch of land in Wyoming and Montana. The new research results, published this week in the journal Science, represent the first use of molecular data to place a non-avian dinosaur in a phylogenetic tree, a "tree of life," that traces the evolution of species. "These results match predictions made from skeletal anatomy, providing the first molecular evidence for the evolutionary relationships of a non-avian dinosaur," says Science paper co-author Chris Organ, a researcher at Harvard University. "Even though we only had six peptides – just 89 amino acids – from T. rex, we were able to establish these relationships." "Tests of the peptide sequences in T. rex bone fossils have confirmed that newer methods of molecular systematics agree with more traditional methods of taxonomic classification based on morphology, or shapes," says Paul Filmer, program director in the National Science Foundation (NSF)'s Division of Earth Sciences, which funded the research. Paper co-author Mary Schweitzer of North Carolina State University (NCSU) and the North Carolina Museum of Natural Sciences first discovered the soft-tissue preservation in the T. rex bone in 2005. The current paper builds on work reported in Science last year. In that paper, a team headed by John Asara and Lewis Cantley, both of Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), first captured and sequenced tiny pieces of collagen protein from T. rex. Asara became involved in analysis of the collagen protein because of his expertise in mass spectrometry techniques capable of sequencing minute amounts of protein from human tumours. For the current work, Organ, Asara and colleagues compared collagen protein from several dozen species. The goal: placing T. rex on the animal kingdom's family tree using molecular evidence.

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Genetic sequencing show link of T. rex with birds and mastodons with elephants. Credit: Zina Deretsky, National Science Foundation.

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"Most of the collagen sequence was obtained from protein and genome databases, but we also needed to sequence some critical organisms, including modern alligator and modern ostrich, by mass spectrometry," says Asara. "We determined that T. rex, in fact, grouped with birds – ostrich and chicken – better than any other organism that we studied," he says. "We also showed that it groups better with birds than modern reptiles, such as alligators and green anole lizards." While scientists have long suspected that birds, and not more basal reptiles, are dinosaurs' closest living relatives, for years that hypothesis rested largely on morphological similarities in bird and dinosaur skeletons. The scientists also report that a similar analysis of 160,000 – to 600,000-year-old collagen protein sequences derived from a mastodon bone establishes a close phylogenetic relationship between that extinct species and modern elephants. ......... ZenMaster

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Heart Derived Stem Cells Develop Into Heart Muscle

A First In Stem Cell Research Wednesday, 23 April 2008 Dutch researchers at University Medical Center Utrecht and the Hubrecht Institute have succeeded in growing large numbers of stem cells from adult human hearts into new heart muscle cells. This is a breakthrough in stem cell research. Until now, it was necessary to use embryonic stem cells to make this happen. The work, which was funded in part by the EU, are published in the latest issue of the journal Stem Cell Research. The stem cells are derived from material left over from open-heart operations. Researchers at UMC Utrecht used a simple method to isolate the stem cells from this material and reproduce them in the laboratory, which they then allowed to develop. The cells grew into fully developed heart muscle cells that contract rhythmically, respond to electrical activity, and react to adrenaline. “We’ve got complete control of this process, and that’s unique,” says principal investigator Prof. Pieter Doevendans. “We’re able to make heart muscle cells in unprecedented quantities, and on top of it they’re all the same. This is good news in terms of treatment, as well as for scientific research and testing of potentially new drugs.” Doevendans will use the cultured heart muscle cells to study things like cardiac arrhythmia (abnormal heart rhythms). Stem cells from the hearts of patients with genetic heart defects can be grown into heart muscle cells in the lab. Researchers can then study the cells responsible for the condition straight away. They can also be used to test new medicines. This could mean that research into genetic heart conditions can move forward at a much faster pace. In the future, new heart muscle cells can likely be used to repair heart tissue damaged during a heart attack. For some time now, it has been known that the heart is a source of stem cells. Although in the past researchers from other countries have succeeded in using these cells to make heart muscle cells, this always required the presence of heart muscle cells from newborn mice or rats in the growth medium. The stem cells discovered by the UMC Utrecht researchers are able to develop on their own. Heart muscle cells can also be made from embryonic stem cells (see e.g. article by Lei Yang et al. below). The disadvantage of this method is that the yield is low, because not all cells develop into muscle cells. Also, the ethical considerations of isolating stem cells from embryos are the subject of controversy. EU support for the research came from the EU-funded SC&CR ('Application and process optimization of human stem cells for myocardium repair') project, which is financed through the 'Life sciences, genomics and biotechnology for health' Thematic Area of the Sixth Framework Programme (FP6) and the Heart Development and Heart Repair project. References: TGF-beta-1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro Marie-José Goumans, Teun P. de Boer, Anke M. Smits, Linda W. van Laake, Patrick van Vliet, Corina H.G. Metz, Tom H. Korfage, K. Peter Kats, Ron Hochstenbach, Gerard Pasterkamp, Marianne C. Verhaar, Marcel A.G. van der Heyden, Dominique de Kleijn, Christine L. Mummery, Toon A.B. van Veen, Joost P.G. Sluijter, Pieter A. Doevendans Stem Cell Research, In Press, Available online 12 March 2008, doi:10.1016/j.scr.2008.02.003 Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population Lei Yang, Mark H. Soonpaa, Eric D. Adler, Torsten K. Roepke, Steven J. Kattman, Marion Kennedy, Els Henckaerts, Kristina Bonham, Geoffrey W. Abbott, R. Michael Linden, Loren J. Field & Gordon M. Keller Nature , doi:10.1038/nature06894; Published online 23 April 2008 ......... ZenMaster

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Mature B Cells Reprogrammed To Stem-cell-like State

Fully differentiated cells, can be reprogrammed to induced pluripotent stem cells Thursday, 17 April 2008 Fully mature, differentiated B cells can be reprogrammed to an embryonic-stem-cell-like state, without the use of an egg according to a study published in the April 18 issue of Cell. In previous research, induced pluripotent stem (iPS) cells have been created from fibroblasts, a specific type of skin cells that may differentiate into other types of skin cells. Because there is no way to tell if the fibroblasts were fully differentiated, the cells used in earlier experiments may have been less differentiated and therefore easier to convert to the embryonic-stem-cell-like state of iPS cells. B cells are immune cells that can bind to specific antigens, such as proteins from bacteria, viruses or microorganisms. Unlike fibroblasts, mature B cells have a specific part of their DNA cut out as a final maturation step. “Once that piece of DNA is cut out, it can’t come back,” says Jacob Hanna, first author on the paper and a postdoctoral fellow in Whitehead Member Rudolf Jaenisch’s lab. “Checking the genome give us a way to make sure the resulting iPS cells were not from immature cells.” Hanna and his colleagues began the experiment by generating iPS cells from immature B cells. Similar to the process used to create iPS cells from fibroblast cells, Hanna successfully reprogrammed the immature B cells into iPS cells by using retroviruses to transfer four genes (Oct4, Sox2, c-Myc and Klf4) into the cells DNA. However, an additional factor, CCAAT/enhancer-binding-protein-alfa (C/EBP-alfa), was needed to nudge mature B cells to be reprogrammed as iPS cells. Like iPS cells from earlier fibroblast studies, the iPS cells from both the mature and immature B cells could be used to create mice. The mice grown from the reprogrammed mature B cells were missing the same part of their DNA as the mature B cells, demonstrating that Hanna and his colleagues had successfully reprogrammed fully differentiated cells. In addition to demonstrating the power of reprogramming, this work offers the promise of powerful new mouse models for autoimmune diseases such as multiple sclerosis and type 1 diabetes, in which the body attacks certain types of its own cells. For example, mature B or T cells specific for nerve cells called glia could be reprogrammed to iPS cells and then used to create mice with an entire immune system that is primed to only attack the glia cells, thereby creating a mouse model for studying multiple sclerosis. Eventually, researchers will be able to study diseases by following a similar process with human cells, predicts Jaenisch, who is also a professor of biology at Massachusetts Institute of Technology. “In principle, this will allow you to transfer a complex genetic human disease into a Petri dish, and study it,” he says. “That could be the first step to analyze the disease and to define a therapy.” Reference: Direct reprogramming of terminally differentiated mature B lymphocytes to pluripotency Jacob Hanna, Styliani Markoulaki, Patrick Schorderet, Caroline Beard, Bryce W. Carey, Marius Wernig, Menno P. Creyghton, Eveline J. Steine, John P. Cassady, Christopher J. Lengner, Jessica A. Dausman, Rudolf Jaenisch Cell, Vol 133, 250-264, 18 April 2008 ......... ZenMaster

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James Watson's DNA sequenced... II

James Watson's DNA sequence published Wednesday, 16 April 2008 James Watson's DNA sequence, the first full genome to be sequenced using next-generation rapid-sequencing technology, is published today in Nature. See: The complete genome of an individual by massively parallel DNA sequencing Nature 452, 872-876 17 April 2008, doi:10.1038/nature06884 Comments: James Watson's genome sequenced at high speed Nature 16 April 2008, doi:10.1038/452788b ......... ZenMaster

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Ethics of Lab Made Gametes

The Hinxton Group on Science, Ethics and Policy Challenges of Pluripotent Stem Cell-Derived Gametes Tuesday, 15 April 2008 The Hinxton Consortium, which was formed in 2004 to investigate the ethics and legality of stem cells, yesterday issued its recommendations for how research aimed at creating artificial gametes – sperm and eggs – should proceed. They warn politicians not to block scientific inquiry into subjects such as stem cells and embryo research just because there is a difference of opinion on the ethics or morality of the work. They also said that moral disagreements in society should never be used on their own to stop scientific investigation. "Societies have the authority to regulate science, and scientists have a responsibility to obey the law. However, policy-makers should refrain from interfering with scientific inquiry unless there is a substantial justification for doing so that reaches beyond disagreements based solely on divergent moral conviction. Any interference with scientific inquiry should be derived from reasonable concerns about demonstrable risks of harm to persons, societal institutions, or society as a whole," the consortium said. Scientists are working on a number of ways of making stem cells derived from embryos, or ordinary tissue such as skin, and turning them in the laboratory into mature sperm and eggs that could then be used in IVF clinics for fertility treatment. In Britain, the Human Tissues and Embryo Bill, that is currently making its way through Parliament, would allow research into human artificial gametes but further changes to the law would be needed to allow doctors to use such sperm and eggs on patients. Professor John Harris, a bioethicist at Manchester University who is part of the consortium, said that while the development of artificial sperm or eggs to treat infertile couples was still a long way off, it is important the work is not blocked from the start. "At this stage the real ethical issue is to ensure that the science can continue... Is society ready for it? We don't know that, and of course if it isn't, then it won't happen, but there is probably some considerable time in which this could be discussed," Professor Harris said. "Any tool can have applications that people can object to, from kitchen knives to anything else." The research has also prompted speculation that sperm could be produced from a woman or eggs from a man, allowing lesbian or gay couples to have children to whom both partners make an equal genetic contribution. One possible way of making sperm and eggs would be to engineer them from skin cells. Researchers, however, dismissed the prospect of male eggs and female sperm as science fiction in the new Hinxton group report. Professor Robin Lovell-Badge, of the National Institute for Medical Research in London, and a member of the group’s steering committee, said there may be insuperable barriers to the possibility of one sex making both types of gametes. “It would be very difficult to get eggs from XY cells, and even more difficult to get sperm from XX cells – my own view, indeed, is that the latter is impossible.” Human sex is determined by the inheritance patterns of the X and Y chromosomes: women have two copies of the X, while men have one X and one Y. As several genes that are critical to sperm production are carried on the Y chromosome, this will make it “difficult or even impossible” to turn female cells with two X chromosomes into sperm under any circumstances currently known to science. The production of eggs from male cells is a little less problematic, but even this is likely to be “very difficult”, the report said. Reference: Consensus Statement: Science, Ethics and Policy Challenges of Pluripotent Stem Cell-Derived Gametes The Hinxton Group ......... ZenMaster

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ESCs and Cancer Stem Cells Share Genetic Expression Pattern

ESCs and Cancer Stem Cells Share Genetic Expression Pattern Wednesday, 09 April 2008 A new study suggests that a genetic fingerprint associated with normal embryonic stem cells may be important for the development and function of cancer stem cells. The research, published by Cell Press in the April 10th issue of Cell Stem Cell, demonstrates that embryonic stem cells and multiple types of human cancer cells share a genetic expression pattern that is repressed in normal differentiated cells, a finding that may have significant clinical implications for cancer therapeutics. “Self-renewal is a hallmark of stem cells and cancer, but existence of a shared stemness program remains controversial,” explains study co-author, Dr. Howard Y. Chang from Stanford University. Dr. Chang, Dr. Eran Segal from the Weizmann Institute in Israel and their colleagues constructed a gene module map to systematically relate transcriptional programs in embryonic stem cells (ESCs), adult tissue stem cells and human cancers. The researchers identified two predominant gene modules that distinguish ESCs and adult tissue stem cells. “Importantly, the ESC-like transcriptional program was activated in diverse human epithelial cancers and strongly predicted metastasis and death,” says Dr. Segal. Conversely, the adult tissue stem gene module had an opposite pattern, activated in normal tissues relative to cancer and repressed in various human cancers when compared to normal tissues. Cancer Stem Cells Created With a bit of genetic trickery, the researchers turned normal skin cells into cancer stem cells, a step that will make these naturally rare cells easier to study. Dr. Chang said being able to generate cancer stem cells from normal cells will help move that research forward. "The upshot is that there may be a way to directly create cancer stem cells in the lab so you don't always have to purify these rare cells from patients in order to study them directly," he said. Cancer stem cells are thought to be the ones that drive a cancer, and are therefore the targets of any cancer therapy that must kill them in order to be effective. Understanding these cells has been a challenge, however, because they are rare, difficult to isolate and don't grow well in the lab. The researchers went on to demonstrate that c-Myc, but not other oncogenes, was sufficient to reactivate the ESC-like program in normal and cancer cells. In primary cells transformed by tumour-inducing genes Ras and I(kappa)B(alfa), c-Myc increased the number of tumour-initiating cells that exhibited key properties associated with cancer stem cells and dramatically increased the frequency of tumour formation in mice. The study also demonstrated that cancer stem cells are much more similar to the stem cells found in embryos, which can develop to form all tissue types, than they are to the more-restricted adult stem cells. This finding has important implications for understanding how cells go awry when they become cancerous. Cancer stem cells were first discovered in 1994 by researchers at the University of Toronto. In 2003, Michael Clarke, PhD, who was then at the University of Michigan, discovered cancer stem cells in the first solid tumour, breast cancer in this case, showing that the concept of cancer stem cells wasn't restricted to blood cancers. Clarke has since moved to Stanford, where he is the Karel H. and Avice N. Beekhuis Professor in Cancer Biology. One question among cancer stem cell researchers has been how those cells originate. "By the time a patient comes to a hospital, they already have a cancer, so that process has already happened," Chang said. Generating cancer stem cells in the lab gives scientists insight into how the transformation happens and could lead to new ways of either stopping the transformation early on or detecting and destroying those cells once they form. Chang and first author David Wong, MD, PhD, postdoctoral scholar, began to answer the question of how cancer stem cells originate by comparing genetic activity in embryonic stem cells with the activity in normal adult stem cells. They found a large group of genes that were active only in embryonic cells. They then looked at which genes were active in cancer stem cells and found that the pattern resembled that of embryonic stem cells. The finding was a surprise, given that once embryonic stem cells become committed to forming adult cells, such as skin, brain or blood, they were thought to forever deactivate those embryonic genes. Instead, Chang said this work suggests that when those adult cells become cancerous, they turn those embryonic genes back on. The group also noticed that the genes active in both embryonic and cancer stem cells are controlled by a few biological master regulators. One of those genes, called Myc, has also been shown recently to help convert normal skin cells into embryonic-like cells. By activating two genes in addition to Myc in normal skin cells, those cells were transformed into what appeared to be cancer stem cells. When transplanted into laboratory mice, the cells formed tumours, one hallmark of a true cancer stem cell. From here, Chang and Wong hope to learn more about how these genes activate a cancerous state. "Our particular interest is in using this approach to find the mechanism that turns a normal cell into a cancer stem cell," said Chang. In conclusion, these findings suggest that activation of an ESC-like transcriptional program in differentiated adult cells may induce pathologic self-renewal characteristics of cancer stem cells. Further, the map of gene modules may prove to be a valuable tool for establishing improved standards for classifying and defining stem cells by using the expression signature modules as “fingerprints” rather than reliance on just a few molecular markers. References: Module Map of Stem Cell Genes Guides Creation of Epithelial Cancer Stem Cells David J. Wong, Helen Liu, Todd W. Ridky, David Cassarino, Eran Segal, and Howard Y. Chang Cell Stem Cell, Vol 2, 333-344, 10 April 2008 Inappropriate Expression of Stem Cell Programs? Yingzi Wang, and Scott A. Armstrong Cell Stem Cell, Vol 2, 297-299, 10 April 2008 ......... ZenMaster

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Human ESC Research Reveals Earliest Step in Human Development

Human ESC Research Reveals Earliest Step in Human Development Wednesday, 09 April 2008 Researchers at Johns Hopkins have uncovered the molecular underpinnings of one of the earliest steps in human development using human embryonic stem cells. Their identification of a critical signal mediated by the protein BMP-4 that drives the differentiation of stem cells into what will become the placenta, will be published in the April issue of Cell Stem Cell. The finding, they say, also highlights one aspect of human cell biology that has not been replicated in other animal model systems. It is virtually impossible to use anything other than human embryonic stem cells to gather information of this kind. One reason for the excitement, the investigators say, is that the system can provide a research model to study very early human development, including the formation of placenta which develops from the same early embryo. “The findings was serendipitous and at the same time a very important addition to our understanding of early human development,” says Linzhao Cheng, Ph.D., an associate professor of gynaecology and obstetrics and co-director of the stem cell program of the Johns Hopkins Institute for Cell Engineering. “This is one area of stem cell biology where human and mouse differs significantly and we never would have discovered this if we had limited our studies to using only mouse embryonic stem cells. Adult human stem cells just didn’t work for this.” The research team uncovered their finding during efforts to study a rare human blood disorder caused by mutations in a gene called PIG-A. According to Cheng, a good model to study the disease does not exist as engineered mice without the gene either die before birth, or do not reproduce symptoms found in patients. So using a conventional genetic engineering tool, the researchers tried for years – literally – to knock out PIG-A in adult stem cells, without success. They then turned to knocking out PIG-A in human embryonic stem cells. “Only with the human embryonic stem cells could we grow out the rare cells engineered to lack PIG-A,” says Cheng. The result was the growth of two human embryonic stem cell lines that lack PIG-A, and therefore do not contain any proteins known as glycosylphosphatidylinositol (GPI) anchor proteins on the cell’s surface. GPI anchor proteins attach many different types of proteins involved in cell communication to a cell’s outside surface. Without certain GPI proteins, cells may not function properly. Then the researchers took one more step to verify that their engineered embryonic stem cells behaved like normal stem cells. “We just wanted to make sure that our knockout cells could still differentiate and specialise,” says Cheng. One of the earliest steps of embryonic stem cell differentiation in normal embryonic development is the development of the trophoblast, a layer of seed cells that later develops into the placenta. Trophoblast differentiation, according to Cheng, occurs when embryonic stem cells are exposed to BMP-4 protein, either naturally or in the lab. To their surprise, however, when they treated their knockout cells with BMP-4, the cells did not become trophoblasts. Only when they added the PIG-A gene back into their cells did BMP-4 do its work and cause the cells to become trophoblasts, allowing the researchers to conclude that trophoblast differentiation depends on certain cell surface proteins to receive the BMP-4 signal. Reference: Trophoblast Differentiation Defect in Human Embryonic Stem Cells Lacking PIG-A and GPI-Anchored Cell-Surface Proteins Guibin Chen, Zhaohui Ye, Xiaobing Yu, Jizhong Zou, Prashant Mali, Robert A. Brodsky, and Linzhao Cheng Cell Stem Cell, Vol 2, 345-355, 10 April 2008 ......... ZenMaster

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German Stem Cell Research Debated

DFG Vice President Hacker reinforces call for amendments Wednesday, 09 April 2008 A few days before the German Federal Parliament reaches a decision on the Stem Cell Act, the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) has reinforced its stance on amending current legislation. “The current qualifying date rule, in particular, strongly impedes German stem cell research,” explained DFG Vice President Professor Jörg Hinrich Hacker, while participating in a live chat session on the DFG website. “The best thing for basic research would be if this qualifying date rule, a deadline which restricts the period in which embryonic stem cell lines are allowed to be imported, were to be abolished altogether, as the DFG recommended in a statement on stem cell research it released 18 months ago,” he emphasised. Hacker recently also became President of the Robert Koch Institute (RKI) in Berlin. From the point of view of molecular biologists, even moving the deadline would be an improvement compared to the current situation. Hacker also called for an end to the “criminalisation of German researchers.” The current legislation leaves the legal situation of German researchers involved in cooperative projects with stem cell researchers abroad unclear. “This deters young researchers, in particular, from becoming involved in stem cell research.” The DFG is also of the opinion, said Hacker, that stem cell lines should also be used for diagnostic, therapeutic and preventative purposes. Other topics touched upon during the one-hour live chat session were the prospects for research on adult stem cells. This, Hacker emphasised, is not viewed by the DFG as standing in contrast to research on embryonic stem cells, but as a logical extension. The recent scientific findings on “induced pluripotent stem cells” were also addressed, a topic which Hacker described as a major breakthrough for molecular biology. He also pointed out, however, that research on human embryonic stem cell lines is indispensable in order to be able to estimate and compare the potential for adult or reprogrammed cells. “Embryonic stem cell lines are more or less the gold standard for studies of this kind.” Hacker also took a stand on the issue of ovum donation, which is permitted in some countries. This practice is rejected by the DFG and has nothing to do with the production of embryonic stem cell lines. The debate in Germany is essentially about importing cell lines that have been produced abroad and have already been used for research purposes. Culturing new stem cell lines in Germany is already prohibited by the Embryo Protection Law. The DFG has repeatedly spoken out in favour of keeping the Embryo Protection Law in its current form. In answer to another question, Hacker pointed out that any stem cell lines imported from other countries are also subject to strict assessment. They are required to have originated from embryos that were produced for use in reproductive medicine, but for any one of a number of reasons can no longer be used for that purpose. “Here again, no money is allowed to change hands and the couple from whom the cell line originates need to have given their express permission,” Hacker added. On the question of potential therapeutic uses, Hacker said that “as a general rule of thumb, it takes about ten to fifteen years for a new form of therapy to be developed in biomedicine. If we assume that the first human embryonic stem cell lines were produced ten years ago, then we are now looking at new therapies becoming available in the medium to long term.” He also pointed out that the findings being made in research involving embryonic stem cell lines were also contributing to basic research as well as research aimed at developing new forms of therapy. “Without basic research there is no way we can develop new forms of therapy,” he emphasised. Further Information: Additional information on stem cell research can be found on the DFG’s website. ......... ZenMaster

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Reprogrammed Cells Reduce Parkinson's Symptoms in Rats

Dopamine-producing neurons transplanted into adult rat brains treat behavioural symptoms related to low dopamine levels Tuesday, 08 April 2008 Neurons derived from reprogrammed adult skin cells successfully integrated into foetal mouse brains and reduced symptoms in a Parkinson’s disease rat model, according to a study published on April 7 in the online Early Edition of PNAS. “This is the first demonstration that reprogrammed cells can integrate into the neural system or positively affect neurodegenerative disease,” says Marius Wernig, lead author of the article and a postdoctoral researcher in Whitehead Institute for Biomedical Research member Rudolph Jaenisch’s lab. Researchers in the Jaenisch lab showed in December 2007 that mice with a human sickle-cell anaemia disease trait could also be treated successfully with adult skin cells that had been reprogrammed to an embryonic stem cell-like state. For the neural experiments Wernig used induced pluripotent stem cells (IPS cells), which were created by reprogramming adult skin cells using retroviruses to express four genes (Oct4, Sox2, c-Myc and Klf4) into the cells’ DNA. The IPS cells were then differentiated into neural precursor cells and dopamine neurons using techniques originally developed in embryonic stem cells. In one experiment, Wernig transplanted the neural precursor cells into brain cavities of mouse embryos. The mice were naturally delivered and analyzed nine weeks after the transplantation. Wernig saw that transplanted cells formed clusters where they had been injected and then migrated extensively into the surrounding brain tissues. Using electrophysiological studies conducted by Martha Constantine-Paton from MIT’s McGovern Institute for Brain Research and structural analysis, Wernig also saw that the neural precursor cells that migrated had differentiated into several subtypes of neural cells, including neurons and glia, and had functionally integrated into the brain. The cells "migrate nicely into the brain and mature in the brain," says Marius Wernig. "They adopt functions of mature neurons." To assess the therapeutic potential of the IPS cells, the Jaenisch lab collaborated with Ole Isacson's group at Mclean Hospital/Harvard Medical School and used a rat model for Parkinson's disease, a human condition caused by insufficient levels of the hormone dopamine in a specific part of the midbrain. To mimic this state, the dopamine-producing neurons were killed on one side of the rat brains and the researchers then grafted differentiated dopamine neurons into a part of the rat brains called the striatum. Four weeks after surgery, the rats were tested for dopamine-related behaviour. In response to amphetamine injections, rats typically walk in circles toward the side with less dopamine activity in the brain. Eight of nine rats that received the dopamine neuron transplants showed markedly less or even no circling. Eight weeks after transplantation, the researchers could see that the dopamine neurons had extended into the surrounding brain. “This experiment shows that in vitro reprogrammed cells can in principle be used to treat Parkinson’s disease,” says Jaenisch. “It’s a proof of principle experiment that argues, yes, these cells may have the therapeutic promise that people ascribe to them.” For many years, a small group of patients with Parkinson's disease have received experimental cell transplants using dopamine neurons derived from foetuses. But the use of foetal tissue poses ethical and logistical hurdles for widespread use. Scientists have performed similar experiments in animals using stem cells derived from embryos or created with nuclear transfer, also known as therapeutic cloning. But iPS cells offer a way to avoid the use of embryos as well as the technical challenges of nuclear transfer. And if the cells came from a patient's own skin, there would be no potential complications from immune rejection of foreign tissue. When the team first performed the experiment, many rats developed tumours, which seemed to arise from the fact that not all of the iPS cells had fully transformed into neurons when they were transplanted. Tumours such as these have also been observed in experiments with embryonic stem cells. In this study, however, the researchers performed another set of transplants, first using a cell-sorting method that can identify and remove any cells that have failed to differentiate. "When we eliminated the undifferentiated cells from mixture, we got very clean transplants," says Ole Isacson, a neurologist at Harvard Medical School who collaborated on the transplant experiments. The rats given these purified cells did not go on to develop tumours. He believes that the varying purity of transplants may prove to be a key factor in why some of the foetal cell transplants have not succeeded as well as others. Jaenisch and Wernig are optimistic that this work eventually could be applied to human patients, but caution that major hurdles must be addressed first. Those include finding alternatives to the potentially cancer-causing retroviruses used to transform the skin cells into IPS cells and figuring out the best methods and places to transplant the neural precursor cells in humans. Reference: Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of adult rats with Parkinson’s Marius Wernig, Jian-Ping Zhao, Jan Pruszak, Eva Hedlund, Dongdong Fu, Frank Soldner, Vania Broccoli, Martha Constantine-Paton, Ole Isacson, Rudolf Jaenisch Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0801677105 ......... ZenMaster

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Comprehensive Protein Map of A Stem Cell

A Comprehensive Protein Map of A Stem Cell Friday, 04 April 2008 Researchers have successfully identified over 5,000 proteins that are present in embryonic stem cells, tripling the size of previous results and in the process creating the largest quantified protein map to date. Stem cells hold great potential in biology and medicine, but a host of questions lingers about how they operate and convert into other cells. To help answer these questions, researchers have begun taking a ‘big picture’ approach, identifying all the proteins that are expressed in stem cells. Currently, around 1700 proteins have been identified in stem cells. Now, using mass spectrometry and special “heavy” amino acids (made with carbon-13), Matthias Mann and colleagues quantified 5111 distinct mouse stem cell proteins. As expected, a good portion of these proteins are involved in rapid cell growth, but overall the proteome encompassed a broad range of cell functions. While this study may help uncover new clues to stem cell biology, it does raise the bar on the complexity of these important cells, considering they express at least 25% of all known mouse proteins. Reference: SILAC-labeling and proteome quantitation of mouse embryonic stem cells to a depth of 5111 proteins Johannes Graumann, Nina Hubner, Jeong Beom Kim, Kinarm Ko, Markus Moser, Chanchal Kumar, Jürgen Cox, Hans Schöler and Matthias Mann Molecular and Cellular Proteomics, April 2008, Vol. 7, No. 4 ......... ZenMaster

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Stem Cell Breakthrough Offers Diabetes Hope

Stem Cell Breakthrough Offers Diabetes Hope Thursday, 03 April 2008 Scientists have discovered a new technique for turning embryonic stem cells into insulin-producing pancreatic tissue in what could prove a significant breakthrough in the quest to find new treatments for diabetes. The University of Manchester team, working with colleagues at the University of Sheffield, were able to genetically manipulate the stem cells so that they produced an important protein known as a ‘transcription factor’. Stem cells have the ability to become any type of cell, so scientists believe they may hold the key to treating a number of diseases including Alzheimer’s, Parkinson’s and diabetes. However, a major stumbling block to developing new treatments has been the difficulty scientists have faced ensuring the stem cells turn into the type of cell required for any particular condition – in the case of diabetes, pancreatic cells. “Unprompted, the majority of stem cells turn into simple nerve cells called neurons,” explained Dr Karen Cosgrove, who led the team in Manchester’s Faculty of Life Sciences. “Less than one per cent of embryonic stem cells would normally become insulin-producing pancreatic cells, so the challenge has been to find a way of producing much greater quantities of these cells.” The pancreas contains different types of specialised cells – exocrine cells, which produce enzymes to aid digestion, and endocrine cells, including beta cells, which produce the hormone insulin to regulate the blood glucose levels. Diabetes results when there is not enough insulin to meet the body’s demands. There are two forms of the disease: type-1 diabetes is due to not enough insulin being produced by the pancreas, while type-2 or adult-onset diabetes occurs when the body fails to respond properly to the insulin that is produced. The team found that the transcription factor PAX4 encouraged high numbers of embryonic stem cells – about 20% – to become pancreatic beta cells with the potential to produce insulin when transplanted into the body. Furthermore, the scientists for the first time were able to separate the new beta cells from other types of cell produced using a technique called ‘fluorescent-activated cell sorting’ which uses a special dye to colour the pancreatic cells green. “Research in the United States has shown that transplanting a mixture of differentiated cells and stem cells can cause cancer, so the ability to isolate the pancreatic cells in the lab is a major boost in our bid to develop a successful therapy,” said Dr Cosgrove. “Scientists have had some success increasing the number of pancreatic cells produced by altering the environment in which the stem cells develop, so the next stage of our research will be to combine both methods to see what proportions we can achieve.” Scientists believe that transplanting functional beta cells into patients, most likely into their liver where there is a strong blood supply, offers the best hope for finding a cure for type-1 diabetes. It could also offer hope to those with type-2 diabetes whose condition requires insulin injections. But the more immediate benefit of the team’s research is likely to be in providing researchers with a ready-made supply of human pancreatic cells on which to study the disease process of diabetes and test new drugs. The research, which was funded by the Juvenile Diabetes Research Foundation and the Medical Research Council, is published in the journal Public Library of Science (PLoS) One. Reference: Pax4 enhances beta-cell differentiation of human embryonic stem cells. Liew CG, Shah NN, Briston SJ, Shepherd RM, Khoo CP, Dunne MJ, Moore HD, Cosgrove KE and Andrews PW PLoS One 3(3): e1783, doi:10.1371/journal.pone.0001783 (2008). ......... ZenMaster

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Role For microRNAs In Limb Regeneration

Role For microRNAs In Limb Regeneration Thursday, 03 April 2008 In the March 15th issue of G&D, Dr. Kenneth Poss (Duke University Medical Center) and colleagues reveal that microRNA depletion is a necessary step in tissue regeneration – a discovery with interesting implications for their use in regenerative medicine. Dr. Poss is excited at the prospect that “there may indeed be microRNAs that when manipulated appropriately could impact and even increase the ability of a damaged human organ to regenerate healthy tissue.” Regeneration, the replacement of damaged or lost body parts, is a shared trait among some animal species – as any youngster who has cut an earthworm in half can attest to. But the repair of damaged tissue and organs in higher animals is also one of the primary goals of current stem cell research. The common aquarium pet, zebrafish, is an excellent genetic model system, capable of regenerating its spinal cord, retina, heart and fins. First author, Viravuth Yin, and his colleagues focused on fin regeneration, as it entails the coordination of a large number of different cells types to recreate the functional organ. The scientists noted that many microRNAs were differentially regulated during fin regeneration, but that the expression of one microRNA in particular – miR-133 – showed an antagonistic relationship with fin regeneration: When miR-133 levels are high, fin regeneration is inhibited; When miR-133 levels are low, fin regeneration is promoted. miR-133 is regulated by the FGF signalling pathway, so by tweaking FGF activity, Dr. Poss and colleagues were able to manipulate miR-133 levels. The researchers found that experimentally increasing miR-133 levels slowed regeneration, while decreasing miR-133 levels enhanced regeneration. “The finding that microRNA levels are being controlled during appendage regeneration to assist changes in gene expression makes sense, given how important these RNAs are in developmental biology. We were surprised, though, to see that modulating the amount of a single microRNA family could influence regenerative success in zebrafish,” explains Dr. Poss. ......... ZenMaster

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Human-animal Hybrid Embryos Created in Newcastle

Human-animal Hybrid Embryos Created in Newcastle Wednesday, 02 April 2008 Britain's first human-animal hybrid embryos have been created, forming a crucial first step, scientists believe, towards a supply of stem cells that could be used to investigate debilitating and so far untreatable conditions such as Alzheimer's disease, Parkinson's and motor neurone disease. Lyle Armstrong, who led the work, gained permission in January from the Human Fertilisation and Embryology Authority (HFEA) to create the embryos, known as "cytoplasmic hybrids". He presented the preliminary findings of the project at a conference at the Sennet in Israel the 25th March 2008. His team at Newcastle University produced the embryos by inserting human “banked” cells - derived from a human embryonic stem cell line from Newcastle (Ncl-1) - into a hollowed-out cow egg. An electric shock then induced the hybrid embryo to grow. The embryo, 99.9% human and 0.1% other animal, grew for three days, until it had 32 cells. Eventually, scientists hope to grow such embryos for six days, and then extract stem cells from them. The researchers insisted the embryos would never be implanted into a woman and that the only reason they used cow eggs was due to the scarcity of human eggs. John Burn, head of the Institute of Human Genetics at Newcastle University, said the embryos had been created purely for research and that the research is entirely ethical. He told the BBC's Six O'Clock News last night: "If you look down the microscope it looks like semolina and it stays like that. It's never going to be anything other than a pile of cells. What it does is give us the tools to find out the simple questions: how can we better understand the disease processes by working with those cells in the body?" "This is licensed work which has been carefully evaluated. This is a process in a dish, and we are dealing with a clump of cells which would never go on to develop. It's a laboratory process and these embryos would never be implanted into anyone.” "We now have preliminary data which looks promising but this is very much work in progress and the next step is to get the embryos to survive to around six days when we can hopefully derive stem cells from them." The research has not yet been published, but the team plans to submit the work for peer review in the coming months. Other scientists welcomed the work but also urged caution in interpreting the results. Colin Blakemore, a former head of the Medical Research Council, said: "The creation of hybrid embryos is not illegal and researchers in Newcastle and London were granted provisional licences for such research in January, after extensive consultation by the HFEA ... This research is at a very early stage and no results have been peer-reviewed or published.” "However, these preliminary reports give hope that this approach is likely to provide stem cells for research without the use of human eggs or normal human embryos. The new bill is intended to confirm the arrangements for regulation of this important area of research."

See more:

Scientists create Britain's first hybrid embryos Independent, UK - April 2 2008 British scientists create human hybrid Guardian, UK - April 2 2008 Embryo breakthrough ITN, UK - April 2 2008 British team makes mixed human animal embryos Times Online, UK - April 2 2008 Hybrid embryos made by UK scientists Telegraph, United Kingdom - April 1 2008 UK's first hybrid embryos created BBC News, UK - April 1 2008 ......... ZenMaster

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