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Researchers Induce Alzheimer's Neurons From Pluripotent Stem Cells

2012-01-26T00:22:00.000+01:00

First-ever feat provides new method to understand cause of disease, develop drugs
Thursday, 26 January 2012

Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.

Stem-cell-derived neurons, made from patients
with Alzheimer's disease, provide a new tool for
unraveling the mechanisms underlying the
neurodegenerative disease. In this image, DNA
is shown in blue, dendrites and cell bodies in red
and endosomal markers Rab5 and EEA1 in
green and orange, respectively. Credit: UC San
Diego School of Medicine.

"Creating highly purified and functional human Alzheimer's neurons in a dish – this has never been done before," said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program.

"It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it."

The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

"We're dealing with the human brain. You can't just do a biopsy on living patients," said Goldstein.

"Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory."

Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.

The iPSC-derived neurons from the Alzheimer's patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.

With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.

"The differences between a healthy neuron and an Alzheimer's neuron are subtle," said Goldstein.

"It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results."

The researchers have already produced some surprising findings.

"In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant," Goldstein said, adding that they discovered a different early event plays a bigger role.

The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.

Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer's neurons present a huge opportunity in a desperate fight.

"At the end of the day, we need to use cells like these to better understand Alzheimer's and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us – emotionally and financially."

Source: University of California - San Diego

Contact: Scott LaFee
.........

ZenMaster

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Scientists Learn How Stem Cell Implants Help Heal Traumatic Brain Injury

2012-01-13T00:57:00.003+01:00

Scientists Learn How Stem Cell Implants Help Heal Traumatic Brain Injury
Friday, 13 January 2012

For years, researchers seeking new therapies for traumatic brain injury have been tantalized by the results of animal experiments with stem cells. In numerous studies, stem cell implantation has substantially improved brain function in experimental animals with brain trauma. But just how these improvements occur has remained a mystery.

Now, an important part of this puzzle has been pieced together by researchers at the University of Texas Medical Branch at Galveston. In experiments with both laboratory rats and an apparatus that enabled them to simulate the impact of trauma on human neurons, they identified key molecular mechanisms by which implanted human neural stem cells — stem cells that are in the process of developing into neurons but have not yet taken their final form — aid recovery from traumatic axonal injury.

A significant component of traumatic brain injury, traumatic axonal injury involves damage to axons and dendrites, the filaments that extend out from the bodies of the neurons. The damage continues after the initial trauma, since the axons and dendrites respond to injury by withdrawing back to the bodies of the neurons.

"Axons and dendrites are the basis of neuron-to-neuron communication, and when they are lost, neuron function is lost," said UTMB professor Ping Wu, lead author of a paper on the research appearing in the Journal of Neurotrauma.

"In this study, we found that our stem cell transplantation both prevents further axonal injury and promotes axonal regrowth, through a number of previously unknown molecular mechanisms."

The UTMB researchers began their investigation with a clue from their previous work: they had determined that their neural stem cells secreted a substance called glial derived neurotropic factor, which seemed to help injured rat brains recover from injury. As a first step toward identifying the processes by which GDNF and neural stem cell transplantation produced their beneficial effects, Wu enlisted UTMB professors Larry Denner, Douglas Dewitt and Dr. Donald Prough to use proteomic techniques to compare injured rat brains with injured rat brains into which neural stem cells had been transplanted.

"We identified about 400 proteins that respond differently after injury and after grafting with neural stem cells," Wu said.

"When we grouped them using a state-of-the-art Internet database, we found that a group of cytoskeleton proteins was being changed, and in particular one called alpha-smooth muscle actin, which had never been reported in the neurons before."

Because so many of the proteins that changed were related to axonal structure and function, the UTMB scientists then focused on traumatic axonal injury. Initially working with rats, they confirmed that axons and dendrites suffered damage from trauma; implanted neural stem cells reduced this harm, as well as lowering levels of alpha-smooth muscle actin inside neurons that were raised after trauma.

To probe further into the molecular details of GDNF's role in reducing traumatic axonal injury, the researchers used a system in which human neurons were placed on a flexible membrane that was then suddenly distended with a precisely calibrated puff of gas. Their goal was to simulate the sudden compression and stretching forces exerted on brain cells by a blow to the head.

Initial results from this "rapid stretch injury model" matched those seen in rat experiments, with GDNF protecting axons and dendrites from additional damage in the period after trauma and significantly reducing alpha-smooth muscle actin levels boosted by the simulated injury. In addition, they found evidence linking alpha-smooth muscle actin with RhoA, a small protein that blocks axonal growth after injury. Finally, again taking a cue from their proteomic study, they turned their attention to one component of a protein known as calcineurin, finding that it interacted with GDNF to protect axons and dendrites in the RSI model.

"We're quite excited about these discoveries, because they're highly novel — we now know much more about how GDNF protects axons and dendrites from further injury and promotes their re-growth after trauma," Wu said.

"This kind of detailed study is essential to developing safe and effective therapies for traumatic brain injury."

Source: University of Texas Medical Branch at Galveston
Contact: Jim Kelly
.........

ZenMaster

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Chimeric Macaques Produced for the First Time

2012-01-06T00:07:00.001+01:00

OHSU research produces the world's first primate chimeric offspring
Thursday, 05 January 2012

Newly published research by scientists at Oregon Health & Science University provides significant new information about how early embryonic stem cells develop and take part in formation of the primate species. The research, which took place at OHSU's Oregon National Primate Research Center, has also resulted in the first successful birth of chimeric monkeys — monkeys developed from stem cells taken from two separate embryos. The research will be published this week in the online edition of the journal Cell and will be published in a future printed copy of the journal.

Chimeric macaques. Credit:

Oregon Health & Science
University.

The research was conducted to gain a better understanding of the differences between natural stem cells residing in early embryos and their cultured counterparts called embryonic stem cells. This study also determined that stem cell functions and abilities are different between primates and rodents.

Here's more information about the early primate stem cells that were studied: The first cell type was totipotent cells — cells from the early embryo that have the ability to divide and produce all of the differentiated cells in the placenta and the body of organism. These were compared with pluripotent cells — cells derived from the later stage embryo that have only the ability to become the body but not placenta.

In mice, either totipotent or pluripotent cells from two different animals can be combined to transform into an embryo that later becomes a chimeric animal. However, the current research demonstrated that for reasons yet unknown, chimeric animals can only develop from totipotent cells in a higher animal model: the rhesus macaque. OHSU showed this to be the case by successfully producing the world's first primate chimeric offspring, three baby rhesus macaques named Roku, Hex and Chimero.

"This is an important development — not because anyone would develop human chimeras — but because it points out a key distinction between species and between different kind of stem cells that will impact our understanding of stem cells and their future potential in regenerative medicine," explained Shoukhrat Mitalipov, Ph.D., an associate scientist in the Division of Reproductive and Developmental Sciences at ONPRC.

"Stem cell therapies hold great promise for replacing damaged nerve cells in those who have been paralyzed due to a spinal cord injury or for example, in replacing dopamine-producing cells in Parkinson's patients who lose these brain cells resulting in disease. As we move stem cell therapies from the lab to clinics and from the mouse to humans, we need to understand what these cells do and what they can't do and also how cell function can differ in species."

Source: Oregon Health & Science University

Contact: Jim Newman
.........

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Bone Marrow-derived Cells Differentiate in the Brain through Mechanisms of Plasticity

2011-12-20T01:16:00.000+01:00

Bone Marrow-derived Cells Differentiate in the Brain through Mechanisms of Plasticity
Monday, 19 December 2011

Bone marrow-derived stem cells (BMDCs) have been recognized as a source for transplantation because they can contribute to different cell populations in a variety of organs under both normal and pathological conditions. Many BMDC studies have been aimed at repairing damaged brain tissue or helping to restore lost neural function, with much research focused on BMDC transplants to the cerebellum at the back of the brain. In a recent study, a research team from Spain has found that BMDCs, can contribute to a variety of neural cell types in other areas of the brain as well, including the olfactory bulb, because of a mechanism of "plasticity".

Their results are published in the current issue of Cell Transplantation (20:8).

"To our knowledge, ours is the first work reporting the BMDC's contribution to the olfactory neurons," said study corresponding author Dr. Eduardo Weruaga of the University of Salamanca, Spain.

"We have shown for the first time how BMDCs contribute to the central nervous system in different ways in the same animal depending on the region and cell-specific factors."

In this study, researchers grafted bone marrow cells into mutant mice suffering from the degeneration of specific neuronal populations at different ages, then compared them to similarly transplanted healthy controls. An increase in the number of BMDCs was found along the lifespan in both experimental groups. Six weeks after transplantation, however, more bone marrow-derived microglial cells were observed in the olfactory bulbs of the test animals where the degeneration of mitral cells was still in progress. The difference was not observed in the cerebellum where cell degeneration had been completed.

"Our findings demonstrate that the degree of neurodegenerative environment can foster the recruitment of neural elements derived from bone marrow," explained Dr. Weruaga.

"But we also have provided the first evidence that BMDCs can contribute simultaneously to different encephalic areas through different mechanisms of plasticity – cell fusion for Purkinje cells - among the largest and most elaborately dendritic neurons in the human brain – and differentiation for olfactory bulb interneurons."

Dr. Weruaga noted that they confirmed that BMDCs fuse with Purkinje cells but, unexpectedly, they found that the neurodegenerative environment had no effect on the behavior of the BMDCs.

"Interestingly, the contribution of BMDCs occurred through these two different plasticity mechanisms, which strongly suggests that plasticity mechanisms may be modulated by region and cell type-specific factors," he said.

"This study shows a potential new contribution of bone marrow derived cells following transplantation into the brain, making these cells highly versatile, in their ability to both differentiate into and fuse with endogenous neurons" said Dr. Paul R. Sanberg , coeditor-in-chief of Cell Transplantation and distinguished professor of Neuroscience at the Center of Excellence for Aging and Brain Repair, University of South Florida.

Source: Cell Transplantation Center of Excellence for Aging and Brain Repair

Contact: David Eve

Reference:

Bone Marrow Contributes Simultaneously to Different Neural Types in the Central Nervous System Through Different Mechanisms of Plasticity
Recio, J. S.; Álvarez-Dolado, M.; Díaz, D.; Baltanás, F. C.; Piquer-Gil, M.; Alonso, J. R.; Werunga, E.
Cell Transplant. 20(8):1179-1192; 2011
.........

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Grafting of Human Spinal Stem Cells into ALS Rats Best with Immunosuppressant Combination

2011-12-20T01:08:00.000+01:00

Grafting of Human Spinal Stem Cells into ALS Rats Best with Immunosuppressant Combination
Monday, 19 December 2011

A team of researchers grafting human spinal stem cells into rats modeled with amyotrophic lateral sclerosis (ALS), also known as "Lou Gehrig's Disease," a degenerative, lethal, neuromuscular disease, have tested four different immunosuppressive protocols aimed at determining which regimen improved long-term therapeutic effects. Their study demonstrated that a combined, systematically delivered immunosuppression regimen of two drugs significantly improved the survival of the human spinal stem cells. Their results are published in the current issue of Cell Transplantation (20:8).

"There are no therapeutic strategies that successfully modify ALS progression or outcome," said study corresponding author Dr. Michael P. Hefferan of the University of California at San Diego Neurodegeneration Laboratory.

"Cell-based transplantation therapies have emerged as potential treatments for several neurological disorders, including ALS. However, cell graft survival seems to greatly depend on an accompanying immunosuppression regimen, yet there are differential responses to identical immunosuppressive therapies."

While the reason for this differential response is unclear, the study authors suggest that several mechanisms, including distinct types of acute and inflammatory responses, may be to blame.

Their study aimed at optimizing an immunosuppressive protocol for transplanting human spinal cord cells into pre-symptomatic ALS G93A rats with the G93A superoxide dismutase (SOD1) mutation. Two drugs, tacrolimus (FK506) and mycophenolate, were used alone and in combination.

"Although FK506 has been used successfully as monotherapy in our previous studies of spinal ischemia, it failed in the present study on ALS," explained Dr. Hefferan, who speculated that inflammation played a role in the failure.

"In contrast to ALS, where spinal inflammation continues and likely worsens until end stage, the traumatically-injured spinal cord is typically characterized by an acute inflammatory phase followed by a progressive loss of most inflammatory markers."

According to the researchers, the animals receiving combined immunosuppression of both FK506 and mycophenolate likely benefited from the longer half-life of mycophenolate rather than from its action.

"The addition of mycophenolate seemed to supplement inhibition of T-cell formation and led to a robust graft survival when analyzed three weeks after grafting," concluded Dr. Hefferan.

Source: Cell Transplantation Center of Excellence for Aging and Brain Repair

Contact: David Eve

Reference:

Optimization of Immunosuppressive Therapy for Spinal Grafting of Human Spinal Stem Cells in a Rat Model of ALS
Hefferan, M. P.; Johe, K.; Hazel, T.; Feldman, E. L.; Lunn, J. S.; Marsala, M.
Cell Transplant. 20(8):1153-1161; 2011
.........

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iPS Cells Match Embryonic Stem Cells in Modeling Human Disease

2011-12-20T00:56:00.003+01:00

iPS Cells Match Embryonic Stem Cells in Modeling Human Disease
Monday, 19 December 2011

Stanford University School of Medicine investigators have shown that iPS cells, viewed as a possible alternative to human embryonic stem cells, can mirror the defining defects of a genetic condition — in this instance, Marfan syndrome — as well as embryonic stem cells can. An immediate implication is that iPS cells could be used to examine the molecular aspects of Marfan on a personalized basis. Embryonic stem cells, on the other hand, can't do this because their genetic contents are those of the donated embryo, not the patient's.

This proof-of-principle regarding the utility of induced pluripotent stem cells also has more universal significance, as it advances the credibility of an exciting approach that's been wildly acclaimed by some and viewed through gimlet eyes by others: the prospect of using iPS cells in modeling a broad range of human diseases. These cells, unlike ESCs, are easily obtained from virtually anyone and harbor a genetic background identical to the patient from which they were derived. Moreover, they carry none of the ethical controversy associated with the necessity of destroying embryos.

"Our in vitro findings strongly point to the underlying mechanisms that may explain the clinical manifestations of Marfan syndrome," said Michael Longaker, MD, professor of surgery and senior author of the study, which will be published online Dec. 12 in Proceedings of the National Academy of Sciences. Longaker is the Dean P. and Louise Mitchell Professor in the School of Medicine and co-director of the school's Institute for Stem Cell Biology and Regenerative Medicine. The study's first author is Natalina Quarto, PhD, a senior research scientist in Longaker's laboratory.

Marfan syndrome is an inherited connective-tissue disorder that occurs in one in 10,000 to one in 20,000 individuals. It is caused by any of a large number of defects in one gene. People with this condition tend to be very tall and thin and to suffer from osteopenia, or poor bone mineralization. Medical experts speculate that Abraham Lincoln, for example, suffered from this disorder. Marfan can also profoundly affect the eyes and cardiovascular system.

In this study, both iPS cells and embryonic stem cells carrying a mutation that causes Marfan syndrome showed impaired ability to form bone, and all too readily formed cartilage. These aberrations mirror the most prominent clinical manifestation of the disease.

Discovered in 2006, induced pluripotent stem cells, or iPS cells, are derived from fully differentiated tissues such as the skin. Yet they harbor the same capacity of embryonic stem cells to differentiate into all the tissues of the body as well as to replicate for indefinite periods in a dish. Because they offer an ethically uncomplicated alternative to embryonic stem cells, iPS cells have fueled the hope that they can replace ESCs in scientists' efforts to analyze, in a dish, the cellular defects ultimately responsible for diseases ranging from diabetes to Parkinson's and even such complex conditions as cardiovascular disease and autism.

One hope for iPS cells is to be able to differentiate them in a dish into tissues of interest — say, nerve cells of a patient with Parkinson's or autism — and study these resulting cells' characteristics with an eye to understanding the disease in a patient-specific way. This would be impossible to do with embryonic stem cells, unless ESCs from donated human eggs could be modified through the so-far insurmountable feat of substituting a patient's own genetic material into these eggs to reflect the patient's own genetic background.

While scientists have set the goal of using these cells for more than research purposes — developing therapeutic applications in regenerative medicine — that prospect is more distant. Scientists will have to develop the capacity first to repair within such cells, whether iPS or ESC, the genetic defects determined to be responsible for a patient's condition, and then differentiate the cells in bulk into the affected tissue, which could be used for regenerative medicine. Again, iPS cells in theory might be a better bet because, being initially derived from a particular patient, they could differentiate into tissues that are less likely to provoke graft rejection than similar tissues produced using a donor embryo's ESCs.

However, a number of studies have reported subtle differences between iPS cells and ESCs, implying that the two may not be equivalent. Experts have wondered whether these differences may render iPS cells inadequate substitutes for ESCs in modeling disease states. This study suggests otherwise, Longaker said.

The opportunity for a head-to-head comparison of ESCs and iPS cells arose serendipitously when Barry Behr, PhD, professor of obstetrics and gynecology and director of the Stanford Fertility & Reproductive Medicine Center, performed pre-implantation genetic diagnosis to select embryos for in vitro fertilization. Behr and Renee Reijo-Pera, PhD, professor of obstetrics and gynecology and director of the Stanford Center for Reproductive and Stem Cell Biology, discovered that one candidate embryo carried a genetic mutation that causes Marfan syndrome. This embryo was thus not deemed fit for implantation. But it was a potential source of embryonic stem cells, each of which would carry the Marfan-causing mutation. So, rather than discarding or storing it, the researchers received permission to derive the embryonic stem cells Longaker's team studied. (Both Behr and Reijo-Pera are co-authors of the study.)

What followed was a collaboration featuring an all-star cast that included senior faculty members from several departments in the medical school as well as researchers at the University of Naples Federico II in Italy. The researchers generated ESCs from the Marfan-carrying embryo. They also obtained skin biopsies from Marfan patients from another Stanford co-author, Uta Francke, MD, professor of genetics and of pediatrics, and used cells called fibroblasts from these samples to derive iPS cells by means of what have now become routine procedures.

"Here we had both iPS cells and embryonic stem cells side by side in culture dishes, both containing the defective gene responsible for Marfan. This was a perfect opportunity to compare them head to head," Longaker said.

When they did that, Longaker, Quarto and their associates found that both the iPS cells derived from the skin of Marfan patients and the ESCs from the embryonic Marfan carrier exhibited aberrations identical to those that characterize the disorder's observed skeletal symptoms — a diminished capacity to form bone and a heightened propensity for forming cartilage instead.

The scientists began the study with the knowledge that mutations causing Marfan syndrome are found in a gene that codes for a protein called FIBRILLIN-1. Importantly, FIBRILLIN-1 is known, in turn, to inhibit the activity of an intercellular signaling molecule named TGF-beta. Mouse studies have indicated that the absence or mutation of FIBRILLIN-1 results in a failure of this inhibition. This study showed for the first time in humans that the reason for stem cells' failure to form bone and overzealous conversion to cartilage directly resulted from their consequent exposure to more, and more-activated, TGF-beta than normal people's cells are.

The success of iPS cells in faithfully reproducing Marfan's cellular and molecular defects every bit as well as ESCs do may allow the disease to be studied (and, in the long run, even treated) in a case-by-case manner. While Marfan is a single-gene disorder, it can and does result from any of a large number of mutations to that one gene — upward of 600 have been identified so far —which manifest as a spectrum of subtle differences in symptoms from one patient to the next.

Source: Stanford University Medical Center

Contact: Bruce Goldman
.........

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Adult Stem Cells Use Special Pathways to Repair Damaged Muscle

2011-12-03T00:56:00.001+01:00

Discovery could help future treatments for muscle repairs, disorders
Saturday, 03 December 2011

When a muscle is damaged, dormant adult stem cells called satellite cells are signaled to "wake up" and contribute to repairing the muscle. University of Missouri researchers recently found how even distant satellite cells could help with the repair, and are now learning how the stem cells travel within the tissue. This knowledge could ultimately help doctors more effectively treat muscle disorders such as muscular dystrophy, in which the muscle is easily damaged and the patient's satellite cells have lost the ability to repair.

D Cornelison, an associate professor of biological

sciences in the College of Arts and Science and

a researcher in the Bond Life Sciences Center,

says knowing how adult stem cells travel could

help treatments for muscle disorders such as

muscular dystrophy. Credit: MU News Bureau.

"When your muscles are injured, they send out a 'mayday' for satellite cells to come and fix them, and those cells know where to go to make more muscle cells, and eventually new muscle tissue," said D Cornelison, an associate professor of biological sciences in the College of Arts and Science and a researcher in the Bond Life Sciences Center.

"There is currently no effective satellite cell-based therapy for muscular dystrophy in humans. One problem with current treatments is that it requires 100 stem cell injections per square centimeter, and up to 4,000 injections in a single muscle for the patient, because the stem cells don't seem to be able to spread out very far. If we can learn how normal, healthy satellite cells are able to travel around in the muscles, clinical researchers might use that information to change how injected cells act and improve the efficiency of the treatment."

Video: When a muscle is damaged, dormant

adult stem cells called satellite cells are signaled

to “wake up” and contribute to repairing the

muscle. Credit: MU News Bureau.

In a new study, researchers in Cornelison's lab used time-lapse microscopy to follow the movement of the satellite cells over narrow "stripes" of different proteins painted onto the glass slide. The researchers found that several versions of a protein called ephrin had the same effect on satellite cells: the cells that touch stripes made of ephrin immediately turn around and travel in a new direction.

"The stem cell movement is similar to the way a person would act if asked to walk blindfolded down a hallway. They would feel for the walls," Cornelison said.

"Because the long, parallel muscle fibers carry these ephrin proteins on their surface, ephrin might be helping satellite cells move in a straighter line towards a distant 'mayday' signal."

Source: University of Missouri-Columbia

Contact: Steven Adams
.........

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Not All Cellular Reprogramming is Created Equal

2011-12-03T00:42:00.001+01:00

Not All Cellular Reprogramming is Created Equal
Friday, 02 December 2011

Like embryonic stem cells, iPS cells can become any cell type in the body, a characteristic that could make them well-suited for therapeutic cell transplantation or for creating cell lines to study such diseases as Parkinson's and Alzheimer's. Inconsistencies in iPS cell quality reported in a number of recent studies have tarnished their promise, dampened enthusiasm, and fueled speculation that they may never be used therapeutically.

Tweaking the levels of factors used during the reprogramming of adult cells into induced pluripotent stem (iPS) cells greatly affects the quality of the resulting iPS cells, according to Whitehead Institute researchers.

"This conclusion is something that I think is very surprising or unexpected — that the levels of these reprogramming factors determine the quality of the iPS cells," says Whitehead Founding Member Rudolf Jaenisch.

"We never thought they'd make a difference, but they do."

An article describing this work is published in the December 2 issue of Cell Stem Cell.

iPS cells are made by introducing specific reprogramming genes into adult cells. These factors push the cells into a pluripotent state similar to that of embryonic stem (ES) cells. Like ES cells, iPS cells can become any cell type in the body, a characteristic that could make them well-suited for therapeutic cell transplantation or for creating cell lines to study such diseases as Parkinson's and Alzheimer's.

Since the creation of the first iPS cells in 2006, researchers using various reprogramming techniques have reported a broad spectrum of efficiency rates and quality of resulting iPS cells. Although researchers have shown iPS cells can fulfill all developmental tests applied to ES cells, recent reports have identified molecular differences that can influence their developmental potential and render them less-than-equivalent partners to ES cells. These inconsistencies have tarnished the promise of iPS cells, dampened enthusiasm, and fueled speculation that they may never be used therapeutically.

In one example reported last year, a lab created iPS cells using a cutting-edge technique in which a piece of DNA containing four reprogramming genes is safely integrated in the genome of adult mouse cells. In this highly publicized study, the resulting iPS cells performed poorly in tests of pluripotency and failed to produce adult mice, which is the most stringent test of pluripotency. Yet again this called into question the fidelity by which reprogramming factors could consistently generate fully reprogrammed cells equivalent to ES cells. Many in the field saw this as another nail in the coffin of iPS cells.

To Bryce Carey, first author of the Cell Stem Cell paper and a graduate student in Jaenisch's lab at the time, this death knell seemed premature. He repeated the experiment, changing a few details, including the order in which the reprogramming factors were placed on the inserted piece of DNA. Surprisingly, such small alterations had a profound effect — more adult cells were converted to high-quality iPS cells than in the earlier, nearly identical study.

"We are trying to show that the reprogramming process is not as flawed as some have thought, and that you can isolate these fully pluripotent iPS cells that have all of the developmental potential as embryonic stem cells at a pretty high frequency," says Carey, who is now a postdoctoral associate at Rockefeller University.

"A lot of times these parameters are very difficult to control, so while the approach first described by [Shinya] Yamanaka back in 2006 is still the most reliable method for research purposes, we should be cautious in concluding there are inherent limitations. We show recovery of high-quality cells doesn't have to be the exception."

Source: Whitehead Institute for Biomedical Research

Contact: Nicole Giese

Reference:

Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells
Bryce W. Carey, Styliani Markoulaki, Jacob Hanna, Dina A. Faddah, Yosef Buganim, Jongpil Kim, Kibibi Ganz, Eveline J. Steine, John P. Cassady, Menno P. Creyghton, G. Grant Welstead, Qing Gao, and Rudolf Jaenisch
Cell Stem Cell, December 2, 2011, 10.1016/j.stem.2011.11.003
.........

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Japanese Researchers Repairing Spinal Cord Injury with Human Dental Pulp Stem Cells

2011-12-03T00:27:00.001+01:00

Japanese Researchers Repairing Spinal Cord Injury with Human Dental Pulp Stem Cells
Saturday, 03 December 2011

One of the most common causes of disability in young adults is spinal cord injury. Currently, there is no proven reparative treatment. Hope that a stem cell population, specifically dental pulp stem cells, might be of benefit to individuals with severe spinal cord injury has now been provided by the work of Akihito Yamamoto and colleagues, at Nagoya University Graduate School of Medicine, Japan, in a rat model of this devastating condition.

In the study, when rats with severe spinal cord injury were transplanted with human dental pulp stem cells they showed marked recovery of hind limb function. Detailed analysis revealed that the human dental pulp stem cells mediated their effects in three ways: they inhibited the death of nerve cells and their support cells; they promoted the regeneration of severed nerves; and they replaced lost support cells by generating new ones. Yamamoto and colleagues therefore hope that this approach can be translated into an effective treatment for severe spinal cord injury.

Source: Journal of Clinical Investigation

Contact: Karen Honey

Reference:

Human dental pulp–derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms
Kiyoshi Sakai, Akihito Yamamoto, Kohki Matsubara, Shoko Nakamura, Mami Naruse, Mari Yamagata, Kazuma Sakamoto, Ryoji Tauchi, Norimitsu Wakao, Shiro Imagama, Hideharu Hibi, Kenji Kadomatsu, Naoki Ishiguro and Minoru Ueda
J Clin Invest. 2011, doi:10.1172/JCI59251
.........

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Bush Embryonic Stem Cell Lines Different from Newly Derived Cell Lines

2011-12-03T00:17:00.001+01:00

Bush Embryonic Stem Cell Lines Different from Newly Derived Cell Lines
Friday, 02 December 2011

Established human embryonic cell lines, including those approved for federal research funding under former President George W. Bush, are different than newly derived human embryonic stem cell lines, according to a study by UCLA stem cell researchers.

The finding, by scientists with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, points to the importance of continuing to derive new stem cell lines so researchers can better understand pluripotency, the ability of these cells to make every cell in the human body, said study senior author Amander Clark, an assistant professor of molecular, cell and developmental biology in Life Sciences.

"It is critical to find out the characteristics that result in the highest quality pluripotent stem cell lines that we can make," Clark said.

"It is possible that we have not set the bar high enough yet for embryonic stem cells or induced pluripotent stem cells. We now know that established lines are different from newly derived lines and now we have to find out how important that is."

The study appears Nov. 30, 2011 in the early online edition of the peer-reviewed journal Human Molecular Genetics.

The study looked at the first six human embryonic stem cell lines developed by Clark's research team at UCLA from 2009 to 2011, which have since been accepted by the National Institute of Health's embryonic stem cell registry, founded by executive order in March 2009. Acceptance into the registry allows the UCLA lines to be used in federally funded research projects.

In her study, Clark decided to examine X chromosome inactivation and the mechanisms by which female stem cells turn off one X chromosome during development because it is a large physical marker that is easy to visualize in individual cells. Clark wanted to compare this specific molecular signature in established embryonic stem cell lines versus what occurs during the derivation of new embryonic stem cell lines from human blastocysts.

The established lines examined in the study were from a group of stem cell lines derived prior to 2001. The field has known for many years that the majority of established lines, Clark said, had already undergone X chromosome inactivation, and her work confirmed this finding. However, with the progression of time, Clark found that the molecular signature no longer reflected the normal process of X chromosome inactivation.

The X chromosome normally is inactivated by non-coding RNA and a special form of chromatin in female cells. In abnormal states, such as those found in the older, established human embryonic stem cells, the X chromosome is inactive, but this process is not regulated by the non-coding RNA and the chromatin is different.

"The classic signature is gone, so something else is regulating X chromosome inactivation in the established cell lines," Clark said.

"It will be important not only to find out what that is, but also to discover what else is changing in the nucleus that we cannot see regardless of whether the cell line is male or female."

The new cell lines generated by Clark's research team were derived from human embryos that were donated to the Broad Stem Cell Research Center by couples who had previously undergone in vitro fertilization to overcome infertility. The couples no longer planned to store or use their frozen embryos for reproductive purposes and had declined to donate the embryos to others for reproductive use.

The human embryos were transferred from the fertility clinic to the derivation lab at UCLA in frozen vials. They were then thawed by Clark's research team, and at six to seven days of development the embryos, or blastocysts, contained a cluster of cells called the inner cell mass. The inner cell mass is the source of new embryonic stem cell lines.

Clark's lab examined the human embryonic stem cell lines three to four weeks after growth from the inner cell mass and found that both X chromosomes were still active in many cells, making them more like the cells from the original inner cell mass.

Slowly, with time in culture and cryopreservation – how the lines are ultimately stored – one X chromosome is inactivated and the cell lines become identical to the older, established lines, including abnormal X chromosome inactivation, Clark said.

The question, Clark said, is whether the first cells to grow out from the inner cell mass are of a higher quality, and therefore the ones researchers should be aspiring to use for research and potentially therapeutically.

"It may prove to be important to stabilize these cells at that very young state, one that's closest in identity to the inner cell mass," Clark said.

"And then we can ask whether these cells give the best quality when differentiated into clinical cell types."

Keeping both X chromosomes active will also be important in modeling diseases such as Rett syndrome.

Going forward, Clark will study human embryonic stem cells in three states, lines in which the X chromosome is inactivated by normal means, lines in which the chromosome is inactivated abnormally and lines in which both X chromosomes remain active. Clark will seek to understand the differentiation potential of each of the three states.

"Our data highlights the importance of maintaining human embryonic stem cell derivation efforts. Gold standard human embryonic stem cell lines should be the benchmark for all human pluripotent stem cell research," the study states.

"Developing new experimental approaches aimed at sustaining human pluripotent nuclei in an epigenetic state closer in identity to the day six or seven day human blastocyst is to work towards a more robust gold standard."

Source: University of California - Los Angeles Health Sciences

Contact: Kim Irwin
.........

ZenMaster

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Singapore Scientists Lead Human Embryonic Stem Cell Study

2011-12-02T23:51:00.001+01:00

Singapore Scientists Lead Human Embryonic Stem Cell Study
Friday, 02 December 2011

Researchers from A*STAR Singapore took lead roles in a study that identified a portion of the genome mutated during long-term culture of human embryonic stem cells (hESCs). The study was a worldwide collaboration, led by Drs Peter Andrews of the University of Sheffield (UK), Paul Robson of the Genome Institute of Singapore (GIS), Steve Oh of Singapore's Bioprocessing Technology Institute (BTI), and Barbara Knowles and others in the international stem cell community. The GIS, IMB and BTI are research institutes under the umbrella of the Agency for Science, Technology and Research, (A*STAR), Singapore.

Involving 125 ethnically diverse hESC lines originating from 38 laboratories globally, and now identified to represent multiple ethnic groups from different parts of the globe, the study is the largest to be conducted on the genetic stability of cultured hESCs. The findings are published today in the journal Nature Biotechnology.

Research into the variability of hESCs is very important as these cells may lead to future cell therapy and regenerative medicine. During long-term culture, however, these cells can acquire genetic changes (mutations), some of which could compromise the cells' utility for regenerative medicine. It is believed that mutations that arise and endure over long-term culture provide a selective advantage for the cells, such as a greater propensity for self-renewal.

The study re-emphasized that many chromosome changes occur repeatedly, resulting in increased copies in specific areas of the genome. Interestingly, through molecular karyotyping performed in Dr Robson's laboratory at the GIS, about 20% of the karyotypically normal cell lines exhibited subkaryotypic amplifications of a specific region in chromosome 20. This is also one of the karyotypically defined areas of change. The minimal region common to these cells contains three ES-cell expressed genes, and one of them, BCL2L1, is a strong candidate for driving hESC culture adaptation. The data generated in this study will be useful for understanding the frequency and types of genetic changes affecting cultured hESCs, an important issue in evaluating the cells for potential therapeutic applications.

Dr Paul Robson, Senior Group Leader of the Developmental Cellomics Laboratory, GIS, said:
"Not only does this work provide important information for evaluating human embryonic stem cell genetic integrity, it also highlights the general utility of these cells in understanding human biology and disease. This same region has recently been identified to repeatedly occur in numerous human cancer cell types, this likely indicative of similar selection pressures at play in stem cells and cancer cells. Interestingly, we found the propensity for mutation at this location is associated with a relatively recent chromosomal rearrangement that occurred in the last common ancestor of the human, chimp, and gorilla thus pointing to the value of having a comparative perspective for understanding human biology."

Dr Barbara Knowles, Principle Investigator at IMB added:
"This is a prodigious piece of community work comparing the genome of cell lines from around the world that were sampled after they had been grown in cell culture for a short period of time to samples from the same cell lines taken after they had been in culture for a longer period of time. Scientists at GIS used these globally obtained samples to pinpoint an area of the genome that contains a gene(s) that affects the cell's ability to control its own growth."

Dr Steve Oh, Principal Scientist at BTI said:
"This study took over three years to complete and is a great testimony of the international stem cell community working persistently together as a force for good. A special thanks goes to Prof Peter Andrews for his leadership! The fact that of the 125 cell lines tested, over 65% of them exhibited normal karyotypes in long term culture bodes well for the use of human embryonic stem cells for cell therapy in the future."

Source: Agency for Science, Technology and Research (A*STAR), Singapore

Contact: Winnie Serah Lim

Reference:

Screening a large, ethnically diverse population of human embryonic stem cells identifies a chromosome 20 minimal amplicon that confers a growth advantage
The International Stem Cell Initiative
Nature Biotechnology, 27 November, 2011, doi:10.1038/nbt.2051
.........

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Neurons Grown from Skin Cells May Hold Clues to Autism

2011-11-27T20:16:00.001+01:00

Rare syndrome's workings could help explain how brain wiring goes awry
Sunday, 27 November 2011

Potential clues to how autism miswires the brain are emerging from a study of a rare, purely genetic form of the disorders that affects fewer than 20 people worldwide. Using cutting-edge "disease-in a-dish" technology, researchers funded by the National Institutes of Health have grown patients' skin cells into neurons to discover what goes wrong in the brain in Timothy Syndrome. Affected children often show symptoms of autism spectrum disorders along with a constellation of physical problems.

Representative iPSC-derived neurons from

Timothy syndrome patient (bottom) shows

increased numbers of neurons that produce

the chemical messengers norepinephrine

and dopamine, compared to those from a

control subject (top). Credit: Ricardo

Dolmetsch, Ph.D., Stanford University.

Abnormalities included changes in the composition of cells in the cortex, the largest brain structure in humans, and of neurons that secrete two key chemical messengers. Neurons that make long-distance connections between the brain's hemispheres tended to be in short supply.

Most patients with Timothy Syndrome meet diagnostic criteria for an autism spectrum disorder. Yet, unlike most cases of autism, Timothy syndrome is known to be caused by a single genetic mutation.

"Studying the consequences of a single mutation, compared to multiple genes with small effects, vastly simplifies the task of pinpointing causal mechanisms," explained Ricardo Dolmetsch, Ph.D., of Stanford University, a National Institute of Mental Health (NIMH) grantee who led the study. His work was partially funded by a NIH Director's Pioneer Award.

Dolmetsch, and colleagues, report on their findings Nov. 27, 2011 in the journal Nature Medicine.

"Unlike animal research, the cutting-edge technology employed in this study makes it possible to pinpoint molecular defects in a patient's own brain cells," said NIMH Director Thomas R. Insel, M.D..

"It also offers a way to screen more rapidly for medications that act on the disordered process."

Prior to the current study, researchers knew that Timothy syndrome is caused by a tiny glitch in the gene that code for a calcium channel protein in cell membranes. The mutation results in too much calcium entering cells, causing a tell-tale set of abnormalities throughout the body. Proper functioning of the calcium channel is known to be particularly critical for proper heart rhythm – many patients die in childhood of arrhythmias – but its role in brain cells was less well understood.

To learn more, Dolmetsch and colleagues used a new technology called induced pluripotent stem cells (iPSCs). They first converted skin cells from Timothy Syndrome patients into stem cells and then coaxed these to differentiate into neurons.

"Remarkable reproducibility" observed across multiple iPSC lines and individuals confirmed that the technique can reveal defects in neuronal differentiation – such as whether cells assume the correct identity as the brain gets wired-up in early development, said the researchers. Compared to those from controls, fewer neurons from Timothy Syndrome patients became neurons of the lower layers of the cortex and more became upper layer neurons. The lower layer cells that remained were more likely to be the kind that project to areas below the cortex. In contrast, there were fewer-than-normal neurons equipped to form a structure, called the corpus callosum, which makes possible communications between the left and right hemispheres.

Forebrain of a mouse genetically engineered

to express the mutated gene that causes

Timothy syndrome (TS) shows fewer neurons

contributing to a brain structure responsible

for long-distance communications between

the left and right hemispheres, called the

corpus callosum, compared to the same

structure in a control animal (Ctrl). Human

iPSCs from TS patients showed a similar

reduction. Credit: Ricardo Dolmetsch, Ph.D.,

Stanford University.

Many of these defects were also seen in parallel studies of mice with the same genetic mutation found in Timothy syndrome patients. This supports the link between the mutation and the developmental abnormalities.

Several genes previously implicated in autism were among hundreds found to be expressed abnormally in Timothy Syndrome neurons. Excess cellular calcium levels also caused an overproduction of neurons that make key chemical messengers. Timothy Syndrome neurons secreted 3.5 times more norepinephrine and 2.3 times more dopamine than control neurons. Addition of a drug that blocks the calcium channel reversed the abnormalities in cultured neurons, reducing the proportion of catecholamine-secreting cells by 68 percent.

The findings in Timothy Syndrome patient iPSCs follow those in Rett Syndrome, another single gene disorder that often includes autism-like symptoms. About a year ago, Alysson Muotri, Ph.D., and colleagues at University of California, San Diego, reported deficits in the protrusions of neurons, called spines, which help form connections, or synapses. The Dolmetsch team's discovery of earlier (neuronal fate) and later (altered connectivity) defects suggest that disorders on the autism spectrum affect multiple stages in early brain development.

"Most of these abnormalities are consistent with other emerging evidence that ASDs arise from defects in connectivity between cortex areas and show decreased size of the corpus callosum," said Dolmetsch.

"Our study reveals how these might be traceable to specific mechanisms set in motion by poor regulation of cellular calcium. It also demonstrates that neurons derived from iPSCs can be used to identify the cellular basis of a neurodevelopmental disorder."

The mechanisms identified in this study may become potential targets for developing new therapies for Timothy Syndrome and may also provide insights into the neural basis of deficits in other forms of autism, said Dolmetsch.

Source: NIH/National Institute of Mental Health

Contact: Jules Asher

Reference:

Using iPS cell-derived neurons to uncover cellular phenotypes associated with Timothy Syndrome
Pasca SP, Portmann T, Voineagu I, Yazawa M, Shcheglovitov O, Pasca AM, Cord B, Palmer TD, Chikahisa S, Seiji N, Bernstein JA, Hallmayer J, Geschwind DH, Dolmetsch RE.
Nature Medicine, November 27, 2011, doi:10.1038/nm.2576
.........

ZenMaster

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Genetic Study Confirms that the First Dogs Came from East Asia

2011-11-23T21:31:00.001+01:00

Researchers at Sweden's KTH Royal Institute of Technology say they have found further proof that the wolf ancestors of today's domesticated dogs can be traced to southern East Asia
Wednesday, 23 November 2011

Researchers at Sweden's KTH Royal Institute of Technology say they have found further proof that the wolf ancestors of today's domesticated dogs can be traced to southern East Asia – findings that run counter to theories placing the cradle of the canine line in the Middle East.

Dr Peter Savolainen, KTH researcher in evolutionary genetics, says a new study released Nov. 23 confirms that an Asian region south of the Yangtze River was the principal and probably sole region where wolves were domesticated by humans.

Data on genetics, morphology and behaviour show clearly that dogs are descended from wolves, but there's never been scientific consensus on where in the world the domestication process began.

"Our analysis of Y-chromosomal DNA now confirms that wolves were first domesticated in Asia south of Yangtze River – we call it the ASY region – in southern China or Southeast Asia", Savolainen says.

The Y data supports previous evidence from mitochondrial DNA.

"Taken together, the two studies provide very strong evidence that dogs originated in the ASY region", Savolainen says.

Archaeological data and a genetic study recently published in Nature suggest that dogs originate from the Middle East. But Savolainen rejects that view.

"Because none of these studies included samples from the ASY region, evidence from ASY has been overlooked," he says.

Peter Savolainen and PhD student Mattias Oskarsson worked with Chinese colleagues to analyse DNA from male dogs around the world. Their study was published in the scientific journal Heredity.

Approximately half of the gene pool was universally shared everywhere in the world, while only the ASY region had the entire range of genetic diversity.

"This shows that gene pools in all other regions of the world most probably originate from the ASY region", Savolainen says.

"Our results confirm that Asia south of the Yangtze River was the most important – and probably the only – region for wolf domestication, and that a large number of wolves were domesticated", says Savolainen.

In separate research published recently in Ecology and Evolution, Savolainen, PhD student Arman Ardalan and Iranian and Turkish scientists conducted a comprehensive study of mitochondrial DNA , with a particular focus on the Middle East. Because mitochondrial DNA is inherited only from the mother in most species, it is especially useful in studying evolutionary relationships.

"Since other studies have indicated that wolves were domesticated in the Middle East, we wanted to be sure nothing had been missed. We find no signs whatsoever that dogs originated there", says Savolainen.

In their studies, the researchers also found minor genetic contributions from crossbreeding between dogs and wolves in other geographic regions, including the Middle East.

"This subsequent dog/wolf hybridisation contributed only modestly to the dog gene pool", Savolainen explains.

Source: Swedish Research Council

Contact: Katarina Ahlfort
.........

ZenMaster

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Lab Creates Cells Used by Brain to Control Muscle Cells

2011-11-22T20:09:00.001+01:00

Lab Creates Cells Used by Brain to Control Muscle Cells
Tuesday, 22 November 2011

University of Central Florida researchers, for the first time, have used stem cells to grow neuromuscular junctions between human muscle cells and human spinal cord cells, the key connectors used by the brain to communicate and control muscles in the body.

Dr. Hickman has been working on this

project for more than a decade.

Credit: University of Central Florida.

The success at UCF is a critical step in developing "human-on-a-chip" systems. The systems are models that recreate how organs or a series of organs function in the body. Their use could accelerate medical research and drug testing, potentially delivering life-saving breakthroughs much more quickly than the typical 10-year trajectory most drugs take now to get through animal and patient trials.

"These types of systems have to be developed if you ever want to get to a human-on-a-chip that recreates human function," said James Hickman, a UCF bioengineer who led the breakthrough research.

"It's taken many trials over a number of years to get this to occur using human derived stem cells."

Hickman's work, funded through the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health, is described in the December issue of Biomaterials.

Hickman is excited about the future of his research because several federal agencies recently launched an ambitious plan to jump-start research in "human-on-a-chip" models by making available at least $140 million in grant funding.

The National Institutes of Health (NIH), the Defense Advanced Research Projects Agency (DARPA), and the Federal Drug Administration (FDA) are leading the research push.

The goal of the call for action is to produce systems that include various miniature organs connected in realistic ways to simulate human body function. This would make it possible, for instance, to test drugs on human cells well before they could safely and ethically be tested on living humans. The technique could potentially be more effective than testing in mice and other animals currently used to screen promising drug candidates and to develop other medical treatments.

Such conventional animal testing is not only slow and expensive, but often leads to failures that might be overcome with better testing options. The limitations of conventional testing options have dramatically slowed the emergence of new drugs, Hickman said.

The successful UCF technique began with a collaborator, Brown University Professor Emeritus Herman Vandenburgh, who collected muscle stem cells via biopsy from adult volunteers. Stem cells are cells that can, under the right conditions, grow into specific forms. They can be found among normal cells in adults, as well as in developing fetuses.

Nadine Guo, a UCF research professor, conducted a series of experiments and found that numerous conditions had to come together just right to make the muscle and spinal cord cells "happy" enough to join and form working junctions. This meant exploring different concentrations of cells and various timescales, among other parameters, before hitting on the right conditions.

"Right now we rely a lot on animal systems for medical research but this is a pure human system," Guo said.

"This work proved that, biologically, this is workable."

Besides being a key requirement for any complete human-on-a-chip model, such nerve-muscle junctions might themselves prove important research tools. These junctions play key roles in Amyotrophic lateral sclerosis, commonly known as Lou Gehrig's disease, in spinal cord injury, and in other debilitating or life threatening conditions. With further development, the team's techniques could be used to test new drugs or other treatments for these conditions even before more expansive chip-based models are developed.

Source: University of Central Florida

Contact: Barbara Abney
.........

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Researchers Turn Embryonic Stem Cells into Functioning Neurons

2011-11-22T17:15:00.001+01:00

Implanted neurons, grown in the lab, take charge of brain circuitry
Tuesday, 22 November 2011

Among the many hurdles to be cleared before human embryonic stem cells can achieve their therapeutic potential is determining whether or not transplanted cells can functionally integrate into target organs or tissues.

Writing today (Monday, Nov. 21) in the Proceedings of the National Academy of Sciences, a team of Wisconsin scientists reports that neurons, forged in the lab from blank slate human embryonic stem cells and implanted into the brains of mice, can successfully fuse with the brain's wiring and both send and receive signals.

Neurons are specialized, impulse conducting cells that are the most elementary functional unit of the central nervous system. The 100 billion or so neurons in the human brain are constantly sending and receiving the signals that govern everything from walking and talking to thinking. The work represents a crucial step toward deploying customized cells to repair damaged or diseased brains, the most complex human organ.

"The big question was can these cells integrate in a functional way," says Jason P. Weick, the lead author of the new study and a staff scientist at the University of Wisconsin-Madison's Waisman Center.

"We show for the first time that these transplanted cells can both listen and talk to surrounding neurons of the adult brain."

The Wisconsin team tested the ability of their lab grown neurons to integrate into the brain's circuitry by transplanting the cells into the adult mouse hippocampus, a well-studied region of the brain that plays a key role in processing memory and spatial navigation. The capacity of the cells to integrate was observed in live tissue taken from the animals that received the cell transplants.

Weick and colleagues also reported that the human neurons adopted the rhythmic firing behavior of many brain cells talking to one another in unison. And, perhaps more importantly, that the human cells could modify the way the neural network behaved.

A critical tool that allowed the UW group to answer this question was a new technology known as optogenetics, where light, instead of electric current, is used to stimulate the activity of the neurons.

"Previously, we've been limited in how efficiently we could stimulate transplanted cells. Now we have a tool that allows us to specifically stimulate only the transplanted human cells, and lots of them at once in a non-invasive way," says Weick.

Weick explains that the capacity to modulate the implanted cells was a necessary step in determining the function of implanted cells because previous technologies were too imprecise and unreliable to accurately determine what transplanted neurons were doing.

Embryonic stem cells, and the closely related induced pluripotent stem cells can give rise to all of the 220 types of tissues in the human body, and have been directed in the lab to become many types of cells, including brain cells.

The appeal of human embryonic stem cells and induced pluripotent cells is the potential to manufacture limitless supplies of healthy, specialized cells to replace diseased or damaged cells. Brain disorders such as Parkinson's disease and amyotrophic lateral sclerosis, more widely known as Lou Gehrig's disease, are conditions that scientists think may be alleviated by using healthy lab grown cells to replace faulty ones. Multiple studies over the past decade have shown that both embryonic stem cells and induced cells can alleviate deficits of these disorders in animal models.

The new study opens the door to the potential for clinicians to deploy light-based stimulation technology to manipulate transplanted tissue and cells.

"The marriage between stem cells and optogenetics has the potential to assist in the treatment of a number of debilitating neurodegenerative disorders," notes Su-Chun Zhang, a UW-Madison professor of neuroscience and one of the authors of the new PNAS report.

"You can imagine that if the transplanted cells don't behave as they should, you could use this system to modulate them using light."

Source: University of Wisconsin-Madison

Contact: Jason P. Weick

Reference:

Human embryonic stem cell-derived neurons adopt and regulate the activity of an established neural network
Jason P. Weick, Yan Liu, and Su-Chun Zhang
Proceedings of the National Academy of Sciences, November 21, 2011, doi:10.1073/pnas.1108487108
.........

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Recipient's Immune System Governs Stem Cell Regeneration

2011-11-20T21:31:00.001+01:00

Controlling a stem cell transplant recipient’s immune response may be major key to successful bone regeneration
Sunday, 20 November 2011

A new study in Nature Medicine describes how different types of immune system T-cells alternately discourage and encourage stem cells to regrow bone and tissue, bringing into sharp focus the importance of the transplant recipient's immune system in stem cell regeneration.

The study, conducted at the Center for Craniofacial Molecular Biology at the Ostrow School of Dentistry of USC, examined how mice with genetic bone defects responded to infusions of bone marrow mesenchymal stem cells, or BMMSC.

Under normal conditions, the mice's T-cells produced an inflammatory response and triggered the creation of cellular proteins interferon (INF)-g and tumor necrosis factor (TNF)-a. These attacked and killed the stem cells, preventing the production of new bone.

"Normally, T-cells protect us from infection," said Professor Songtao Shi, corresponding author for the study, "but they can block healthy regeneration from happening."

However, when the mice were given infusions of regulatory T-cells, or Treg, the levels of the interfering INF- g and TNF- a decreased, increasing the rate of bone growth and defect repair. Furthermore, administering the anti-inflammatory drug aspirin at the site of the bone defect also increased the rate at which the BMMSCs were able to regrow bone.

Postdoctoral Research Associate and lead author Yi Liu said the findings illustrate the previously unrecognized role of T-cells in tissue regeneration. They also highlight the need for scientists exploring the possibilities of stem cell regeneration to shift their focus to the immune system, she added.

"Based on what we've found, this should be the direction of more research in the future," Liu said.

Source: University of Southern California

Contact: Beth Dunham

Reference:

Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α
Yi Liu, Lei Wang, Takashi Kikuiri, Kentaro Akiyama, Chider Chen, Xingtian Xu, Ruili Yang, WanJun Chen, Songlin Wang, and Songtao Shi
Nature Medicine doi: 10.1038/nm.2542
.........

ZenMaster

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Foetal Stem Cells from Placenta May Help Maternal Heart Recover from Injury

2011-11-15T08:46:00.001+01:00

Foetal Stem Cells from Placenta May Help Maternal Heart Recover from Injury
Tuesday, 15 November 2011

Researchers from Mount Sinai School of Medicine have discovered the therapeutic benefit of foetal stem cells in helping the maternal heart recover after heart attack or other injury. The research, which marks a significant advancement in cardiac regenerative medicine, was presented today at the American Heart Association's (AHA) Scientific Sessions 2011 in Orlando, Florida, and is also published in the current issue of Circulation Research, a journal of the AHA.

In the first study of its kind, the Mount Sinai researchers found that foetal stem cells from the placenta migrate to the heart of the mother and home to the site where an injury, such as a heart attack, occurred. The stem cells then reprogram themselves as beating heart stem cells to aid in its repair. The scientists also mimicked this reprogramming in vitro, showing that the foetal cells became spontaneously beating heart cells in cell culture, which has broad-reaching implications in treating heart disease.

Previous studies have documented a phenomenon in which half of women with a type of heart failure called peripartum cardiomyopathy saw their condition spontaneously recover in the months following pregnancy. Based on this evidence, the Mount Sinai team wanted to determine whether foetal stem cells played a role in maternal recovery.

They evaluated the hearts of pregnant female mice that underwent mid-gestation heart injury and survived. Using green fluorescent protein in the foetuses to tag the foetal stem cells derived from the placenta, they found that the green fluorescent stem cells homed to the injured hearts of their mothers, grafted onto the damaged tissue, and differentiated into smooth muscle cells, blood vessel cells, or another type of heart cell called cardiomyocytes.

"Our research shows that foetal stem cells play an important role in inducing maternal cardiac repair," said Hina Chaudhry, MD, Director of Cardiovascular Regenerative Medicine at Mount Sinai School of Medicine, and principal investigator of the study.

"This is an exciting development that has far-reaching therapeutic potential."

With a broader understanding of the role of foetal stem cells, Dr. Chaudhry and her team then isolated the foetal cells that had grafted onto the maternal hearts and recreated the environment in vitro. They found that the cells spontaneously differentiated into cardiac cells in cell culture as well.

Until now, researchers have had limited success in discovering the regenerative potential of stem cells in heart disease. The use of bone marrow cells in cardiac regeneration has largely failed as well. Dr. Chaudhry's research team has found that foetal cells may potentially be a viable therapeutic agent, both through in vivo and in vitro studies.

"Identifying an ideal stem cell type for cardiac regeneration has been a major challenge in heart disease research," said Dr. Chaudhry.

"Embryonic stem cells have shown potential but come with ethical concerns. We've shown that foetal stem cells derived from the placenta, which is discarded postpartum, have significant promise. This marks a significant step forward in cardiac regenerative medicine."

These findings have implications beyond cardiovascular disease. The foetal stem cells travelled only to the injury site on the damaged heart, and not to other undamaged organs, meaning research on the benefit of these cells on organs damaged by other diseases would be beneficial. Importantly, a significant percentage of the foetal cells isolated from maternal hearts express a protein called Cdx2, which indicates that the cells may not have developed mature immune recognition molecules and therefore are unlikely to cause a negative immune response, which occurs in organ transplant.

"Our study shows the promise of these cells beyond just cardiovascular disease," said Dr. Chaudhry.

"Additionally, this breakthrough greatly underscores the importance of translational research. As a clinician who also has a basic science laboratory, I am in the unique position to assess the needs of my patients, evaluate how they respond to treatment and recover from illness, and bring that anecdotal knowledge to the experiments in my lab."

Source: Mount Sinai School of Medicine

Contact: Mount Sinai Press Office
.........

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Stem Cell Study Helps Clarify the Best Time for Therapy to Aid Heart Attack Survivors

2011-11-15T08:39:00.001+01:00

Stem Cell Study Helps Clarify the Best Time for Therapy to Aid Heart Attack Survivors
Tuesday, 15 November 2011

A research network led by a Mayo Clinic physician found that stem cells obtained from bone marrow delivered two to three weeks after a person has a heart attack did not improve heart function. This is the first study to systematically examine the timing and method of stem cell delivery and provides vital information for the field of cell therapy.

The results were presented this morning at the 2011 Scientific Sessions of the American Heart Association Meeting in Orlando, Fla. They also will be published online in JAMA to coincide with the presentation.

"Some data suggests that stem cell therapy is helpful within the first week after a heart attack," says Robert Simari, M.D., cardiologist at Mayo Clinic and chairman of the Cardiovascular Cell Therapy Research Network (CCTRN). The network includes five clinics and other sites supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.

"Our study helps identify the limits of when stem cell therapy might be beneficial. We now know that this therapy should not be extended two to three weeks after a heart attack. While it is safe to do so, we did not find any benefit to heart function after six months."

Between July 2008 and February 2011, 87 people with heart attacks and moderate to severe left ventricular dysfunction received their own bone marrow mononuclear stem cells (BMCs) or placebo. The study, called LateTIME, developed a standardized method of processing the BMCs and was the first such trial to provide a uniform dose to each participant.

The researchers assessed heart function through a cardiac MRI by measuring the ejection fraction, or what percentage of blood is pumped out of the left ventricle during each contraction. No significant differences were found in the cardiac function readings between baseline and six months in the BMC group (from 48.7 percent to 49.2 percent) or the placebo group (from 45.3 percent to 48.8 percent).

Dr. Simari says that earlier studies suggest patients with severe heart attacks benefit most from stem cell therapy. The researchers were interested in studying the two- to three-week period because many people who have severe heart attacks are not well enough or stable enough to receive cells right after their heart attacks.

"Many are on life support or other systems, and we didn't think that studying them that early was the best way to assess the benefits to the sickest patients," Dr. Simari says.

The LateTIME study offers a cautionary lesson for people who have had heart attacks and are considering going overseas to seek stem cell treatment.

"We would suggest that individuals not seek treatment outside of the U.S. for therapies that aren't proven effective," Dr. Simari says. The researchers think that the heart may be less receptive to such therapies two to three weeks after a heart attack, or that a person's stem cells are less potent at that time.

Jay Traverse, M.D., lead author of the study and a cardiologist at the Minneapolis Heart Institute at Abbott Northwestern Hospital, says patients will be followed clinically for two years in the LateTIME study.

"There may still be other benefits to stem cell therapy that may be uncovered over time," Dr. Traverse says.

"We observed that patients who received the cell therapy had fewer adverse events such as placement of defibrillators or repeat revascularization compared to patients who got the placebo, consistent with observations in some of the European trials. This therapy may provide hidden safety measures that reduce adverse events and that's something we will follow closely."

LateTIME is one of three heart stem cell trials being conducted by CCTRN. The other trials will explore the effectiveness of stem cell therapy delivered at three days and seven days following a heart attack, and the usefulness of stem cell therapy in people with chronic heart failure.

Source: Mayo Clinic

Contact: Traci Klein
.........

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Delayed Stem Cell Therapy Following Heart Attack is Safe but Not Effective

2011-11-15T08:33:00.001+01:00

NIH-funded trial shows that therapy with bone-marrow derived cells does not improve heart function after six months; Future clinical benefits still possible
Tuesday, 15 November 2011

Stem cells obtained from bone marrow, known as BMCs, can be safely injected into people 2-3 weeks following a heart attack, reports a new clinical trial supported by the National, Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health. However, while safe, the BMCs did not improve heart function six months after their administration.

This study, called LateTIME (Transplantation in Myocardial Infarction Evaluation), is the first trial to rigorously examine the safety and potential benefits of extending the timing of stem cell delivery to 2-3 weeks following a heart attack. The results will be presented Monday, Nov. 14, at the 2011 Scientific Sessions of the American Heart Association Meeting in Orlando, Fla. They will also appear online in the Journal of the American Medical Association.

"Although treatment and survival following a heart attack have improved over the years, the risk of heart failure following a heart attack has not decreased," said Susan B. Shurin, M.D., acting director of the NHLBI.

"Stem cell therapy is a promising direction for repairing the damage done by a heart attack. We do not fully understand the optimal use of these cells; studies like LateTIME will help us understand how to perform and monitor these procedures.''

Previous studies have suggested that injecting BMCs into the heart could improve cardiac function following a heart attack and perhaps reduce the need for future hospitalizations and heart surgeries. In contrast to LateTIME, earlier studies delivered BMCs within a few days of the heart attack. In many cases, a patient will not be able to get such immediate treatment, due to poor health following a heart attack or because the hospital providing care doesn't have a stem cell therapy program.

Between July 2008 and February 2011, LateTIME enrolled 87 people with heart attacks who had undergone cardiac procedures to open blocked arteries. The participants all had moderate to severe impairment in their left ventricle, which pumps oxygen-rich blood to the body. All the participants had stem cells taken from bone marrow in their hip for processing. LateTIME researchers developed a standardized method of processing and purifying these stem cells, and this was the first BMC trial to provide a uniform dose of BMCs to each participant. The study then randomly assigned the participants to receive either their purified BMCs or inactive (placebo) cells.

After six months, improvement of heart function was assessed by measuring the percentage of blood that gets pumped out of the left ventricle during each contraction (left-ventricular ejection fraction, or LVEF) by cardiac MRI. There were no significant differences between the change in LVEF readings between baseline and six months in the BMC (from 48.7 percent to 49.2 percent) or placebo (from 45.3 percent to 48.8 percent) groups.

"This does not mean that stem cell therapy will only work if done immediately following a heart attack or that later beneficial effects on clinical outcomes won't emerge," noted Lemuel A. Moyé, M.D., Ph.D., professor of biostatistics at the University of Texas School of Public Health, Houston, and a LateTIME researcher.

"Many factors influence how the heart responds to stem cells, which highlights the critical need to continue rigorous tracking studies in this area."

Moyé added that the health of the study participants will continue to be evaluated for two years, so the BMC therapy may yet demonstrate health benefits such as a lower risk of subsequent heart attacks or heart failure, in which the heart cannot pump enough blood to meet the body's needs.

LateTIME is one of three heart stem cell trials being undertaken by the NHLBI-sponsored Cardiovascular Cell Therapy Research Network. The other trials under way by this multicentre consortium are TIME, which is comparing the effectiveness of stem cell therapy delivered at three days versus seven days following a heart attack, and FOCUS, which is examining stem cell therapy in people with chronic heart failure.

Source: NIH/National Heart, Lung and Blood Institute

Contact: NHLBI Communications
.........

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New Method for Producing Precursor of Neurons, Bone and Other Important Tissues from Stem Cells

2011-11-15T06:52:00.001+01:00

New Method for Producing Precursor of Neurons, Bone and Other Important Tissues from Stem Cells
Tuesday, 15 November 2011

In principle, stem cells offer scientists the opportunity to create specific cell types — such as nerve or heart cells — to replace tissues damaged by age or disease. In reality, coaxing stem cells to become the desired cell type can be challenging, to say the least.

University of Georgia Researcher Stephen

Dalton has developed a method that – in a

single step – directs undifferentiated, or

pluripotent, stem cells to become neural

crest cells, which are the precursors of

bone cells, smooth muscle cells and

neurons. Credit: University of Georgia.

In a paper published this week in the journal Proceedings of the National Academy of Sciences, however, scientists at the University of Georgia describe a method that — in a single step — directs undifferentiated, or pluripotent, stem cells to become neural crest cells, which are the precursors of bone cells, smooth muscle cells and neurons.

"Now that we have methods for efficiently making neural crest stem cells, we can start to use them to better understand human diseases," said lead author Stephen Dalton, Georgia Research Alliance Eminent Scholar of Molecular Biology and professor of cellular biology in the UGA Franklin College of Arts and Sciences.

"The cells can be also used in drug discovery and potentially in cell therapy, which involves the transplantation of cells."

The process by which a pluripotent stem cell, which has the ability to become any type of cell in the body, becomes a specific cell type is orchestrated by signaling molecules that activate specific "decision" pathways within cells. As a stem cell divides, various combinations of these molecules at different points during its development narrow its possible outcomes so that it ultimately becomes one type of cell, a skin cell, for example, instead of, say, a muscle cell.

Until now, creating neural crest cells relied on a mix of science and serendipity. Scientists would take undifferentiated stem cells and direct them to become a related but different cell type known as neural progenitor cells. The neural crest cells they really wanted would often show up as contaminants, which scientists would then isolate and use for their studies. Not surprisingly, the process was laborious, time consuming, expensive and sub-optimal for clinical applications.

The method developed by Dalton and a post-doctoral researcher in his laboratory, Laura Menendez, involves bathing cells in a solution of small molecules that suppress one pathway, known as Smad, and amplify another, known as Wnt. The inhibition of Smad is used in the process that creates the related neural progenitor cells, which suggested that the pathway could also play a role in the development of neural crest cells. Observing that the Wnt pathway is highly active in the formation of the neural crest in developing organisms led Dalton and his team to suspect that activating the pathway could give them the cells they needed. After testing various concentrations of the signaling molecules and determining the optimal time to deliver them, the scientists discovered that they could create neural crest cells with little or no contamination of other cell types.

The new method cuts the amount of time required to generate the cells by approximately one-half. Dalton said another benefit is that instead of using costly large-molecule compounds known as growth factors and cytokines to direct the differentiation of cells, his method uses inexpensive small molecules that have a much higher degree of consistency.

With their newly developed ability to create neural crest cells, Dalton and his team are working to gain a deeper understanding of normal development — as well as what goes wrong in devastating diseases that are associated with neural crest defects, such as Hirschsprung's disease, DiGeorge syndrome and Treacher-Collins syndrome.

The cells that Dalton and his team have created are self-renewing, which means that multiple additional cells can be created from an initial batch. Having large numbers of cells that can easily be stored is essential for drug testing as well as for cell transplantation, the holy grail of stem cell science.

"Now that we've worked out ways for making the cells, we've greatly enhanced their potential in disease modeling and regenerative medicine," Dalton said.

Source: University of Georgia

Contact: Stephen Dalton
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Self-organized Pituitary-like Tissue from Mouse ES Cells

2011-11-15T05:53:00.001+01:00

Self-organized Pituitary-like Tissue from Mouse ES Cells
Tuesday, 15 November 2011

The possibility that functional, three-dimensional tissues and organs may be derived from pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), represents one of the grand challenges of stem cell research, but is also one of the fundamental goals of the emerging field of regenerative medicine. Developmental biology has played a central role in informing such efforts, as it has been shown that stem cell differentiation can be directed to follow a given lineage pathway by culturing stem cells in conditions that recapitulate the specific cellular and molecular environment from which such cells normally emerge during embryogenesis. Intriguingly, recent work has shown that when ES cells are cultured under the appropriate conditions, they can be driven to self-organize into complex, three-dimensional tissue-like structures that closely resemble their physiological counterparts, a remarkable advance for the field.

New work by Hidetaka Suga of the Division of Human Stem Cell Technology, Yoshiki Sasai, Group Director of the Laboratory for Organogenesis and Neurogenesis, and others has unlocked the most recent achievement in self-organized tissue differentiation, steering mouse ESCs to give rise to tissue closely resembling the hormone-secreting component of the pituitary, known as the adenohypophysis, in vitro. Conducted in collaboration with Yutaka Oiso at the Nagoya University Graduate School of Medicine, this work was published in Nature.

The Sasai group has complied an impressive list of achievements in induced differentiation using an ES cell culture technique dubbed SFEBq (shorthand for "serum-free floating culture of embryoid body-like aggregates with quick re-aggregation"), including high-efficiency methods for the differentiation of dopaminergic, cerebral cortex, cerebellar Purkinje, and other neuronal cell types. In recent years, refinements of this approach have enabled the first tantalizing insights into the developmental capacity of pluripotent stem cells, showing their ability to give rise to multi-cell-type populations of cortical and retinal neurons that spontaneously self-organize into stratified tissue nearly identical to that of the developing embryo.

In the group's most recent work, Suga sought to use SFEBq to derive the secretory component of the pituitary (hypophysis) from mouse ES cells. In embryonic development, the pituitary emerges from a region of the non-neural (rostral) head ectoderm, adjacent to the anterior neural plate. Guided by molecular interactions, this placodal region forms an indentation, known as Rathke's pouch, in the developmental predecessor of the roof of the mouth, and eventually gives rise to the anterior section of the pituitary, the source of hormones involved in growth, reproduction and modulating the physiological response to stress.

The Sasai lab had previously reported how a modified version of the SFEBq approach lacking extrinsic growth factors could spur ES cells to give rise to hypothalamic neurons. Building on this finding, Suga found by further tweaking the conditions he could steer populations of such stem cells to differentiate simultaneously into the neighboring rostral head ectoderm and hypothalamic neuroectoderm, both of which are required to development of the adenohypophysis. Interestingly, the cells in these clusters spontaneously organized into distinct layers resembling those of the corresponding embryonic tissues. This effect appears to be attributable to the increase of BMP signaling in larger cell aggregates, leading to differentiation into non-neural ectoderm. To test whether co-culture of this ectoderm with hypothalamic tissue would lead to the formation of Rathke's pouch-like structures, Suga observed the ESC-derived aggregates for nearly two weeks, and found that by adding the signaling factor Sonic hedgehog, he was able to induce the self-directed formation of this vesicular tissue.

The next important test was whether this in vitro anterior pituitary anlage would show similar functionality to the physiological activity of the adenohypophysis. Of the many critically important pituitary hormones, they chose adenocorticotropic hormone (ACTH) for their first assay. Previous research had suggested that Notch signaling interferes with the development of ACTH-secreting cells, so the group added a Notch blocker to the culture medium and found that this triggered the generation of such cells at high efficiencies. Following a similar principle, they showed that by adding Wnt, glucocorticoid and insulin to the culture at appropriate doses and stages, they could obtain growth hormone-secreting cells in quantity. By varying the recipe of the growth factor cocktail, they were able to induce other pituitary hormones as well. And, critically, the group was able to show that in vitro hormone secretion could respond to requisite signals and engage in regulatory feedback just as in the body.

In a final series of experiments, Suga et al. transplanted the ESC-derived ACTH-secreting tissue into the kidneys of adult mice whose own pituitary glands had been ablated, to see whether it would be capable of compensating for pituitary function in this model system. Within a week of transplantation, these mice showed strong overall survival, a marked rise in ACTH levels and a concomitant increase in corticosterone (a glucocorticoid hormone stimulated by ACTH) over un-transplanted controls, which uniformly weakened and died within eight weeks of hypophysectomy.

Yoshiki Sasai, leader of the study, commented on this most recent demonstration of the remarkable self-organizing capabilities of embryonic stem cells in vitro.

"We have previously shown how ES cells can give rise to self-organized, three-dimensional neuronal and sensory tissues, and in this report we describe for the first time how this principle can be used to generate to an endocrine tissue, suggesting our approach is of general applicability. Suga, himself an endocrinologist, remarks, "We currently treat pituitary deficiencies by hormone replacement, but achieving the correct dosage is not a straightforward problem, given the naturally fluctuating levels secreted within the body. I am hopeful that this new finding will lead to further advances in regenerative medicine in the endocrine system."

Source: RIKEN

Contact: Douglas Sipp
.........

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Stem Cell Research Hopes to Repair Brain Damage of Parkinson's disease

2011-11-12T00:12:00.001+01:00

Stem Cell Research Hopes to Repair Brain Damage of Parkinson's disease
Friday, 11 November 2011

Australian scientists have developed a new technique using stem cells, in the hope to replace damaged cells in Parkinson's disease. The technique could be developed for application in other degenerative conditions.

Drs Clare Parish and Lachlan Thompson lead the research from the Florey Neuroscience Institutes and the University of Melbourne. They are members of the newly established Stem Cells Australia collaboration being launched at the University of Melbourne today.

Stem Cells Australia is a new $21m Australian Research Council Special Research Initiative bringing together Australia's leading stem cell scientists.

Led by internationally renowned stem cell expert Professor Martin Pera and administered by the University of Melbourne, the Initiative links Australia's leading experts in bioengineering, nanotechnology, stem cell biology, advanced molecular analysis and clinical research to solve some of the our biggest health challenges.

"Stem Cells Australia will not only play a major role in leading Australian research into stem cell science, it will help the Australian community to understand the impact of scientific breakthroughs in this fast-paced and fascinating field," he said.

Opening Stem Cells Australia on behalf of Innovation Minister Senator Kim Carr, ARC Chief Executive Officer Professor Margaret Sheil said the Initiative would make an important contribution to life-changing research.

"It will enable the delivery of stem cell research breakthroughs that will help ease suffering and save lives," Professor Sheil said.

Key areas of research include investigating the use of stem cells to rejuvenate and repair damaged and diseased cells in organs such as the heart, brain and blood that are affected in conditions such as heart disease, Parkinson's disease, stroke and leukaemia.

In regards to Parkinson's disease there is a progressive and permanent loss of a group of dopamine-producing brain cells that form an essential pathway in the brain circuitry controlling movement.

Drs Parish and Thompson's respective research groups have developed a novel technique using stem cells to replace the dopamine-producing brain cells.

The first step of the technique is led by Dr Parish's team which has expertise in generating the dopamine brain cells that are missing in Parkinson's disease.

"By following what we know about brain development we have been able to re-create an environment in the culture dish that allows us to generate specific cell types that may be therapeutic," she said.

"A limitation of the procedure, however, is that it is inefficient. This means that only around 30 per cent of the cells become dopamine brain cells while the others may remain as stem cells. This poses significant risks in a transplantation setting because the stem cells may continue to grow and form tumours," she said.

Dr Lachlan Thompson's team is working on an innovative approach using a state of the art cell-sorting technology to solve this problem.

"Overall we have identified some interesting findings that help us to isolate the dopamine brain cells and discard the stem cells prior to transplantation," he said.

"It's a strategy that we hope will bring us a step closer to clinical trials for a stem cell based treatment for Parkinson's. The broader significance is that this novel approach will likely be applicable to the development of stem cell-based treatments for other neurological conditions such as stroke, motor neuron disease and Huntington's disease," he said.

"There is still a lot of basic research to do to develop this technology to a point where it would be safe to proceed with trials in patients, however, there's no reason to think that it couldn't happen within the next 5-10 years with the proper funding."

Stem Cells Australia is a collaboration with eight Australian research partners: The University of Melbourne, Monash University, Walter and Eliza Hall Institute of Medical Research, The University of Queensland, University of NSW, Victor Chang Cardiac Research Institute, CSIRO and Florey Neuroscience Institutes. Former Governor of Victoria Professor David de Kretser is the Chair of the Governance Committee.

Professor Martin Pera said one of the major assets of the unique multidisciplinary approach of Stem Cells Australia is that it will foster and train the next generation of Australian stem cell scientists, cementing Australia's position in the field.

"This collaboration will not only support excellence in stem cell research to address diseases that are hardest to treat, but will also guide public debate about the important ethical, legal and societal issues associated with stem cell science," he said.

Source: University of Melbourne

Contact: Rebecca Scott
.........

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Food Increases Gut Size by Stimulating Stem Cells and Insulin

2011-11-11T23:57:00.001+01:00

Penn study on gut cell regeneration reconciles long-standing research controversy
Friday, 11 November 2011

The lining of the intestine regenerates itself every few days as compared to say red blood cells that turn over every four months. The cells that help to absorb food and liquid that humans consume are constantly being produced. The various cell types that do this come from stem cells that reside deep in the inner recesses of the accordion-like folds of the intestines, called villi and crypts.

This is a stem cell (blue) from the

intestinal crypt. Credit: Norifumi

Takeda, Raj Jain and Jon Epstein,

Perelman School of Medicine,

University of Pennsylvania.

But exactly where the most important stem cell type is located — and how to identify it — has been something of a mystery. In fact, two types of intestinal stem cells have been proposed to exist but the relationship between them has been unclear. One type of stem cell divides slowly and resides at the sides of intestinal crypts. The other divides much more quickly and resides at the bottom of the crypts.

Some researchers have been proponents of one type of stem cell or the other as the "true" intestinal stem cell. Recent work published this week in Science from the lab of Jonathan Epstein, MD, chairman of the Department of Cell and Developmental Biology from the Perelman School of Medicine at the University of Pennsylvania, may reconcile this controversy. The findings suggest that these two types of stem cells are related. In fact, each can produce the other, which surprised the researchers.

"We actually began our studies by looking at stem cells in the heart and other organs," Epstein said.

"In other tissues in the body, slowly dividing cells can sometimes give rise to more rapidly dividing stem cells that are called to action when tissue regeneration is required. Our finding that this can happen in reverse in the intestine was not expected."

The discovery that rapidly cycling gut stem cells can regenerate the quiescent stem cells — slowly dividing and probably long-lived — suggests that the developmental pathways in human organs that regenerate quickly like in the gut, skin, blood, and bone, may be more flexible than previously appreciated.

"This better appreciation and understanding may help us learn how to promote the regeneration of tissue-specific adult stem cells that could subsequently help with tissue regeneration," says Epstein.

"It may also help us to understand the cell types that give rise to cancer in the colon and stomach."

Source: University of Pennsylvania School of Medicine

Contact: Karen Kreeger
.........

ZenMaster

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Cambridge Stem Cells United

2011-10-24T02:10:00.001+02:00

Cohesion, collaboration and clinical impact are the watchwords of a new phase of stem cell research in Cambridge, UK
Monday, 24 October 2011

Few areas of research have been surrounded by such hope – and such hype – as stem cell biology. With their unique capacity to renew themselves and to give rise to the body’s many different cell types, stem cells have the potential to repair tissues damaged by disease or trauma: from a failing heart to lost nerve cells.

Rosettes of human, patient-specific

neural stem cells. Credit: Rick Livesey

and Yichen Shi.

But the route from the laboratory to the clinic is a long one. Before patients can be treated, many years of fundamental research and clinical testing have to take place.

“Rushing into the clinic without basic understanding may create some headlines but no real benefit for patients,” said Professor Austin Smith, Director of Cambridge’s Wellcome Trust (WT) Centre for Stem Cell Research.

“Cambridge is one of the few places in the world that has a critical mass in both basic stem cell science and medical translation.”

Since 2007, the University has invested over £38 million in laboratories and posts, and has prioritised stem cell biology as a Strategic Research Initiative. There are now 26 stem cell laboratories across the University, which have attracted some £95 million in funding. Many of the researchers are hosted by the WT Centre and the University’s Medical Research Council (MRC) Laboratory for Regenerative Medicine (established by Professor Roger Pedersen), which focus on fundamental and translational stem cell research, respectively.

Now, a major effort is under way to draw together stem cell research across the University into a new Stem Cell Institute (SCI). The SCI currently spans several sites but the intention is to bring all these groups together ultimately in a major new research institute on the Cambridge Biomedical Campus. Unification will create the ideal stage for the translation of fundamental research into clinical benefits – research such as the long-running programme led by Professor Robin Franklin in the Department of Veterinary Medicine, whose work on multiple sclerosis is about to move into clinical trials (see below).

“Collaboration has always happened in Cambridge,” explained Professor Smith, “but pulling people together will capitalise fully on the rich opportunities. SCI will provide a unified organisation and a strategic direction for stem cell research that starts from basic science but sets clinical delivery and interaction with bio industry firmly in its sights.”

A key component will be interdisciplinary research teams that link stem cell biology with molecular disease mechanisms through to clinical applications.

Alongside Professor Smith in spearheading the reshaping will be the newly established Chair of Stem Cell Medicine, to which Professor Oliver Brüstle has been elected. Professor Brüstle is currently Director of the Institute of Reconstructive Neurobiology at the University Of Bonn, Germany, and an expert in stem cells of the nervous system and their application in neurodegenerative disease.

Professor Brüstle – who notably fought for legalisation of research on human embryonic stem (ES) cells in Germany and finally became the first scientist to obtain a respective license – regards stem cell therapies as “just another way to treat disease”. He is at pains to emphasise that cell transplantation is not the only way that stem cells can bring clinical benefit.

“In fact, a much closer prospect is the use of stem cells to study specific diseases in the laboratory and to develop new drugs.”

Another important opportunity is the possibility of improving cancer treatment by identifying and targeting tumour stem cells.

“Of course there are challenges to overcome before stem-cell-based medicine is commonplace,” added Professor Brüstle.

“For example, we need to learn more about how human ES cells differ from mouse ES cells, and how their fate is controlled.”

In fact, a major discovery about the differences between human and mouse ES cells was made in Cambridge. Professor Pedersen and Dr Ludovic Vallier and colleagues showed that human ES cells represent a developmentally more mature stage than naive mouse ES cells. This can explain why some procedures for producing specific cell types from mouse ES cells do not work well with human cells.

“Human ES cells are less versatile. This research has changed the way stem cell researchers think about human ES cells,” explained Professor Smith.

The goal now is to understand this difference at a molecular level. Professor Azim Surani at the WT/Cancer Research UK Gurdon Institute in Cambridge has pioneered a deep-sequencing technique to do precisely this. His team can now analyse the entire transcriptome (all the gene products) in a single stem cell, opening the door not only to understanding the specific nature of human ES cells but perhaps also to how to make them more like mouse cells.

Professor Smith foresees a time when stem cells will permeate all areas of biology.

“Stem cells are going to be instrumental in taking us to the next level of understanding about how cells make decisions about their fate. Increasingly, we’ll see them being used in laboratories as systems to look at basic biological questions that may have nothing directly to do with stem cell biology. Stem cells will soon become the research tool of choice in mammalian cell biology.”

Self-service brain repair in multiple sclerosis (MS)

Researchers led by Professor Robin Franklin at the MS Society Cambridge Centre for Myelin Repair recently discovered a molecule that is capable of activating the brain’s own stem cells to repair damage caused by MS. Now, preparations have begun for a small-scale trial to test whether this process can regenerate lost nerve function, for which there is currently no treatment available.

Nerve fibres are progressively damaged in MS because they lose a protective coating of myelin when the cells that make it (the oligodendrocytes) are destroyed by the body’s immune system. The aim of the new treatment will be to stimulate stem cells that occur naturally in the brain and which have the ability to regenerate lost oligodendrocytes.

In the course of over two decades of research, Professor Franklin and colleagues have found that one of the major problems in MS is that the patient’s stem cells lose the ability to become normal oligodendrocytes. When oligodendrocytes are destroyed during the MS disease process, they are not replenished from the brain’s pool of stem cells. But the ability can be regained when the patient’s stem cells are activated through the retinoid acid receptor RXR-γ, as shown in collaboration with colleagues in Edinburgh using animal models and published in Nature Neuroscience in January 2011.

The discovery was a landmark moment in the search for treatments for MS, as Professor Franklin explained.

“If we can encourage the patient’s own stem cells to develop into oligodendrocytes and replace the lost myelin, then this might restore the nerve functions lost in MS.”

The idea behind the proposed treatment is not only to repair the damage but also to arrest any further damage caused by the patient’s immune system. An effective treatment for halting the destruction of oligodendrocytes, alemtuzumab (Campath), was developed in Cambridge by Professor Alastair Compston and Dr Alasdair Coles at the Department of Clinical Neuroscience.

The prospective new trial, which is currently being designed by Dr Coles together with colleagues at University College London and the University of Edinburgh, and is not yet recruiting patients, plans to use a licensed drug, bexarotene, which activates RXR-γ.

Professor Franklin added: “Essentially, the philosophy of our approach is not to transplant stem cells from elsewhere but to encourage the patient’s own stem cells to do the work of repairing the damaged tissue.”

Source: Cambridge University

.........

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Seeking Superior Stem Cells: New Technique Reprograms Human Cells into Stem Cells

2011-10-10T23:56:00.003+02:00

100-fold increase in efficiency in reprogramming human cells to induced stem cells
Monday, 10 October 2011

Researchers from the Wellcome Trust Sanger Institute have today announced a new technique to reprogram human cells, such as skin cells, into stem cells. Their process increases the efficiency of cell reprogramming by one hundred-fold and generates cells of a higher quality at a faster rate.

Until now cells have been reprogrammed using four specific regulatory proteins. By adding two further regulatory factors, Liu and co-workers brought about a dramatic improvement in the efficiency of reprogramming and the robustness of stem cell development. The new streamlined process produces cells that can grow more easily.

"This research is a milestone in human stem cells," explains Wei Wang, first author on the research from the Wellcome Trust Sanger Institute.

"Our technique provides a foundation to unlock the full potential of stem cells."

Stem cells are unspecialized cells that are able to renew themselves through cell division and can be induced to become functional tissue- or organ-specific cells. It is hoped that stem cells will be used to replace dying or damaged cells with healthy, functional cells. This could have wide-ranging uses in medicine such as organ replacement, bone replacement and treatment of neurodegenerative diseases.

With more than 20 years of research, gold standard stem cells are derived from mice, largely because they are easy to work with and provide accurate and reproducible results. The team's aim was to develop human cells of equivalent quality to mouse stem cells.

"The reprogrammed cells developed by our team have proved to have the same capabilities as mouse stem cells," states Pentao Liu, senior author from the Sanger Institute.

"Our approach will enable researchers to easily engineer and reprogram human stem cells to generate cell types for cell replacement therapies in humans."

Retinoic acid receptor gamma (RAR-γ) and liver receptor homolog (Lrh-1), the additional regulatory factors used by Liu and co-workers, were introduced into the skin cells along with the four other regulatory proteins. The team's technology produced reprogrammed cells after just four days, compared to the seven days required for the four-protein approach. Key indicators of successfully reprogrammed cells, Oct4 and Rex-1 genes, were seen to be switched on much faster in a much higher number of cells, demonstrating increased efficiency in reprogramming.

"This is the most promising and exciting development in our attempt to develop human stem cells that lend themselves in practical applications. It bears comparison to other technologies as it is simple, robust and reliable," says Allan Bradley, Senior Group Leader and Director of Emeritus at Sanger Institute.

Source: Wellcome Trust Sanger Institute

Contact: Don Powell, Media Manager
.........

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