Posts tagged stem cells
Articles and news from the latest research reports.
Stem cell transplant restores memory, learning in mice
For the first time, human embryonic stem cells have been transformed into nerve cells that helped mice regain the ability to learn and remember.
A study at UW-Madison is the first to show that human stem cells can successfully implant themselves in the brain and then heal neurological deficits, says senior author Su-Chun Zhang, a professor of neuroscience and neurology.
Once inside the mouse brain, the implanted stem cells formed two common, vital types of neurons, which communicate with the chemicals GABA or acetylcholine. “These two neuron types are involved in many kinds of human behavior, emotions, learning, memory, addiction and many other psychiatric issues,” says Zhang.
The human embryonic stem cells were cultured in the lab, using chemicals that are known to promote development into nerve cells — a field that Zhang has helped pioneer for 15 years. The mice were a special strain that do not reject transplants from other species.
After the transplant, the mice scored significantly better on common tests of learning and memory in mice. For example, they were more adept in the water maze test, which challenged them to remember the location of a hidden platform in a pool.
The study began with deliberate damage to a part of the brain that is involved in learning and memory.
Three measures were critical to success, says Zhang: location, timing and purity. “Developing brain cells get their signals from the tissue that they reside in, and the location in the brain we chose directed these cells to form both GABA and cholinergic neurons.”
The initial destruction was in an area called the medial septum, which connects to the hippocampus by GABA and cholinergic neurons. “This circuitry is fundamental to our ability to learn and remember,” says Zhang.
The transplanted cells, however, were placed in the hippocampus — a vital memory center — at the other end of those memory circuits. After the transferred cells were implanted, in response to chemical directions from the brain, they started to specialize and connect to the appropriate cells in the hippocampus.
The process is akin to removing a section of telephone cable, Zhang says. If you can find the correct route, you could wire the replacement from either end.
For the study, published in the current issue of Nature Biotechnology, Zhang and first author Yan Liu, a postdoctoral associate at the Waisman Center on campus, chemically directed the human embryonic stem cells to begin differentiation into neural cells, and then injected those intermediate cells. Ushering the cells through partial specialization prevented the formation of unwanted cell types in the mice.
Ensuring that nearly all of the transplanted cells became neural cells was critical, Zhang says. “That means you are able to predict what the progeny will be, and for any future use in therapy, you reduce the chance of injecting stem cells that could form tumors. In many other transplant experiments, injecting early progenitor cells resulted in masses of cells — tumors. This didn’t happen in our case because the transplanted cells are pure and committed to a particular fate so that they do not generate anything else. We need to be sure we do not inject the seeds of cancer.”
Brain repair through cell replacement is a Holy Grail of stem cell transplant, and the two cell types are both critical to brain function, Zhang says. “Cholinergic neurons are involved in Alzheimer’s and Down syndrome, but GABA neurons are involved in many additional disorders, including schizophrenia, epilepsy, depression and addiction.”
Though tantalizing, stem-cell therapy is unlikely to be the immediate benefit. Zhang notes that “for many psychiatric disorders, you don’t know which part of the brain has gone wrong.” The new study, he says, is more likely to see immediate application in creating models for drug screening and discovery.
(Source: news.wisc.edu)
Big boost in drug discovery: New use for stem cells identifies a promising way to target ALS
Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them.
The new screening technique developed by Lee Rubin, a member of HSCI’s executive committee and a professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that.
“It’s a deep, dark secret of drug discovery that very few drugs have been tested on human-diseased cells before being tested in a live person,” said Rubin, who heads HSCI’s program in translational medicine. “We were interested in the notion that we can use stem cells to correct that situation.”
Rubin’s model is built on an earlier proof of concept developed by HSCI principal faculty member Kevin Eggan, who demonstrated that it was possible to move a neuron-based disease into a laboratory dish using stem cells carrying the genes of patients with the disease.
In a paper published today in the journal Cell Stem Cell, Rubin laid out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS, also known as Lou Gehrig’s disease. The illness is associated with the progressive death of motor neurons, which pass information between the brain and the muscles. As cells die, people with ALS experience weakness in their limbs, followed by rapid paralysis and respiratory failure. The disease typically strikes later in life. Ten percent of cases are genetically predisposed, but for most patients there is no known trigger.
Rubin’s lab began by studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS. Investigators starved the cells of nutrients and then screened 5,000 druglike molecules to find any that would keep the motor neurons alive.
Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. “Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in,” Rubin said.
Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or were placed in a toxic environment.
After further investigation, Rubin’s lab discovered that kenpaullone’s potency came from its ability also to inhibit HGK, an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.
“I think that stem cell screens will discover new compounds that have never been discovered before by other methods,” Rubin said. “I’m excited to think that someday one of them might actually be good enough to go into the clinic.”
To find out if kenpaullone worked in diseased human cells, Rubin’s lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little response, and the other drug failed to keep any cells alive.
According to Rubin, before kenpaullone could be used as a drug, it would need a substantial molecular makeover to make it better able to target cells and find its way into the spinal cord so it can access motor neurons.
“This is kind of a proof of principle on the do-ability of the whole thing,” he said. “I think it’s possible to use this method to discover new drug targets and to prevalidate compounds on real human disease cells before putting them in the clinic.”
Rubin’s next steps will be to continue searching for better druglike compounds that can inhibit HGK and thus enhance motor neuron survival. He believes that the new information that comes out of this research will be useful to academia and the pharmaceutical industry.
“These kinds of exploratory screens are hard to fund, so being part of the HSCI” — which provided some of the funding — “has been absolutely essential,” Rubin said.
(Source: news.harvard.edu)
Researchers find out why some stress is good for you
Overworked and stressed out? Look on the bright side. Some stress is good for you.
“You always think about stress as a really bad thing, but it’s not,” said Daniela Kaufer, associate professor of integrative biology at the University of California, Berkeley. “Some amounts of stress are good to push you just to the level of optimal alertness, behavioral and cognitive performance.”
New research by Kaufer and UC Berkeley post-doctoral fellow Elizabeth Kirby has uncovered exactly how acute stress – short-lived, not chronic – primes the brain for improved performance.
In studies on rats, they found that significant, but brief stressful events caused stem cells in their brains to proliferate into new nerve cells that, when mature two weeks later, improved the rats’ mental performance.
“I think intermittent stressful events are probably what keeps the brain more alert, and you perform better when you are alert,” she said.
Kaufer, Kirby and their colleagues in UC Berkeley’s Helen Wills Neuroscience Institute describe their results in a paper published April 16 in the new open access online journal eLife.
The UC Berkeley researchers’ findings, “in general, reinforce the notion that stress hormones help an animal adapt – after all, remembering the place where something stressful happened is beneficial to deal with future situations in the same place,” said Bruce McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University, who was not involved in the study.
Kaufer is especially interested in how both acute and chronic stress affect memory, and since the brain’s hippocampus is critical to memory, she and her colleagues focused on the effects of stress on neural stem cells in the hippocampus of the adult rat brain. Neural stem cells are a sort of generic or progenitor brain cell that, depending on chemical triggers, can mature into neurons, astrocytes or other cells in the brain. The dentate gyrus of the hippocampus is one of only two areas in the brain that generate new brain cells in adults, and is highly sensitive to glucocorticoid stress hormones, Kaufer said.
Much research has demonstrated that chronic stress elevates levels of glucocorticoid stress hormones, which suppresses the production of new neurons in the hippocampus, impairing memory. This is in addition to the effect that chronically elevated levels of stress hormones have on the entire body, such as increasing the risk of chronic obesity, heart disease and depression.
Less is known about the effects of acute stress, Kaufer said, and studies have been conflicting.
To clear up the confusion, Kirby subjected rats to what, to them, is acute but short-lived stress – immobilization in their cages for a few hours. This led to stress hormone (corticosterone) levels as high as those from chronic stress, though for only a few hours. The stress doubled the proliferation of new brain cells in the hippocampus, specifically in the dorsal dentate gyrus.
Kirby discovered that the stressed rats performed better on a memory test two weeks after the stressful event, but not two days after the event. Using special cell labeling techniques, the researchers established that the new nerve cells triggered by the acute stress were the same ones involved in learning new tasks two weeks later.
“In terms of survival, the nerve cell proliferation doesn’t help you immediately after the stress, because it takes time for the cells to become mature, functioning neurons,” Kaufer said. “But in the natural environment, where acute stress happens on a regular basis, it will keep the animal more alert, more attuned to the environment and to what actually is a threat or not a threat.”
They also found that nerve cell proliferation after acute stress was triggered by the release of a protein, fibroblast growth factor 2 (FGF2), by astrocytes — brain cells formerly thought of as support cells, but that now appear to play a more critical role in regulating neurons.
“The FGF2 involvement is interesting, because FGF2 deficiency is associated with depressive-like behaviors in animals and is linked to depression in humans,” McEwen said.
Kaufer noted that exposure to acute, intense stress can sometimes be harmful, leading, for example, to post-traumatic stress disorder. Further research could help to identify the factors that determine whether a response to stress is good or bad.
“I think the ultimate message is an optimistic one,” she concluded. “Stress can be something that makes you better, but it is a question of how much, how long and how you interpret or perceive it.”
Do drugs for bipolar disorder “normalize” brain gene function?
Every day, millions of people with bipolar disorder take medicines that help keep them from swinging into manic or depressed moods. But just how these drugs produce their effects is still a mystery.
Now, a new University of Michigan Medical School study of brain tissue helps reveal what might actually be happening. And further research using stem cells programmed to act like brain cells is already underway.
Using genetic analysis, the new study suggests that certain medications may help “normalize” the activity of a number of genes involved in communication between brain cells. It is published in the current issue of Bipolar Disorders.
The study involved brain tissue from deceased people with and without bipolar disorder, which the U-M team analyzed to see how often certain genes were activated, or expressed. Funding support came from the National Institutes of Health and the Heinz C. Prechter Bipolar Research Fund.
“We found there are hundreds of genes whose activity is adjusted in individuals taking medication – consistent with the fact that there are a number of genes that are potentially amiss in people with bipolar,” says senior author Melvin McInnis, M.D., the U-M psychiatrist, U-M Depression Center member and principal investigator of the Prechter Fund Projects who helped lead the study. “Taking the medications, specifically ones in a class called antipsychotics, seemed to normalize the gene expression pattern in these individuals so that it approached that of a person without bipolar.”
Digging deeper into bipolar genetics
Scientists already know that bipolar disorder’s roots lie in genetic differences in the brain — though they are still searching for the specific gene combinations involved.
McInnis and his colleagues have now embarked on research developing several a lines of induced pluripotent stem cells derived (iPSC) from volunteers with and without bipolar disorder, which will allow even more in-depth study of the development and genetics of bipolar disorder.
The newly published study looked at the expression, or activity levels, of 2,191 different genes in the brains of 14 people with bipolar disorder, and 12 with no mental health conditions. The brains were all part of a privately funded nonprofit brain bank that collected and stored donated brains, and recorded what medications the individuals were taking at the time of death.
Seven of the brains were from people with bipolar disorder who had been taking one or more antipsychotics when they died. These drugs include clozapine, risperidone, and haloperidol, and are often used to treat bipolar disorder. Most of the 14 brain donors with bipolar disorder were also taking other medications, such as antidepressants, at the time of death.
When the researchers compared the gene activity patterns among the brains of bipolar disorder patients who had been exposed to antipsychotics with patterns among those who weren’t, they saw striking differences.
Then, when they compared the activity patterns of patients who had been taking antipsychotics with those of people without bipolar disorder, they found similar patterns.
The similarities were strongest in the expression of genes involved in the transmission of signals across synapses – the gaps between brain cells that allow cells to ‘talk’ to one another. There were also similarities in the organization of nodes of Ranvier – locations along nerve cells where signals can travel faster.
McInnis, who is the Thomas B. and Nancy Upjohn Woodworth Professor of Bipolar Disorder and Depression in the U-M Department of Psychiatry, worked with U-M scientists Haiming Chen, M.D. and K. Sue O’Shea, Ph.D., of the U-M Department of Cell and Developmental Biology. They also teamed with Johns Hopkins University researcher Christopher Ross, M.D., Ph.D. on the new research; U-M and Johns Hopkins have a long history of collaboration on bipolar disorder research.
The research used brain tissue samples from the Stanley Brain Collection of the Stanley Medical Research Institute in Maryland.
Using “gene chip” analysis to measure the presence of messenger RNA molecules that indicate gene activity, and sophisticated data analysis, they were able to map the expression patterns from the brains and break the results down by bipolar status and medication use. The bipolar and control (non-bipolar) brains were matched by age, gender and other factors.
“In bipolar disorder, it’s not just one gene that’s involved – it’s a whole symphony of them,” says McInnis, who has helped lead U-M’s bipolar genetics research for nearly a decade. “Medications appear to nudge them in a direction that aligns more with the normal expression pattern.”
Among those that were “nudged” were genes that have already been shown to be linked to bipolar disorder, including glycogen synthase kinase 3 beta (GSK3β), FK506 binding protein 5 (FKBP5), and Ankyrin 3 (ANK3).
Going forward, says McInnis, cell culture studies will be critical to studying how medications for bipolar disorder work, and to screen new molecules as potential new medications.
Spring cleaning in your brain: U-M stem cell research shows how important it is
Deep inside your brain, a legion of stem cells lies ready to turn into new brain and nerve cells whenever and wherever you need them most. While they wait, they keep themselves in a state of perpetual readiness – poised to become any type of nerve cell you might need as your cells age or get damaged.
Now, new research from scientists at the University of Michigan Medical School reveals a key way they do this: through a type of internal “spring cleaning” that both clears out garbage within the cells, and keeps them in their stem-cell state.
In a paper published online in Nature Neuroscience, the U-M team shows that a particular protein, called FIP200, governs this cleaning process in neural stem cells in mice. Without FIP200, these crucial stem cells suffer damage from their own waste products — and their ability to turn into other types of cells diminishes.
It is the first time that this cellular self-cleaning process, called autophagy, has been shown to be important to neural stem cells.
The findings may help explain why aging brains and nervous systems are more prone to disease or permanent damage, as a slowing rate of self-cleaning autophagy hampers the body’s ability to deploy stem cells to replace damaged or diseased cells. If the findings translate from mice to humans, the research could open up new avenues to prevention or treatment of neurological conditions.
In a related review article just published online in the journal Autophagy, the lead U-M scientist and colleagues from around the world discuss the growing evidence that autophagy is crucial to many types of tissue stem cells and embryonic stem cells as well as cancer stem cells.
As stem cell-based treatments continue to develop, the authors say, it will be increasingly important to understand the role of autophagy in preserving stem cells’ health and ability to become different types of cells.
“The process of generating new neurons from neural stem cells, and the importance of that process, is pretty well understood, but the mechanism at the molecular level has not been clear,” says Jun-Lin Guan, Ph.D., the senior author of the FIP200 paper and the organizing author of the autophagy and stem cells review article. “Here, we show that autophagy is crucial for maintenance of neural stem cells and differentiation, and show the mechanism by which it happens.”
Through autophagy, he says, neural stem cells can regulate levels of reactive oxygen species – sometimes known as free radicals – that can build up in the low-oxygen environment of the brain regions where neural stem cells reside. Abnormally higher levels of ROS can cause neural stem cells to start differentiating.
Guan is a professor in the Molecular Medicine & Genetics division of the U-M Department of Internal Medicine, and in the Department of Cell & Developmental Biology.
A long path to discovery
The new discovery, made after 15 years of research with funding from the National Institutes of Health, shows the importance of investment in lab science – and the role of serendipity in research.
Guan has been studying the role of FIP200 — whose full name is focal adhesion kinase family interacting protein of 200 kD – in cellular biology for more than a decade. Though he and his team knew it was important to cellular activity, they didn’t have a particular disease connection in mind. Together with colleagues in Japan, they did demonstrate its importance to autophagy – a process whose importance to disease research continues to grow as scientists learn more about it.
Several years ago, Guan’s team stumbled upon clues that FIP200 might be important in neural stem cells when studying an entirely different phenomenon. They were using FIP200-less mice as comparisons in a study, when an observant postdoctoral fellow noticed that the mice experienced rapid shrinkage of the brain regions where neural stem cells reside.
“That effect was more interesting than what we were actually intending to study,” says Guan, as it suggested that without FIP200, something was causing damage to the home of neural stem cells that normally replace nerve cells during injury or aging.
In 2010, they worked with other U-M scientists to show FIP200’s importance to another type of stem cell, those that generate blood cells. In that case, deleting the gene that encodes FIP200 leads to an increased proliferation and ultimate depletion of such cells, called hematopoietic stem cells.
But with neural stem cells, they report in the new paper, deleting the FIP200 gene led neural stem cells to die and ROS levels to rise. Only by giving the mice the antioxidant n-acetylcysteine could the scientists counteract the effects.
“It’s clear that autophagy is going to be important in various types of stem cells,” says Guan, pointing to the new paper in Autophagy that lays out what’s currently known about the process in hematopoietic, neural, cancer, cardiac and mesenchymal (bone and connective tissue) stem cells.
Guan’s own research is now exploring the downstream effects of defects in neural stem cell autophagy – for instance, how communication between neural stem cells and their niches suffers. The team is also looking at the role of autophagy in breast cancer stem cells, because of intriguing findings about the impact of FIP200 deletion on the activity of the p53 tumor suppressor gene, which is important in breast and other types of cancer. In addition, they will study the importance of p53 and p62, another key protein component for autophagy, to neural stem cell self-renewal and differentiation, in relation to FIP200.
Scientists develop 3-D stem cell culture technique to better understand Alzheimer’s disease
A team of researchers at The New York Stem Cell Foundation Research Institute led by Scott Noggle, PhD, Director of the NYSCF Laboratory and the NYSCF – Charles Evans Senior Research Fellow for Alzheimer’s Disease, and Michael W. Nestor, PhD, a NYSCF Postdoctoral Research Fellow, has developed a technique to produce three-dimensional cultures of induced pluripotent stem (iPS) cells called embryoid bodies, amenable to live cell imaging and to electrical activity measurement. As reported in their Stem Cell Research study, these cell aggregates enable scientists to both model and to study diseases such as Alzheimer’s and Parkinson’s disease.
The NYSCF Alzheimer’s disease research team aims to better understand and to find treatments to this disease through stem cell research. For such disorders in which neurons misfire or degenerate, the NYSCF team creates “disease in a dish” models by reprogramming patients’ skin and or blood samples into induced pluripotent stem (iPS) cells that can become neurons and the other brain cells affected in the diseases.
The cells in our body form three-dimensional networks, essential to tissue function and overall health; however, previous techniques to form complex brain tissue resulted in structures that, while similar in form to naturally occurring neurons, undermined imaging or electrical recording attempts.
In the current study, the Noggle and Nestor with NYSCF scientists specially adapted two-dimensional culture methods to grow three-dimensional neuron structures from iPS cells. The resultant neurons were “thinned-out,” enabling calcium-imaging studies, which measure the electrical activity of cells like neurons.
"Combining the advantages of iPS cells grown in a 3D environment with those of a 2D system, our technique produces cells that can be used to observe electrical activity of putative networks of biologically active neurons, while simultaneously imaging them," said Nestor. "This is key to modeling and studying neurodegenerative diseases."
Neural networks, thought to underlie learning and memory, become disrupted in Alzheimer’s disease. By generating aggregates from iPS cells and comparing these to an actual patient’s brain tissue, scientists may uncover how disease interferes with these cell-to-cell interactions and understand how to intervene to slow or stop Alzheimer’s disease.
"This critical new tool developed by our Alzheimer’s team will accelerate Alzheimer’s research, enabling more accurate manipulation of cells to find a cure to this disease," said Susan L. Solomon, CEO of NYSCF.
(Source: eurekalert.org)
When our noses pick up a scent, whether the aroma of a sweet rose or the sweat of a stranger at the gym, two types of sensory neurons are at work in sensing that odor or pheromone. These sensory neurons are particularly interesting because they are the only neurons in our bodies that regenerate throughout adult life—as some of our olfactory neurons die, they are soon replaced by newborns. Just where those neurons come from in the first place has long perplexed developmental biologists.
Previous hypotheses about the origin of these olfactory nerve cells have given credit to embryonic cells that develop into skin or the central nervous system, where ear and eye sensory neurons, respectively, are thought to originate. But biologists at the California Institute of Technology (Caltech) have now found that neural-crest stem cells—multipotent, migratory cells unique to vertebrates that give rise to many structures in the body such as facial bones and smooth muscle—also play a key role in building olfactory sensory neurons in the nose.
"Olfactory neurons have long been thought to be solely derived from a thickened portion of the ectoderm; our results directly refute that concept," says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech and corresponding author of a paper published in the journal eLIFE on March 19 that outlines the findings.
The two main types of sensory neurons in the olfactory system are ciliated neurons, which detect volatile scents, and microvillous neurons, which usually sense pheromones. Both of these types are found in the tissue lining the inside of the nasal cavity and transmit sensory information to the central nervous system for processing.
In the new study, the researchers showed that during embryonic development, neural-crest stem cells differentiate into the microvillous neurons, which had long been assumed to arise from the same source as the odor-sensing ciliated neurons. Moreover, they demonstrated that different factors are necessary for the development of these two types of neurons. By eliminating a gene called Sox10, they were able to show that formation of microvillous neurons is blocked whereas ciliated neurons are unaffected.
They made this discovery by studying the development of the olfactory system in zebrafish—a useful model organism for developmental biology studies due to the optical clarity of the free-swimming embryo. Understanding the origins of olfactory neurons and the process of neuron formation is important for developing therapeutic applications for conditions like anosmia, or the inability to smell, says Bronner.
"A key question in developmental biology—the extent of neural-crest stem cell contribution to the olfactory system—has been addressed in our paper by multiple lines of experimentation," says Ankur Saxena, a postdoctoral scholar in Bronner’s laboratory and lead author of the study. "Olfactory neurons are unique in their renewal capacity across species, so by learning how they form, we may gain insights into how neurons in general can be induced to differentiate or regenerate. That knowledge, in turn, may provide new avenues for pursuing treatment of neurological disorders or injury in humans."
Next, the researchers will examine what other genes, in addition to Sox10, play a role in the process by which neural-crest stem cells differentiate into microvillous neurons. They also plan to look at whether or not neural-crest cells give rise to new microvillous neurons during olfactory regeneration that happens after the embryonic stage of development.
Stem Cell Research Could Expand Clinical Use of Regenerative Human Cells
Research led by a biology professor in the School of Science at IUPUI has uncovered a method to produce retinal cells from regenerative human stem cells without the use of animal products, proteins or other foreign substances, which historically have limited the application of stem cells to treat disease and other human developmental disorders.
The study of human induced pluripotent stem cells (hiPSCs) has been pursued vigorously since they were first discovered in 2007 due to their ability to be manipulated into specific cell types. Scientists believe these cells hold considerable potential for cell replacement, disease modeling and pharmacological testing. However, clinical applications have been hindered by the fact that, to date, the cells have required animal products and proteins to grow and differentiate
A research team led by Jason S. Meyer, Ph.D., assistant professor of biology, successfully differentiated hiPSCs in a lab environment—completely through chemical methods—to form neural retinal cell types (including photoreceptors and retinal ganglion cells). Tests have shown the cells function and grow just as efficiently as those cells produced through traditional methods.
“Not only were we able to develop these (hiPSC) cells into retinal cells, but we were able to do so in a system devoid of any animal cells and proteins,” Meyer said. “Since these kinds of stem cells can be generated from a patient’s own cells, there will be nothing the body will recognize as foreign.”
In addition, this research should allow scientists to better reproduce these cells because they know exactly what components were included to spur growth and minimize or eliminate any variations, Meyer said. Furthermore, the cells function in a very similar fashion to human embryonic stem cells, but without controversial or immune rejection issues because they are derived from individual patients.
“This method could have a considerable impact on the treatment of retinal diseases such as age-related macular degeneration and forms of blindness with hereditary factors,” Meyer said. “We hope this will help us understand what goes wrong when diseases arise and that we can use this method as platform for the development of new treatments or drug therapies.”
“We’re talking about bringing stem cells a significant step closer to clinical use,” Meyer added.
The research will be published in the April edition of Stem Cells Translational Medicine.
Transplanted brain cells in monkeys light up personalized therapy
For the first time, scientists have transplanted neural cells derived from a monkey’s skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.
Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.
And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”
Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says, “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”
The cells were implanted in the monkeys “using a state-of-the-art surgical procedure” guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson’s disease, which afflicts up to 1 million Americans. Parkinson’s is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain.
The transplanted cells came from induced pluripotent stem cells (iPS cells), which can, like embryonic stem cells, develop into virtually any cell in the body. iPS cells, however, derive from adult cells rather than embryos.
In the lab, the iPS cells were converted into neural progenitor cells. These intermediate-stage cells can further specialize into the neurons that carry nerve signals, and the glial cells that perform many support and nutritional functions. This final stage of maturation occurred inside the monkey.
Zhang, who was the first in the world to derive neural cells from embryonic stem cells and then iPS cells, says one key to success was precise control over the development process. “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells.”
Another positive sign was the absence of any signs of cancer, says Zhang — a worrisome potential outcome of stem cell transplants. “Their appearance is normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, they become neurons with long axons [conducting fibers], as we’d expect. They also produce oligodendrocytes that are helping build insulating myelin sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”
The experiment was designed as a proof of principle, says Zhang, who leads a group pioneering the use of iPS cells at the Waisman Center on the UW-Madison campus. The researchers did not transplant enough neurons to replace the dopamine-making cells in the brain, and the animal’s behavior did not improve.
Although promising, the transplant technique is a long way from the clinic, Zhang adds. “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this transplant improve the symptoms? Is it safe? Six months is not long enough… And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”
Nonetheless, the new study represents a real step forward that may benefit human patients suffering from several diseases, says Emborg. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine.”
The need for treatment is incessant, says Emborg, noting that each year, Parkinson’s is diagnosed in 60,000 patients. “I’m gratified that the Parkinson’s Disease Foundation took a risk as the primary funder for this small study. Now we want to move ahead and see if this leads to a real treatment for this awful disease.”
"It’s really the first-ever transplant of iPS cells from a non-human primate back into the same animal, not just in the brain," says Zhang. "I have not seen anybody transplanting reprogrammed iPS cells into the blood, the pancreas or anywhere else, into the same primate. This proof-of-principle study in primates presents hopes for personalized regenerative medicine."
(Source: news.wisc.edu)
Using Fat to Fight Brain Cancer
In laboratory studies, Johns Hopkins researchers say they have found that stem cells from a patient’s own fat may have the potential to deliver new treatments directly into the brain after the surgical removal of a glioblastoma, the most common and aggressive form of brain tumor.
The investigators say so-called mesenchymal stem cells (MSCs) have an unexplained ability to seek out damaged cells, such as those involved in cancer, and may provide clinicians a new tool for accessing difficult-to-reach parts of the brain where cancer cells can hide and proliferate anew. The researchers say harvesting MSCs from fat is less invasive and less expensive than getting them from bone marrow, a more commonly studied method.
Results of the Johns Hopkins proof-of-principle study are described online in the journal PLOS ONE.
“The biggest challenge in brain cancer is the migration of cancer cells. Even when we remove the tumor, some of the cells have already slipped away and are causing damage somewhere else,” says study leader Alfredo Quinones-Hinojosa, M.D., a professor of neurosurgery, oncology and neuroscience at the Johns Hopkins University School of Medicine. “Building off our findings, we may be able to find a way to arm a patient’s own healthy cells with the treatment needed to chase down those cancer cells and destroy them. It’s truly personalized medicine.”
For their test-tube experiments, Quinones-Hinojosa and his colleagues bought human MSCs derived from both fat and bone marrow, and also isolated and grew their own stem cell lines from fat removed from two patients. Comparing the three cell lines, they discovered that all proliferated, migrated, stayed alive and kept their potential as stem cells equally well.
This was an important finding, Quinones-Hinojosa says, because it suggests that a patient’s own fat cells might work as well as any to create cancer-fighting cells. The MSCs, with their ability to home in on cancer cells, might be able to act as a delivery mechanism, bringing drugs, nanoparticles or some other treatment directly to the cells. Quinones-Hinojosa cautions that while further studies are under way, it will be years before human trials of MSC delivery systems can begin.
Ideally, he says, if MSCs work, a patient with a glioblastoma would have some adipose tissue (fat) removed — from any number of locations in the body — a short time before surgery. The MSCs in the fat would be drawn out and manipulated in the lab to carry drugs or other treatments. Then, after surgeons removed the brain tumor, they could deposit these treatment-armed cells into the brain in the hopes that they would seek out and destroy the cancer cells.
Currently, standard treatments for glioblastoma are chemotherapy, radiation and surgery, but even a combination of all three rarely leads to more than 18 months of survival after diagnosis. Glioblastoma tumor cells are particularly nimble, migrating across the entire brain and establishing new tumors. This migratory capability is thought to be a key reason for the low cure rate of this tumor type.
“Essentially these MSCs are like a ‘smart’ device that can track cancer cells,” Quinones-Hinojosa says.
Quinones-Hinojosa says it’s unclear why MSCs are attracted to glioblastoma cells, but they appear to have a natural affinity for sites of damage in the body, such as a wound. MSCs, whether derived from bone marrow or fat, have been studied in animal models to treat trauma, Parkinson’s disease, ALS and other diseases.