Posts tagged stem cells
Articles and news from the latest research reports.
Stem cell research reveals clues to brain disease
The development of new drugs for improving treatment of Alzheimer’s and Parkinson’s disease is a step closer after recent research into how stem cells migrate and form circuits in the brain.
The results from a study by researchers at The University of Auckland’s Centre for Brain Research may hold important clues into why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease, and links to insulin resistance and diabetes.
The major five-year project to understand how stem cells start and stop migrating in the brain has also helped to unlock the secrets of how stem cells migrate during development and in adulthood.
The study revealed new information on how connectivity between brain cells is improved or worsened, says senior study author, Dr Maurice Curtis who conceived and directed the research. The experiments were carried out at the Centre for Brain Research laboratories by Dr Hector Monzo. Collaborators included a director of the CBR, Distinguished Professor Richard Faull, Dr Thomas Park, Dr Birger Dieriks, Deidre Jansson and Professor Mike Dragunow.
“We have begun testing new novel drug compounds that target how polysialic acid is removed from the cell in the hope of improving neuron connectivity,” says Dr Curtis.
He explains that stem cells in the brain are immature brain cells that must migrate from their birthplace to a position in the brain where they will connect with other brain cells, turn into adult brain cells (neurons) and become part of the brain’s circuitry.
“Even once the neuron has found its location, the neuron’s tentacles (or dendrites) need to forage to find other neurons to connect with to form circuits. This would be easy except that in the adult brain the cells are surrounded by a fairly rigid matrix (extracellular matrix) and so migration or foraging becomes almost impossible in this high friction environment.”
“The way the cell overcomes this ‘friction’ is by placing large amounts of a special slippery molecule called ‘polysialic acid-neural cell adhesion molecule’ onto the cell surface,” says Dr Curtis. “This allows the cell to migrate or forage with only a fraction of the friction it once had and this also reduces the energy requirements of the cell.”
Once the cell has migrated to its destination, the slippery coating is removed and the cell becomes locked in place ready to connect with other cells. In the case of the dendritic foraging, the polysialic acid must be removed in order for the dendrite to connect with another cell (synapse formation).
“We have known for at least 20 years that this process occurs but despite extensive studies by a number of groups internationally we have been in the dark about what controls this process,” he says. “Studies in my laboratory have demonstrated what happens to the slippery molecules once the cell no longer needs them.”
There were three possibilities for this process:
- that enzymes cut them off the outside of the cell
- that the friction wears it off the cell or
- the cell internalises the slippery substance and recycles it ready for future use.
“For the past five years, we have systematically studied how this process is controlled,” says Dr Curtis. “Our findings have demonstrated that cells internalise the slippery molecule after receiving two specific cues.”
One of these cues is from collagen which makes up part of the rigid structure outside of the cell and the other is from a gaseous molecule called nitric oxide which triggers the outer membrane of the cell to internalise the slippery molecules.
“What we also discovered is that when there is an increased amount of insulin and insulin-like growth factor 1 (which has some similar functions to insulin) present in the culture, the cell cannot internalise the slippery molecules and instead they remain on the cell surface.”
“The key to the breakthrough was in determining that the process by which the polysialic acid is added to the cell surface was so persistent that it needed to be stopped in order to study how the polysialic acid was removed,” says Dr Curtis. “This required extensive trialling of many different cell growth conditions, enzyme concentrations and growing the cells in many different extracellular matrices.”
This is interesting because it is well known that in Parkinson’s disease and Alzheimer’s disease the brain is less sensitive to insulin, he says.
“In our studies in cells the insulin blocks the removal of polysialic acid and therefore the cell cannot connect properly and form synapses with other nearby cells.”
“This may hold major clues to why there is less plasticity in brains affected by Parkinson’s and Alzheimer’s disease in adults as well as helping to unlock the secrets of how stem cells migrate during development of the brain”, says Dr Curtis.
The Gus Fisher Postdoctoral Fellowship, the Auckland Medical Research Foundation and the Manchester Trust were the main sponsors of this research work.
The study results were published online this month in an ‘ahead of print’ version of The Journal of Neurochemistry.
(Source: auckland.ac.nz)
Researchers create the inner ear from stem cells, opening potential for new treatments
Indiana University scientists have transformed mouse embryonic stem cells into key structures of the inner ear. The discovery provides new insights into the sensory organ’s developmental process and sets the stage for laboratory models of disease, drug discovery and potential treatments for hearing loss and balance disorders.
A research team led by Eri Hashino, Ph.D., Ruth C. Holton Professor of Otolaryngology at Indiana University School of Medicine, reported that by using a three-dimensional cell culture method, they were able to coax stem cells to develop into inner-ear sensory epithelia — containing hair cells, supporting cells and neurons — that detect sound, head movements and gravity. The research was reportedly online Wednesday in the journal Nature.
Previous attempts to “grow” inner-ear hair cells in standard cell culture systems have worked poorly in part because necessary cues to develop hair bundles — a hallmark of sensory hair cells and a structure critically important for detecting auditory or vestibular signals — are lacking in the flat cell-culture dish. But, Dr. Hashino said, the team determined that the cells needed to be suspended as aggregates in a specialized culture medium, which provided an environment more like that found in the body during early development.
The team mimicked the early development process with a precisely timed use of several small molecules that prompted the stem cells to differentiate, from one stage to the next, into precursors of the inner ear. But the three-dimensional suspension also provided important mechanical cues, such as the tension from the pull of cells on each other, said Karl R. Koehler, B.A., the paper’s first author and a graduate student in the medical neuroscience graduate program at the IU School of Medicine.
"The three-dimensional culture allows the cells to self-organize into complex tissues using mechanical cues that are found during embryonic development," Koehler said.
"We were surprised to see that once stem cells are guided to become inner-ear precursors and placed in 3-D culture, these cells behave as if they knew not only how to become different cell types in the inner ear, but also how to self-organize into a pattern remarkably similar to the native inner ear," Dr. Hashino said. "Our initial goal was to make inner-ear precursors in culture, but when we did testing we found thousands of hair cells in a culture dish."
Electrophysiology testing further proved that those hair cells generated from stem cells were functional, and were the type that sense gravity and motion. Moreover, neurons like those that normally link the inner-ear cells to the brain had also developed in the cell culture and were connected to the hair cells.
Additional research is needed to determine how inner-ear cells involved in auditory sensing might be developed, as well as how these processes can be applied to develop human inner-ear cells, the researchers said.
However, the work opens a door to better understanding of the inner-ear development process as well as creation of models for new drug development or cellular therapy to treat inner-ear disorders, they said.
Dream of regenerating human body parts gets a little closer
Damage to vital organs, the spinal cord, or limbs can have an enormous impact on our ability to move, function – and even live. But imagine if you could restore these tissues back to their original condition and go on with life as normal.
Well, this is the dream for regenerative medicine. And while humans missed out on these abilities in the evolutionary lottery, a recent study in mice shows we’re making small progress to achieving this dream.
Learning from animals
Nature has provided the animal kingdom with many different ways to achieve perfect regeneration. Some amphibians – such as salamanders – are famous for their superhero-like ability to regenerate heart, brain, spinal cord, tail and can even whole limb tissue throughout their life.
Although organ and spinal cord regeneration are clinically important and worthy of intense research investment, regrowing whole limbs provides a flagship example of perfect regeneration in the salamander.
It has been known for more than a hundred years that if a salamander loses a limb, it grows right back. This process is extremely precise and removal of the limb at the shoulder regrows a full limb, but removal at the wrist only regrows the missing hand portion.
Interestingly, there does not seem to be a limit on how many times they can perform this clever trick and each time the limb comes back perfect.
But mammals (including humans and mice) seem to have missed out on this important skill. The question of how to enhance the regenerative capabilities in humans, either by adding the missing ingredients, or activating these latent abilities currently lies wide open.
Extending regeneration to mammals
Mammals currently only have the capacity to regenerate the very tip of their finger. But the result is far from perfect. A range of studies in mice have shown the digit-tip regrowth is severely restricted. Removal of the very tip of the mouse digit will be replaced, but removal of the tissue a small distance further up the digit and closer to nail bed (the equivalent to a human cuticle), will fail to regrow.
Last week, a group of researchers from the United States and Japan published work extending our understanding of the mechanism by which a resident stem cell population within the mouse digit tip nail bed can be activated to induce digit tip regeneration. In other words, we can now grow more of the digit back in mice and possibly more of the human finger.
Resident stem cells are specialised cells found at various locations within the body. When activated, these cells multiply and then transform into other cell types required to replace worn out cells under conditions of normal tissue maintenance.
This work builds on previous studies identifying the stem cell population in the nail bed by unveiling a signalling mechanism that could be exploited to enhance the amount of tissue that could be regrown. The potential for repair after injury appears very limited in many tissues and organs. Understanding how to enhance stem cell activation in these tissues may stimulate repair not previously thought possible.
The ability to switch on and mobilise resident stem cells in regeneration will be important in a wide range of new therapies, particularity for organs affected by injury or disease. On a world stage, momentum is currently growing for these types of strategies. It is clear that once refined, these approaches are sure to have a profound influence on many different aspects of clinical medicine, opening up the possibility of replacing diseased or injured tissues.
We may be some way off from the dream of replacing whole limbs in humans but recent progress confirms that by deepening our understanding of stem cell activation, we can directly unlock more regeneration in mammals than normally possible.
How neural stem cells create new and varied neurons
A new study examining the brains of fruit flies reveals a novel stem cell mechanism that may help explain how neurons form in humans. A paper on the study by researchers at the University of Oregon appeared in the online version of the journal Nature in advance of the June 27 publication date.
"The question we confronted was ‘How does a single kind of stem cell, like a neural stem cell, make all different kinds of neurons?’" said Chris Doe, a biology professor and co-author on the paper "Combinatorial temporal patterning in progenitors expands neural diversity."
Researchers have known for some time that stem cells are capable of producing new cells, but the new study shows how a select group of stem cells can create progenitors that then generate numerous subtypes of cells.
"Instead of just making 100 copies of the same neuron to expand the pool, these progenitors make a whole bunch of different neurons in a particular way, a sequence," Doe said. "Not only are you bulking up the numbers but you’re creating more neural diversity."
The study, funded by the Howard Hughes Medical Institute and the NIH National Institute of Child Health and Human Development, builds on previous research from the Doe Lab published in 2008. That study identified a special set of stem cells that generated neural progenitors. These so-called intermediate neural progenitors (INPs) were shown to blow up into dozens of new cells. The research accounted for the number of cells generated, but did not explain the diversity of new cells.
"While it’s been known that individual neural stem cells or progenitors could change over time to make different types of neurons and other types of cells in the nervous system, the full extent of this temporal patterning had not been described for large neural stem cell lineages, which contain several different kinds of neural progenitors," said lead author Omer Bayraktar, a doctoral student in developmental neurobiology who recently defended his dissertation.
The cell types in the study, Bayraktar said, have comparable analogs in the developing human brain and the research has potential applications for human biologists seeking to understand how neurons form.
The Nature paper appears alongside another study on neural diversity by researchers from New York University. Together the two papers provide new insight into the processes involved in producing the wide range of nerve cells found in the brains of flies.
For their study, Bayraktar and Doe zeroed in on the stem cells in drosophila (fruit flies) known as type II neuroblasts. The neuroblasts, which had previously been shown to generate INPs, were shown in this study to be responsible for a more complex patterning of cells. The INPs were shown to sequentially generate distinct neural subtypes. The research accounted for additional neural diversity by revealing a second axis in the mechanism. Instead of making 100 neurons, as had been previously thought, a stem cell may be responsible for generating some 400 or 500 neurons.
The study concludes that neuroblasts and INP patterning act together to generate increased neural diversity within the central complex of the fruit fly and that progenitors in the human cerebral cortex may use similar mechanisms to increase neural diversity in the human brain. One long-term application of the research may be to eventually pinpoint stem cell treatments to target specific diseases and disorders.
"If human biologists understand how the different types of neurons are made, if we can tell them ‘This is the pathway by which x, y and z neurons are made,’ then they may be able to reprogram and redirect stem cells to make these precise neurons," Doe said.
The mechanism described in the paper has its limits. Eventually the process of generating new cells stops. One of the next questions to answer will be what makes the mechanism turn off, Doe said.
"This vital research will no doubt capture the attention of human biologists," said Kimberly Andrews Espy, vice president for research and innovation and dean of the UO graduate school. "Researchers at the University of Oregon continue to further our understanding of the processes that undergird development to improve the health and well-being of people throughout the world."
Metabolic Molecule Drives Growth Of Aggressive Brain Cancer
- Genomic research has shown that glioblastoma, the most dangerous type of brain cancer, has four subtypes.
- This study examines two of the subtypes and identifies an abnormal metabolic pathway that drives the aggressive growth of one of them.
- The findings could lead to targeted therapies for treating an aggressive form of glioblastoma.
A study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has identified an abnormal metabolic pathway that drives cancer-cell growth in a particular glioblastoma subtype. The finding might lead to new therapies for a subset of patients with glioblastoma, the most common and lethal form of brain cancer.
The physician scientists sought to identify glioblastoma subtype-specific cancer stem cells. Genetic analyses have shown that high-grade gliomas can be divided into four subtypes: proneural, neural, classic and mesenchymal.
This study shows that the mesenchymal subtype is the most aggressive subtype, that it has the poorest prognosis among affected patients, and that cancer stem cells isolated from the mesenchymal subtype have significantly higher levels of the enzyme ALDH1A3 compared with the proneural subtype.
The findings, published recently in the Proceedings of the National Academy of Sciences, show that high levels of the enzyme drive tumor growth.
“Our study suggests that ALDH1A3 is a potentially functional biomarker for mesenchymal glioma stem cells, and that inhibiting that enzyme might offer a promising therapeutic approach for high-grade gliomas that have a mesenchymal signature,” says principal investigator Ichiro Nakano, MD, PhD, associate professor of neurosurgery at the OSUCCC – James. “This indicates that therapies for high-grade gliomas should be personalized, that is, based on the tumor subtype instead of applying one treatment to all patients,” he says.
The National Cancer Institute estimates that 23,130 Americans will be diagnosed with brain and other nervous system tumors in 2013, and that 14,000 people will die of these malignancies. Glioblastoma accounts for about 15 percent of all brain tumors, is resistant to current therapies and has a survival as short as 15 months after diagnosis.
Little is known, however, about the metabolic pathways that drive the growth of individual glioblastoma subtypes – knowledge that is crucial for developing novel and effective targeted therapies that might improve treatment for these lethal tumors.
For this study, Nakano and his collaborators used cancer cells from 40 patients with high-grade gliomas, focusing on tumor cells with a stem-cell signature. The researchers then used microarray analysis and pre-clinical animal assays to identify two predominant glioblastoma subtypes, proneural and mesenchymal.
Key technical findings include:
- Genes involved in glycolysis and gluconeogenesis, particularly ALDH1A3, were significantly up-regulated in mesenchymal glioma stem cells compared to proneural stem cells;
- Mesenchymal glioma stem cells show significantly higher radiation resistance and high expression of DNA-repair genes;
- Radiation induces transformation of proneural glioma stem cells into mesenchymal-like glioma stem cells that are highly resistant to radiation treatment; inhibiting the ALDH1 pathway reverses this resistance.
- Inhibiting ALDH1A3-mediated pathways slows the growth of mesenchymal glioma stem cells and might provide a promising therapeutic approach for glioblastomas with a mesenchymal signature.
“Overall, our data suggest that a novel signaling mechanism underlies the transformation of proneural glioma stem cells to mesenchymal-like cells and their maintenance as stem-like cells,” Nakano says. Currently, their discoveries are in provision patent application, led by the Technology Licensing Office at University of Pittsburgh.
(Source: cancer.osu.edu)
New Molecular-Level Understanding of Brain’s Recovery After Stroke
A specific MicroRNA, a short set of RNA (ribonuclease) sequences, naturally packaged into minute (50 nanometers) lipid containers called exosomes, are released by stem cells after a stroke and contribute to better neurological recovery according to a new animal study by Henry Ford Hospital researchers.
The important role of a specific microRNA transferred from stem cells to brain cells via the exosomes to enhance functional recovery after a stroke was shown in lab rats. This study provides fundamental new insight into how stem cells affect injured tissue and also offers hope for developing novel treatments for stroke and neurological diseases, the leading cause of long-term disability in adult humans.
The study was published in the journal Stem Cells.
Although most stroke victims recover some ability to voluntarily use their hands and other body parts, nearly half are left with weakness on one side of their body, while a substantial number are permanently disabled.
Currently no treatment exists for improving or restoring this lost motor function in stroke patients, mainly because of mysteries about how the brain and nerves repair themselves.
“This study may have solved one of those mysteries by showing how certain stem cells play a role in the brain’s ability to heal itself to differing degrees after stroke or other trauma,” says study author Michael Chopp, Ph.D., scientific director of the Henry Ford Neuroscience Institute and vice chairman of the department of Neurology at Henry Ford Hospital.
The researchers noted that Henry Ford’s Institutional Animal Care and Use Committee approved all the experimental procedures used in the new study.
The experiment began by isolating mesenchymal stem cells (MSCs) from the bone marrow of lab rats. These MSCs are then genetically altered to release exosomes that contain specific microRNA molecules. The MSCs then become “factories” producing exosomes containing specific microRNAs. These microRNAs act as master switches that regulate biological function.
The new study showed for the first time that a specific microRNA, miR-133b, carried by these exosomes contributes to functional recovery after a stroke.
The researchers genetically raised or lowered the amount of miR-133b in MSCs and, respectively, treated the rats. When these MSCs are injected into the bloodstream 24 hours after stroke, they enter the brain and release their exosomes. When the exosomes were enriched with the miR-133b, they amplified neurological recovery, and when the exosomes were deprived of the miR-133b, the neurological recovery was substantially reduced.
Stroke was induced under anesthesia by inserting a nylon thread up the carotid artery to occlude a major artery in the brain, the middle cerebral artery. MSCs were then injected 24 hours after the induction of stroke in these animals and neurological recovery was measured.
As a measure on neurological recovery, rats were given two types of behavioral tests to measure the normal function of their front legs and paws – a “foot-fault test,” to see how well they could walk on an unevenly spaced grid; and an “adhesive removal test” to measure how long it took them to remove a piece of tape stuck to their front paws.
Researchers then separated the disabled rats into several groups and injected each group with a specific dosage of saline, MSCs and MSCs with increased or decreased miR-133b, respectively. The two behavioral tests were again given to the rats three, seven and 14 days after treatment.
The data demonstrated that the enriched miR-133b exosome package greatly promoted neurological recovery and enhanced axonal plasticity, an aspect of brain rewiring, and the diminished miR-133b exosome package failed to enhance neurological recovery
While the research team was careful to note that this was an animal study, its findings offer hope for new ways to address the single biggest concern of stroke victims as well as those with neural injury such as traumatic brain injury and spinal cord damage – regaining neurological function for a better quality of life.
(Source: henryford.com)
Difficult-to-study diseases such as Alzheimer’s, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed skin cells. According to Gong Chen, the Verne M. Willaman Chair in Life Sciences and professor of biology at Penn State University and the leader of the research team, “the most exciting part of this research is that it offers the promise of direct disease modeling, allowing for the creation, in a Petri dish, of mature human neurons that behave a lot like neurons that grow naturally in the human brain.” Chen added that the method could lead to customized treatments for individual patients based on their own genetic and cellular information. The research will be published in the journal Stem Cell Research.
"Obviously, we don’t want to remove someone’s brain cells to experiment on, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening," Chen said. Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized or undifferentiated pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell. So, after generating iPSCs from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish."
Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. Chen explained that, in their natural environment, neurons are always found in close proximity to star-shaped cells called astrocytes, which are abundant in the brain and help neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained.
To test this hypothesis, Chen and his colleagues began by culturing iPSC-derived neural stem cells, which are stem cells that have the potential to become neurons. These cells were cultured on top of a one-cell-thick layer of astrocytes so that the two cell types were physically touching each other.
"We found that these neural stem cells cultured on astrocytes differentiated into mature neurons much more effectively," Chen said, contrasting them with other neural stem cells that were cultured alone in a Petri dish. "It was almost as if the astrocytes were cheering the stem cells on, telling them what to do, and helping them fulfill their destiny to become neurons."
To demonstrate the superiority of the neurons grown next to astrocytes, Chen and his co-authors used an electrophysiology recording technique to show that the cells grown on astrocytes had many more synaptic events — signals sent out from one nerve cell to the others. In another experiment, after growing the neural stem cells next to astrocytes for just one week, the researchers showed that the newly differentiated neurons start to fire action potentials — the rapid electrical excitation signal that occurs in all neurons in the brain. In a final test, the team members added human neural stem cells to a mixture with mouse neurons. “We found that, after just one week, there was a lot of ‘cross-talk’ between the mouse neurons and the human neurons,” Chen said. He explained that “cross-talk” occurs when one neuron contacts its neighbors and releases a chemical called a neurotransmitter to modulate its neighbor’s activity.
"Previous researchers could only obtain brain cells from deceased patients who had suffered from diseases such as Alzheimer’s, schizophrenia, and autism," Chen said. "Now, researchers can take skin cells from living patients — a safe and minimally invasive procedure — and convert them into brain cells that mimic the activity of the patient’s own brain cells." Chen added that, by using this method, researchers also can figure out how a particular drug will affect a particular patient’s own brain cells, without needing the patient to try the drug — eliminating the risk of serious side effects. "The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly," Chen said.
Researchers Identify Genetic Signature of Deadly Brain Cancer
A multi-institutional team of researchers have pinpointed the genetic traits of the cells that give rise to gliomas – the most common form of malignant brain cancer. The findings, which appear in the journal Cell Reports, provide scientists with rich new potential set of targets to treat the disease.
“This study identifies a core set of genes and pathways that are dysregulated during both the early and late stages of tumor progression,” said University of Rochester Medical Center (URMC) neurologist Steven Goldman, M.D., Ph.D., the senior author of the study and co-director of the Center for Translational Neuromedicine. “By virtue of their marked difference from normal cells, these genes appear to comprise a promising set of targets for therapeutic intervention.”
As its name implies, gliomas arise from a cell type found in the central nervous system called the glial cell. Gliomas progress in severity over time and ultimately become highly invasive tumors known as glioblastomas, which are difficult to treat and almost invariably fatal. Current treatments, which include surgery, radiation therapy, and chemotherapy, can delay disease progression, but ultimately prove ineffective.
Cancer research has been transformed over the past several years by new concepts arising from stem cell biology. Scientists now appreciate that many cancers are the result of rogue stem cells or their offspring, known as progenitor cells. Traditional cancer therapies often do not prevent a recurrence of the disease since they may not effectively target and destroy the cancer-causing stem cells that lie at the heart of the tumors.
Gliomas are one such example. The source of the cancer is a cell found in the brain called the glial progenitor cell. The cells, which arise from and maintain characteristics of stem cells, comprise about three percent of the cell population of the human brain. When these cells become cancerous they are transformed into glioma stem cells, essentially glial progenitor cells whose molecular machinery has gone awry, resulting in uncontrolled cell division.
Goldman and his team have long studied normal glial progenitor cells. These cells produce glia, a category that includes both astrocytes – cells that support the function of neurons – and oligodendrocytes – cells that produces myelin, the fatty insulation that allows the long-distance conduction of neural impulses.
While Goldman’s group’s work has primarily focused on ways to use glial progenitor cells to treat neurological disorders such as multiple sclerosis, their understanding of the biology of these cells and mastery of the techniques required to sort, identify, and isolate these cells has also enabled them to explore the molecular and genetic changes that transform these cells into cancers.
Using human tissue samples representing the three principal stages of the cancer, the researchers were able to identify and isolate the cancer-inducing stem cells. Working with Goldman, lead authors Romane Auvergne, Ph.D. and Fraser Sim, Ph.D. then compared the gene expression profiles of these cancer stem cells to those of normal glial progenitor cells. The objective was to both pinpoint the earliest genetic changes associated with cancer formation and identify those genes that were unique to the cancer stem cells and were expressed at every stage of disease progression.
Out of a pool over 44,000 tested genes and sequences, the scientists identified a small set of genes in the cancerous glioma progenitor cells that were over-expressed at all stages of malignancy. These genes formed a unique “signature” that identified the tumor progenitor cells and enabled the scientists to define a corresponding set of potential therapeutic targets present throughout all stages of the cancer.
“One of the key things you are looking for in drug development in cancer is a protein or gene that is over-expressed, so that you can attempt to achieve therapeutic benefit by inhibiting it,” said Goldman.
The researchers chose to test this hypothesis by targeting one such gene, called SIX1, which was highly overexpressed in the glioma progenitor cells. While this particular gene is active in the early development of the nervous system, it had not been observed in the adult brain before. However, SIX1 signaling has been associated with breast and ovarian cancer, raising the possibility of its contribution to brain cancer as well. This turned out to indeed be the case. When the researchers blocked – or knocked down – the expression of this gene, the tumor cells ceased growing, and implanted tumors shrank.
“This study gives us a blueprint to develop new therapies,” said Goldman. “We can now devise a strategy to systematically and rationally analyze – and eliminate – glioma stem and progenitor cells using compounds that may selectively target these cells, relative to the normal glial progenitors from which they derive. By targeting genes like SIX1 that are expressed at all stages of glioma progression, we hope to be able to effectively treat gliomas regardless of their stage of malignancy. And by targeting the glioma-initiating cells in particular, we hope to lessen the likelihood of recurrence of these tumors, regardless of the stage at which we initiate treatment.”
(Source: urmc.rochester.edu)
Menzies’ Alzheimer’s disease research gains momentum
New research focuses on brain protein thought to be bad
Research conducted by Menzies Research Institute Tasmania, an institute of the University of Tasmania, is shedding new light on the biology of Alzheimer’s disease, in particular a protein in the brain that is indirectly responsible for causing Alzheimer’s disease.
Dementia is on the rise in Australia. There will be 75,000 baby boomers with dementia by 2020 and dementia will be the third largest source of health and residential care costs by 2030.*
Approximately 278,700 Australians were living with dementia in 2012. Without a medical breakthrough, the number of people with dementia in Australia is expected to be around 942,620 by 2050.*
Tasmania had over 7,000 people with dementia in 2012; this is projected to increase to 20,650 people by 2050.*
A brain protein known as the amyloid precursor protein (APP) has previously been considered to be mostly bad, in the sense that APP is indirectly responsible for causing Alzheimer’s disease.
Specifically, APP breaks down in the brain to produce a protein called Abeta, which is the direct cause of the disease. However, Menzies researchers have recently discovered that APP has a positive function.
Senior member of Menzies, Professor David Small, said the study discovered that APP is responsible for the growth of new neurons (nerve cells) in the brain.
"In addition to its role in causing Alzheimer’s disease, APP may also be part of a solution to the disease," Professor Small said.
"We may be able to use APP to encourage the brain to replace damaged neurons.
"Dissecting out the yin and yang of APP’s actions may be a key to the treatment of Alzheimer’s disease as well as a number of other similar diseases.
Our recent findings already present us with several avenues for developing new treatment strategies,” he said.
The study was recently published in the prestigious journal, Journal of Biological Chemistry.
(Source: utas.edu.au)
Engineered stem cell advance points toward treatment for ALS
Transplantation of human stem cells in an experiment conducted at the University of Wisconsin-Madison improved survival and muscle function in rats used to model ALS, a nerve disease that destroys nerve control of muscles, causing death by respiratory failure.
ALS (amyotrophic lateral sclerosis) is sometimes called “Lou Gehrig’s disease.” According to the ALS Association, the condition strikes about 5,600 Americans each year. Only about half of patients are alive three years after diagnosis.
In work recently completed at the UW School of Veterinary Medicine, Masatoshi Suzuki, an assistant professor of comparative biosciences, and his colleagues used adult stem cells from human bone marrow and genetically engineered the cells to produce compounds called growth factors that can support damaged nerve cells.
The researchers then implanted the cells directly into the muscles of rats that were genetically modified to have symptoms and nerve damage resembling ALS.
In people, the motor neurons that trigger contraction of leg muscles are up to three feet long. These nerve cells are often the first to suffer damage in ALS, but it’s unclear where the deterioration begins. Many scientists have focused on the closer end of the neuron, at the spinal cord, but Suzuki observes that the distant end, where the nerve touches and activates the muscle, is often damaged early in the disease.
The connection between the neuron and the muscle, called the neuro-muscular junction, is where Suzuki focuses his attention. “This is one of our primary differences,” Suzuki says. “We know that the neuro-muscular junction is a site of early deterioration, and we suspected that it might be the villain in causing the nerve cell to die. It might not be an innocent victim of damage that starts elsewhere.”
Previously, Suzuki found that injecting glial cell line-derived neurotropic factor (GDNF) at the junction helped the neurons survive. The new study, published in the journal Molecular Therapy on May 28, expands the research to show a similar effect from a second compound, called vascular endothelial growth factor.
In the study, Suzuki found that using stem cells to deliver vascular endothelial growth factor alone improved survival and delayed the onset of disease and the decline in muscle function. That result mirrored his earlier study with GDNF.
But the real advance, Suzuki says, was finding an even better result from using stem cells that create both of these two growth factors. “In terms of disease-free time, overall survival, and sustaining muscle function, we found that delivering the combination was more powerful than either growth factor alone. The results would provide a new hope for people with this terrible disease.”
The new research was supported by the ALS Association, the National Institutes of Health, the University of Wisconsin Foundation, and other groups.
The injected stem cells survived for at least nine weeks, but did not become neurons. Instead, their contribution was to secrete one or both growth factors.
Originally, much of the enthusiasm for stem cells focused on the hope of replacing damaged cells, but Suzuki’s approach is different. “These motor nerve cells have extremely long connections, and replacing these cells is still challenging. But we aim to keep the neurons alive and healthy using the same growth factors that the body creates, and that’s what we have shown here.”
For the test, Suzuki used ALS model rats with a mutation that is found in a small percentage of ALS patients who have a genetic form of the disease. “This model has been accepted as the best test bed for ALS experiments,” says Suzuki.
By using adult mesenchymal stem cells, the technique avoided the danger of tumor that can arise with the transplant of embryonic stem cells and related “do-anything” cells. Importantly, mesenchymal stem cells have been already used in clinical trials for various human diseases.
In the future, Suzuki hopes to apply his approach by using clinical grade stem cells. “Because this is a fatal and untreatable disease, we hope this could enter a clinical trial relatively soon.”