Posts tagged stem cells
Articles and news from the latest research reports.
(Image Caption: Human neurons differentiated from induced pluripotent stem cells, with cell nuclei shown in blue and synapses in red and green. Credit: Credit: Zhexing Wen/Johns Hopkins Medicine)
Stem Cells Reveal How Illness-Linked Genetic Variation Affects Neurons
A genetic variation linked to schizophrenia, bipolar disorder and severe depression wreaks havoc on connections among neurons in the developing brain, a team of researchers reports. The study, led by Guo-li Ming, M.D., Ph.D., and Hongjun Song, Ph.D., of the Johns Hopkins University School of Medicine and described online Aug. 17 in the journal Nature, used stem cells generated from people with and without mental illness to observe the effects of a rare and pernicious genetic variation on young brain cells. The results add to evidence that several major mental illnesses have common roots in faulty “wiring” during early brain development.
“This was the next best thing to going back in time to see what happened while a person was in the womb to later cause mental illness,” says Ming. “We found the most convincing evidence yet that the answer lies in the synapses that connect brain cells to one another.”
Previous evidence for the relationship came from autopsies and from studies suggesting that some genetic variants that affect synapses also increase the chance of mental illness. But those studies could not show a direct cause-and-effect relationship, Ming says.
One difficulty in studying the genetics of common mental illnesses is that they are generally caused by environmental factors in combination with multiple gene variants, any one of which usually could not by itself cause disease. A rare exception is the gene known as disrupted in schizophrenia 1 (DISC1), in which some mutations have a strong effect. Two families have been found in which many members with the DISC1 mutations have mental illness.
To find out how a DISC1 variation with a few deleted DNA “letters” affects the developing brain, the research team collected skin cells from a mother and daughter in one of these families who have neither the variation nor mental illness, as well as the father, who has the variation and severe depression, and another daughter, who carries the variation and has schizophrenia. For comparison, they also collected samples from an unrelated healthy person. Postdoctoral fellow Zhexing Wen, Ph.D., coaxed the skin cells to form five lines of stem cells and to mature into very pure populations of synapse-forming neurons.
After growing the neurons in a dish for six weeks, collaborators at Pennsylvania State University measured their electrical activity and found that neurons with the DISC1 variation had about half the number of synapses as those without the variation. To make sure that the differences were really due to the DISC1 variation and not to other genetic differences, graduate student Ha Nam Nguyen spent two years making targeted genetic changes to three of the stem cell lines.
In one of the cell lines with the variation, he swapped out the DISC1 gene for a healthy version. He also inserted the disease-causing variation into one healthy cell line from a family member, as well as the cell line from the unrelated control. Sure enough, the researchers report, the cells without the variation now grew the normal amount of synapses, while those with the inserted mutation had half as many.
“We had our definitive answer to whether this DISC1 variation is responsible for the reduced synapse growth,” Ming says.
To find out how DISC1 acts on synapses, the researchers also compared the activity levels of genes in the healthy neurons to those with the variation. To their surprise, the activities of more than 100 genes were different. “This is the first indication that DISC1 regulates the activity of a large number of genes, many of which are related to synapses,” Ming says.
The research team is now looking more closely at other genes that are linked to mental disorders. By better understanding the roots of mental illness, they hope to eventually develop better treatments for it, Ming says.
(Image caption: MRI scans showing brain damage in the stroke patients before treatment. Source: Stem Cells Translational Medicine.)
Stem cells show promise for stroke in pilot study
A stroke therapy using stem cells extracted from patients’ bone marrow has shown promising results in the first trial of its kind in humans.
Five patients received the treatment in a pilot study conducted by doctors at Imperial College Healthcare NHS Trust and scientists at Imperial College London.
The therapy was found to be safe, and all the patients showed improvements in clinical measures of disability.
The findings are published in the journal Stem Cells Translational Medicine. It is the first UK human trial of a stem cell treatment for acute stroke to be published.
The therapy uses a type of cell called CD34+ cells, a set of stem cells in the bone marrow that give rise to blood cells and blood vessel lining cells. Previous research has shown that treatment using these cells can significantly improve recovery from stroke in animals. Rather than developing into brain cells themselves, the cells are thought to release chemicals that trigger the growth of new brain tissue and new blood vessels in the area damaged by stroke.
The patients were treated within seven days of a severe stroke, in contrast to several other stem cell trials, most of which have treated patients after six months or later. The Imperial researchers believe early treatment may improve the chances of a better recovery.
A bone marrow sample was taken from each patient. The CD34+ cells were isolated from the sample and then infused into an artery that supplies the brain. No previous trial has selectively used CD34+ cells, so early after the stroke, until now.
Although the trial was mainly designed to assess the safety and tolerability of the treatment, the patients all showed improvements in their condition in clinical tests over a six-month follow-up period.
Four out of five patients had the most severe type of stroke: only four per cent of people who experience this kind of stroke are expected to be alive and independent six months later. In the trial, all four of these patients were alive and three were independent after six months.
Dr Soma Banerjee, a lead author and Consultant in Stroke Medicine at Imperial College Healthcare NHS Trust, said: “This study showed that the treatment appears to be safe and that it’s feasible to treat patients early when they might be more likely to benefit. The improvements we saw in these patients are very encouraging, but it’s too early to draw definitive conclusions about the effectiveness of the therapy. We need to do more tests to work out the best dose and timescale for treatment before starting larger trials.”
Over 150,000 people have a stroke in England every year. Survivors can be affected by a wide range of mental and physical symptoms, and many never recover their independence.
Stem cell therapy is seen as an exciting new potential avenue of treatment for stroke, but its exact role is yet to be clearly defined.
Dr Paul Bentley, also a lead author of the study, from the Department of Medicine at Imperial College London, said: “This is the first trial to isolate stem cells from human bone marrow and inject them directly into the damaged brain area using keyhole techniques. Our group are currently looking at new brain scanning techniques to monitor the effects of cells once they have been injected.”
Professor Nagy Habib, Principal Investigator of the study, from the Department of Surgery and Cancer at Imperial College London, said: “These are early but exciting data worth pursuing. Scientific evidence from our lab further supports the clinical findings and our aim is to develop a drug, based on the factors secreted by stem cells, that could be stored in the hospital pharmacy so that it is administered to the patient immediately following the diagnosis of stroke in the emergency room. This may diminish the minimum time to therapy and therefore optimise outcome. Now the hard work starts to raise funds for this exciting research.”
(Image caption: Part of a brain slice in which a transplanted induced neural stem cell is fully integrated in the neuronal network of the brain (blue) to develop into a complex and functional neuron.)
Implanted Neurons become Part of the Brain
Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have grafted neurons reprogrammed from skin cells into the brains of mice for the first time with long-term stability. Six months after implantation, the neurons had become fully functionally integrated into the brain. This successful, because lastingly stable, implantation of neurons raises hope for future therapies that will replace sick neurons with healthy ones in the brains of Parkinson’s disease patients, for example. The Luxembourg researchers published their results in the current issue of ‘Stem Cell Reports’.
The LCSB research group around Prof. Dr. Jens Schwamborn and Kathrin Hemmer is working continuously to bring cell replacement therapy to maturity as a treatment for neurodegenerative diseases. Sick and dead neurons in the brain can be replaced with new cells. This could one day cure disorders such as Parkinson’s disease. The path towards successful therapy in humans, however, is long. “Successes in human therapy are still a long way off, but I am sure successful cell replacement therapies will exist in future. Our research results have taken us a step further in this direction,” declares stem cell researcher Prof. Schwamborn, who heads a group of 15 scientists at LCSB.
In their latest tests, the research group and colleagues from the Max Planck Institute and the University Hospital Münster and the University of Bielefeld succeeded in creating stable nerve tissue in the brain from neurons that had been reprogrammed from skin cells. The stem cell researchers’ technique of producing neurons, or more specifically induced neuronal stem cells (iNSC), in a petri dish from the host’s own skin cells considerably improves the compatibility of the implanted cells. The treated mice showed no adverse side effects even six months after implantation into the hippocampus and cortex regions of the brain. In fact it was quite the opposite – the implanted neurons were fully integrated into the complex network of the brain. The neurons exhibited normal activity and were connected to the original brain cells via newly formed synapses, the contact points between nerve cells.
The tests demonstrate that the scientists are continually gaining a better understanding of how to treat such cells in order to successfully replace damaged or dead tissue. “Building upon the current insights, we will now be looking specifically at the type of neurons that die off in the brain of Parkinson’s patients – namely the dopamine-producing neurons,” Schwamborn reports. In future, implanted neurons could produce the lacking dopamine directly in the patient’s brain and transport it to the appropriate sites. This could result in an actual cure, as has so far been impossible. The first trials in mice are in progress at the LCSB laboratories on the university campus Belval.
'Support cells' in brain play important role in Down syndrome
Researchers from UC Davis School of Medicine and Shriners Hospitals for Children – Northern California have identified a group of cells in the brain that they say plays an important role in the abnormal neuron development in Down syndrome. After developing a new model for studying the syndrome using patient-derived stem cells, the scientists also found that applying an inexpensive antibiotic to the cells appears to correct many abnormalities in the interaction between the cells and developing neurons.
The findings, which focused on support cells in the brain called astroglial cells, appear online today in Nature Communications.
“We have developed a human cellular model for studying brain development in Down syndrome that allows us to carry out detailed physiological studies and screen possible new therapies,” said Wenbin Deng, associate professor of biochemistry and molecular medicine and principal investigator of the study. “This model is more realistic than traditional animal models because it is derived from a patient’s own cells.”
Down syndrome is the most common chromosomal cause of mild to moderate intellectual disabilities in the United States, where it occurs in one in every 691 live births. It develops when a person has three copies of the 21st chromosome instead of the normal two. While mouse models have traditionally been used in studying the genetic disorder, Deng said the animal model is inadequate because the human brain is more complicated, and much of that complexity arises from astroglia cells, the star-shaped cells that play an important role in the physical structure of the brain as well as in the transmission of nerve impulses.
“Although neurons are regarded as our ‘thinking cells,’ the astroglia have an extremely important supportive role,” said Deng. “Astroglial function is increasingly recognized as a critical factor in neuronal dysfunction in the brain, and this is the first study to show its importance in Down syndrome.”
Creating a unique human cellular model
To investigate the role of astroglia in Down syndrome, the research team took skin cells from individuals with Down syndrome and transformed them into stem cells, which are known as induced pluripotent stem cells (iPSC). The cells possess the same genetic make-up as the donor and an ability to grow into different cell types. Deng and his colleagues next induced the stem cells to develop into separate pure populations of astroglial cells and neurons. This allowed them to systematically analyze factors expressed by the astroglia and then study their effects on neuron development.
They found that a certain protein, known as S100B, is markedly increased in astroglial cells from patients with Down syndrome compared with those from healthy controls. S100B released by astroglial cells promotes harmful astroglial activation (astrogliosis) and adversely affects neurons, causing them to die at increased rates or develop in multiple dysfunctional ways.
The investigators obtained further evidence of the critical role of astroglial cells in Down syndrome by implanting the skin-cell derived astroglial cells from Down syndrome patients into mice. Those mice then developed the neuropathological phenotypes of Down syndrome, while mice implanted with Down syndrome neurons did not.
Neuroprotective effects of antibiotics
The research team also screened candidate drugs using a ‘disease-in-a-dish’ model. When they administered minocycline — a tetracycline antibiotic with anti-inflammatory properties commonly used to treat bacterial infections, acne and arthritis — many of the abnormalities in the astroglial cells were corrected and there were more healthy interactions between the astroglia and neurons compared to the control cells without the defect.
“The advent of induced pluripotent stem cell technology has created exciting new approaches to model neurodevelopmental and neurodegenerative diseases for the study of pathogenesis and for drug screening,” said David Pleasure, professor of neurology and pediatrics and a co-author of the study. “Using this technology, the study is the first to discover the critical role of astroglial cells in Down syndrome as well as identify a promising pathway for exploring how a drug such as minocycline may offer an effective way to help treat it.”
Pleasure, who is research director at Shriner’s Hospital for Children Northern California and also directs the Institute for Pediatric Regenerative Medicine, noted that considerable research interest has arisen about the use of minocycline for diseases of the central nervous system because of the increasing evidence about its neuroprotective effects. Unlike many drugs, minocycline can cross from the bloodstream into the brain so that it can act on the astroglial cells. The drug has never been tested as a treatment for Down syndrome, and both Pleasure and Deng cautioned that its safety and efficacy will require clinical trials in people with Down syndrome.
Currently, Deng’s laboratory is conducting additional preclinical studies using the human-derived stem cells from Down syndrome patients and mouse models to determine whether cellular and behavioral abnormalities can be improved with minocycline therapy and other candidate drugs.
“The abnormalities we identified occur in the early stages of Down syndrome,” said Deng. “While much more research is needed, it is exciting to consider that pharmacological intervention in these cellular processes might help slow or even prevent disease progression.”
(Image: iStockphoto)
Researchers find gene critical for development of brain motor centre
In a report published today in Nature Communications, an Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.
Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.
Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.
"As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away," said Dr. Picketts. "Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six."
The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.
"These epigenetic regulators are known to affect memory, behaviour and learning," said Dr. Picketts. "Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal."
There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it “is certainly possible and an interesting avenue to explore.”
In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum.
Embryonic Stem Cells Offer Treatment Promise for Multiple Sclerosis
Scientists in the University of Connecticut’s Technology Incubation Program have identified a novel approach to treating multiple sclerosis (MS) using human embryonic stem cells, offering a promising new therapy for more than 2.3 million people suffering from the debilitating disease.
The researchers demonstrated that the embryonic stem cell therapy significantly reduced MS disease severity in animal models, and offered better treatment results than stem cells derived from human adult bone marrow.
The study was led by ImStem Biotechnology Inc. of Farmington, Conn., in conjunction with UConn Health Professor Joel Pachter, Assistant Professor Stephen Crocker, and Advanced Cell Technology (ACT) Inc. of Massachusetts. ImStem was founded in 2012 by UConn doctors Xiaofang Wang and Ren-He Xu, along with Yale University doctor Xinghua Pan and investor Michael Men.
“The cutting-edge work by ImStem, our first spinoff company, demonstrates the success of Connecticut’s Stem Cell and Regenerative Medicine funding program in moving stem cells from bench to bedside,” says Professor Marc Lalande, director of the UConn’s Stem Cell Institute.
The research was supported by a $1.13 million group grant from the state of Connecticut’s Stem Cell Research Program that was awarded to ImStem and Professor Pachter’s lab.
“Connecticut’s investment in stem cells, especially human embryonic stem cells, continues to position our state as a leader in biomedical research,” says Gov. Dannel P. Malloy. “This new study moves us one step closer to a stem cell-based clinical product that could improve people’s lives.”
The researchers compared eight lines of adult bone marrow stem cells to four lines of human embryonic stem cells. All of the bone marrow-related stem cells expressed high levels of a protein molecule called a cytokine that stimulates autoimmunity and can worsen the disease. All of the human embryonic stem cell-related lines expressed little of the inflammatory cytokine.
Another advantage of human embryonic stem cells is that they can be propagated indefinitely in lab cultures and provide an unlimited source of high quality mesenchymal stem cells – the kind of stem cell needed for treatment of MS, the researchers say. This ability to reliably grow high quality mesenchymal stem cells from embryonic stem cells represents an advantage over adult bone marrow stem cells, which must be obtained from a limited supply of healthy donors and are of more variable quality.
“Groundbreaking research like this furthering opportunities for technology ventures demonstrates how the University acts as an economic engine for the state and regional economy,” says Jeff Seemann, UConn’s vice president for research.
The findings also offer potential therapy for other autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and type-1 diabetes, according to Xu, a corresponding author on the study and one of the few scientists in the world to have generated new human embryonic stem cell lines.
There is no cure for MS, a chronic neuroinflammatory disease in which the body’s immune system eats away at the protective sheath called myelin that covers the nerves. Damage to myelin interferes with communication between the brain, spinal cord, and other areas of the body. Current MS treatments only offer pain relief, and slow the progression of the disease by suppressing inflammation.
“The beauty of this new type of mesenchymal stem cells is their remarkable higher efficacy in the MS model,” says Wang, chief technology officer of ImStem.
The group’s findings appear in the current online edition of Stem Cell Reports, the official journal of the International Society for Stem Cell Research. ImStem is currently seeking FDA approval necessary to make this treatment available to patients.
Researchers Use Human Stem Cells to Create Light-Sensitive Retina in a Dish
Using a type of human stem cell, Johns Hopkins researchers say they have created a three-dimensional complement of human retinal tissue in the laboratory, which notably includes functioning photoreceptor cells capable of responding to light, the first step in the process of converting it into visual images.
(Image caption: Rod photoreceptors (in green) within a “mini retina” derived from human iPS cells in the lab. Image courtesy of Johns Hopkins Medicine)
“We have basically created a miniature human retina in a dish that not only has the architectural organization of the retina but also has the ability to sense light,” says study leader M. Valeria Canto-Soler, Ph.D., an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine. She says the work, reported online June 10 in the journal Nature Communications, “advances opportunities for vision-saving research and may ultimately lead to technologies that restore vision in people with retinal diseases.”
Like many processes in the body, vision depends on many different types of cells working in concert, in this case to turn light into something that can be recognized by the brain as an image. Canto-Soler cautions that photoreceptors are only part of the story in the complex eye-brain process of vision, and her lab hasn’t yet recreated all of the functions of the human eye and its links to the visual cortex of the brain. “Is our lab retina capable of producing a visual signal that the brain can interpret into an image? Probably not, but this is a good start,” she says.
The achievement emerged from experiments with human induced pluripotent stem cells (iPS) and could, eventually, enable genetically engineered retinal cell transplants that halt or even reverse a patient’s march toward blindness, the researchers say.
The iPS cells are adult cells that have been genetically reprogrammed to their most primitive state. Under the right circumstances, they can develop into most or all of the 200 cell types in the human body. In this case, the Johns Hopkins team turned them into retinal progenitor cells destined to form light-sensitive retinal tissue that lines the back of the eye.
Using a simple, straightforward technique they developed to foster the growth of the retinal progenitors, Canto-Soler and her team saw retinal cells and then tissue grow in their petri dishes, says Xiufeng Zhong, Ph.D., a postdoctoral researcher in Canto-Soler’s lab. The growth, she says, corresponded in timing and duration to retinal development in a human fetus in the womb. Moreover, the photoreceptors were mature enough to develop outer segments, a structure essential for photoreceptors to function.
Retinal tissue is complex, comprising seven major cell types, including six kinds of neurons, which are all organized into specific cell layers that absorb and process light, “see,” and transmit those visual signals to the brain for interpretation. The lab-grown retinas recreate the three-dimensional architecture of the human retina. “We knew that a 3-D cellular structure was necessary if we wanted to reproduce functional characteristics of the retina,” says Canto-Soler, “but when we began this work, we didn’t think stem cells would be able to build up a retina almost on their own. In our system, somehow the cells knew what to do.”
When the retinal tissue was at a stage equivalent to 28 weeks of development in the womb, with fairly mature photoreceptors, the researchers tested these mini-retinas to see if the photoreceptors could in fact sense and transform light into visual signals.
They did so by placing an electrode into a single photoreceptor cell and then giving a pulse of light to the cell, which reacted in a biochemical pattern similar to the behavior of photoreceptors in people exposed to light.
Specifically, she says, the lab-grown photoreceptors responded to light the way retinal rods do. Human retinas contain two major photoreceptor cell types called rods and cones. The vast majority of photoreceptors in humans are rods, which enable vision in low light. The retinas grown by the Johns Hopkins team were also dominated by rods.
Canto-Soler says that the newly developed system gives them the ability to generate hundreds of mini-retinas at a time directly from a person affected by a particular retinal disease such as retinitis pigmentosa. This provides a unique biological system to study the cause of retinal diseases directly in human tissue, instead of relying on animal models.
The system, she says, also opens an array of possibilities for personalized medicine such as testing drugs to treat these diseases in a patient-specific way. In the long term, the potential is also there to replace diseased or dead retinal tissue with lab-grown material to restore vision.
(Source: hopkinsmedicine.org)
New Method Reveals Key Protein Interaction For Embryonic Stem Cell Differentiation
Proteins are responsible for the vast majority of the cellular functions that shape life, but like guests at a crowded dinner party, they interact transiently and in complex networks, making it difficult to determine which specific interactions are most important.
Now, researchers from the University of Chicago have pioneered a new technique to simplify the study of protein networks and identify the importance of individual protein interactions. By designing synthetic proteins that can only interact with a pre-determined partner, and introducing them into cells, the team revealed a key interaction that regulates the ability of embryonic stem cells to change into other cell types. They describe their findings June 5 in Molecular Cell.
“Our work suggests that the apparent complexity of protein networks is deceiving, and that a circuit involving a small number of proteins might control each cellular function,” said senior author Shohei Koide, PhD, professor of biochemistry & molecular biophysics at the University of Chicago.
For a cell to perform biological functions and respond to the environment, proteins must interact with one another in immensely complex networks, which when diagrammed can resemble a subway map out of a nightmare. These networks have traditionally been studied by removing a protein of interest through genetic engineering and observing whether the removal destroys the function of interest or not. However, this does not provide information on the importance of specific protein-to-protein interactions.
To approach this challenge, Koide and his team pioneered a new technique that they dub “directed network wiring.” Studying mouse embryonic stem cells, they removed Grb2, a protein essential to the ability of the stem cell to transform into other cell types, from the cells. The researchers then designed synthetic versions of Grb2 that could only interact with one protein from a pool of dozens that normal Grb2 is known to network with. The team then introduced these synthetic proteins back into the cell to see which specific interactions would restore the stem cell’s transformative abilities.
“The name, ‘directed network wiring,’ comes from the fact that we create minimalist networks,” Koide said. “We first remove all communication lines associated with a protein of interest and add back a single line. It is analysis by addition.”
Despite the complexity of the protein network associated with stem cell development, the team discovered that restoring only one interaction—between Grb2 and a protein known as Ptpn11/Shp2 phosphatase—was enough to allow stem cells to again change into other cell types.
“We were really surprised to find that consolidating many interactions down to a single particular connection for the protein was sufficient to support development of the cells to the next stage, which involves many complicated processes,” Koide said. “Our results show that signals travel discrete and simple routes in the cell.”
Koide and his team are now working on streamlining directed network wiring and applying it to other areas of study such as cancer. With the ability to dramatically simplify how scientists study protein interaction networks, they hope to open the door to new research areas and therapeutic approaches.
“We can now design synthetic proteins that are far more sophisticated than natural ones, and use such super-performance proteins toward advancing science and medicine,” he said.
Unlocking the potential of stem cells to repair brain damage
A QUT scientist is hoping to unlock the potential of stem cells as a way of repairing neural damage to the brain.
Rachel Okolicsanyi, from the Genomics Research Centre at QUT’s Institute of Health and Biomedical Innovation, said unlike other cells in the body which were able to divide and replicate, once most types of brain cells died, the damage was deemed irreversible.
Ms Okolicsanyi is manipulating adult stem cells from bone marrow to produce a population of cells that can be used to treat brain damage.
"My research is a step in proving that stem cells taken from the bone marrow can be manipulated into neural cells, or precursor cells that have the potential to replace, repair or treat brain damage," she said.
Ms Okolicsanyi’s research has been published in Developmental Biology journal, and outlines the potential stem cells have for brain damage repair.
"What I am looking at is whether or not stem cells from the bone marrow have the potential to differentiate or mature into neural cells," she said.
"Neural cells are those cells from the brain that make everything from the structure of the brain itself, to all the connections that make movement, voice, hearing and sight possible."
Ms Okolicsanyi’s research is looking at heparin sulfate proteoglycans - a family of proteins found on the surface of all cells.
"What we are hoping is that by manipulating this particular family of proteins we can encourage the stem cells to show a higher percentage of neural markers indicating that they could mature into neural cells rather than what they would normally do, which is form into bone, cartilage and fat," she said.
"We will manipulate these cells by modifying the surrounding environment. For example we will add chemicals such as complex salts and other commonly found biological chemicals to feed these cells and this will either inhibit or encourage cellular processes."
Ms Okolicsanyi said by doing this, it would be possible to see the different reactions stem cells had to particular chemicals and find out whether these chemicals could increase or decrease the neural markers in the cells.
"The proteins that we are interested in are almost like a tree," she said.
"They have a core protein that is attached to the cell surface and they have these heparin sulfate chains that branch off.
"So when the chemicals we add influence the stem cell in different ways, it will help us understand the interactions between proteins and the resulting changes in the cell.
"In the short-term it is proof that simple manipulations can influence the stem cell and in the long-term it is about the possibility of increasing the neural potential of these stem cells."
Ms Okolicsanyi said the big picture plan was to be able to introduce stem cells into the brain that would be able to be manipulated to repair damaged brain cells.
"The idea, for example, is that in stroke patients where the patient loses movement, speech or control of one side of their face because the brain’s electrical current is impaired, that these stem cells will be able to be introduced and help the electrical current reconnect by bypassing the damaged cells."
(Image: Fotolia)
(Image caption: In this artist’s representation of the adult subependymal neurogenic niche (viewed from underneath the ependyma), electrical signals generated by the ChAT+ neuron give rise to newborn migrating neuroblasts, seen moving over the underside of ependymal cells. Credit: Illustration by O’Reilly Science Art.)
Neuron Tells Stem Cells to Grow New Neurons
Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within.
Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explains Chay Kuo, M.D. Ph.D., an assistant professor of cell biology, neurobiology and pediatrics.
In a study with mice, his team found a previously unknown population of neurons within the subventricular zone (SVZ) neurogenic niche of the adult brain, adjacent to the striatum. These neurons expressed the choline acetyltransferase (ChAT) enzyme, which is required to make the neurotransmitter acetylcholine. With optogenetic tools that allowed the team to tune the firing frequency of these ChAT+ neurons up and down with laser light, they were able to see clear changes in neural stem cell proliferation in the brain.
The findings appeared as an advance online publication June 1 in the journal Nature Neuroscience.
The mature ChAT+ neuron population is just one part of an undescribed neural circuit that apparently talks to stem cells and tells them to increase new neuron production, Kuo said. Researchers don’t know all the parts of the circuit yet, nor the code it’s using, but by controlling ChAT+ neurons’ signals Kuo and his Duke colleagues have established that these neurons are necessary and sufficient to control the production of new neurons from the SVZ niche.
"We have been working to determine how neurogenesis is sustained in the adult brain. It is very unexpected and exciting to uncover this hidden gateway, a neural circuit that can directly instruct the stem cells to make more immature neurons," said Kuo, who is also the George W. Brumley, Jr. M.D. assistant professor of developmental biology and a member of the Duke Institute for Brain Sciences. "It has been this fascinating treasure hunt that appeared to dead-end on multiple occasions!"
Kuo said this project was initiated more than five years ago when lead author Patricia Paez-Gonzalez, a postdoctoral fellow, came across neuronal processes contacting neural stem cells while studying how the SVZ niche was assembled.
The young neurons produced by these signals were destined for the olfactory bulb in rodents, as the mouse has a large amount of its brain devoted to process the sense of smell and needs these new neurons to support learning. But in humans, with a much less impressive olfactory bulb, Kuo said it’s possible new neurons are produced for other brain regions. One such region may be the striatum, which mediates motor and cognitive controls between the cortex and the complex basal ganglia.
"The brain gives up prime real estate around the lateral ventricles for the SVZ niche housing these stem cells," Kuo said. "Is it some kind of factory taking orders?" Postdoctoral fellow Brent Asrican made a key observation that orders from the novel ChAT+ neurons were heard clearly by SVZ stem cells.
Studies of stroke injury in rodents have noted SVZ cells apparently migrating into the neighboring striatum. And just last month in the journal Cell, a Swedish team observed newly made control neurons called interneurons in the human striatum for the first time. They reported that interestingly in Huntington’s disease patients, this area seems to lack the newborn interneurons.
"This is a very important and relevant cell population that is controlling those stem cells," said Sally Temple, director of the Neural Stem Cell Institute of Rensselaer, NY, who was not involved in this research. "It’s really interesting to see how innervations are coming into play now in the subventricular zone."
Kuo’s team found this system by following cholinergic signaling, but other groups are arriving in the same niche by following dopaminergic and serotonergic signals, Temple said. “It’s a really hot area because it’s a beautiful stem cell niche to study. It’s this gorgeous niche where you can observe cell-to-cell interactions.”
These emerging threads have Kuo hopeful researchers will eventually be able to find the way to “engage certain circuits of the brain to lead to a hardware upgrade. Wouldn’t it be nice if you could upgrade the brain hardware to keep up with the new software?” He said perhaps there will be a way to combine behavioral therapy and stem cell treatments after a brain injury to rebuild some of the damage.
The questions ahead are both upstream from the new ChAT+ neurons and downstream, Kuo says. Upstream, what brain signals tell ChAT+ neurons to start asking the stem cells for more young neurons? Downstream, what’s the logic governing the response of the stem cells to different frequencies of ChAT+ electrical activity?
There’s also the big issue of somehow being able to introduce new components into an existing neuronal circuit, a practice that parts of the brain might normally resist. “I think that some neural circuits welcome new members, and some don’t,” Kuo said.