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Ordinary Skin Cells Morphed into Functional Brain Cells
Scientists at CWRU School of Medicine Discover New Technique that Holds Promise for the Treatment of Multiple Sclerosis and Cerebral Palsy
Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.
This discovery appears today in the journal Nature Biotechnology.
This breakthrough now enables “on demand” production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced.
The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain.
“Its ‘cellular alchemy,’” explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”
In a process termed “cellular reprogramming,” researchers manipulated the levels of three naturally occurring proteins to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).
Tesar’s team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.
When oligodendrocytes are damaged or become dysfunctional in myelinating diseases, the insulating myelin coating that normally coats nerves is lost. A cure requires the myelin coating to be regenerated by replacement oligodendrocytes.
Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but with limitations.
“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explained co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”
This initial study used mouse cells. The critical next step is to demonstrate feasibility and safety using human cells in a lab setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.
“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”
Researchers Discover New Clues About How Amyotrophic Lateral Sclerosis (ALS) Develops
Johns Hopkins scientists say they have evidence from animal studies that a type of central nervous system cell other than motor neurons plays a fundamental role in the development of amyotrophic lateral sclerosis (ALS), a fatal degenerative disease. The discovery holds promise, they say, for identifying new targets for interrupting the disease’s progress.
In a study described online in Nature Neuroscience, the researchers found that, in mice bred with a gene mutation that causes human ALS, dramatic changes occurred in oligodendrocytes — cells that create insulation for the nerves of the central nervous system — long before the first physical symptoms of the disease appeared. Oligodendrocytes located near motor neurons — cells that govern movement — died off at very high rates, and new ones regenerated in their place were inferior and unhealthy.
The researchers also found, to their surprise, that suppressing an ALS-causing gene in oligodendrocytes of mice bred with the disease — while still allowing the gene to remain in the motor neurons — profoundly delayed the onset of ALS. It also prolonged survival of these mice by more than three months, a long time in the life span of a mouse. These observations suggest that oligodendrocytes play a very significant role in the early stage of the disease.
“The abnormalities in oligodendrocytes appear to be having a negative impact on the survival of motor neurons,” says Dwight E. Bergles, Ph.D., a co-author and a professor of neuroscience at the Johns Hopkins University School of Medicine. “The motor neurons seem to be dependent on healthy oligodendrocytes for survival, something we didn’t appreciate before.”
“These findings teach us that cells we never thought had a role in ALS not only are involved but also clearly contribute to the onset of the disease,” says co-author Jeffrey D. Rothstein, M.D., Ph.D., a professor of neurology at Johns Hopkins and director of the Johns Hopkins Medicine Brain Science Institute.
Scientists have long believed that oligodendrocytes functioned only as structural elements of the central nervous system. They wrap around nerves, making up the myelin sheath that provides the “insulation” that allows nerve signals to be transmitted rapidly and efficiently. However, Rothstein and others recently discovered that oligodendrocytes also deliver essential nutrients to neurons, and that most neurons need this support to survive.
The Johns Hopkins team of Bergles and Rothstein published a paper in 2010 that described in mice with ALS an unexpected massive proliferation of oligodendrocyte progenitor cells in the spinal cord’s motor neurons, and that these progenitors were being mobilized to make new oligodendrocytes. The researchers believed that these cells were multiplying because of an injury to oligodendrocytes, but they weren’t sure what was happening. Using a genetic method of tracking the fate of oligodendrocytes, in the new study, the researchers found that cells present in young mice with ALS were dying off at an increasing rate in concert with advancing disease. Moreover, the development of the newly formed oligodendrocytes was stalled and they were not able to provide motor neurons with a needed source of cell nutrients.
To determine whether the changes to the oligodendrocytes were just a side effect of the death of motor neurons, the scientists used a poison to kill motor neurons in the ALS mice and found no response from the progenitors, suggesting, says Rothstein, that it is the mutant ALS gene that is damaging oligodendrocytes directly.
Meanwhile, in separate experiments, the researchers found similar changes in samples of tissues from the brains of 35 people who died of ALS. Rothstein says it may be possible to see those changes early on in the disease and use MRI technology to follow progression.
“If our research is confirmed, perhaps we can start looking at ALS patients in a different way, looking for damage to oligodendrocytes as a marker for disease progression,” Rothstein says. “This could not only lead to new treatment targets but also help us to monitor whether the treatments we offer are actually working.”
ALS, also known as Lou Gehrig’s disease, named for the Yankee baseball great who died from it, affects nerve cells in the brain and spinal cord that control voluntary muscle movement. The nerve cells waste away or die, and can no longer send messages to muscles, eventually leading to muscle weakening, twitching and an inability to move the arms, legs and body. Onset is typically around age 50 and death often occurs within three to five years of diagnosis. Some 10 percent of cases are hereditary.
There is no cure for ALS and there is only one FDA-approved drug treatment, which has just a small effect in slowing disease progression and increasing survival.
Even though myelin loss has not previously been thought to occur in the gray matter, a region in the brain where neurons process information, the researchers in the new study found in ALS patients a significant loss of myelin in one of every three samples of human tissue taken from the brain’s gray matter, suggesting that the oligodendrocytes were abnormal. It isn’t clear if the oligodendrocytes that form this myelin in the gray matter play a different role than in white matter — the region in the brain where signals are relayed.
The findings further suggest that clues to the treatment of other diseases long believed to be focused in the brain’s gray matter — such as Alzheimer’s disease, Huntington’s disease and Parkinson’s disease — may be informed by studies of diseases of the white matter, such as multiple sclerosis (MS). Bergles says ALS and MS researchers never really thought their diseases had much in common before.
Oligodendrocytes have been under intense scrutiny in MS, Bergles says. In MS, the disease over time can transform from a remitting-relapsing form — in which myelin is attacked but then is regenerated when existing progenitors create new oligodendrocytes to re-form myelin — to a more chronic stage in which oligodendrocytes are no longer regenerated. MS researchers are working to identify new ways to induce the creation of new oligodendrocytes and improve their survival. “It’s possible that we may be able to dovetail with some of the same therapeutics to slow the progression of ALS,” Bergles says.
List: Astrocyte Functions
Astrocytes are a special kind of stellate-shaped brain cells that are found throughout the central nervous system and that play a supportive role for neurons. For a long time, astrocytes were thought of as merely providing “assistance” for neuron function and survival. However, the discovery that astrocytes express voltage-gated channels and neurotransmitter receptors suggests the possibility of an active role for astrocytes in neuronal communication. Astrocytes primarily originate come from either radial glia cells or from cells in the sub ventricular zone and can be visualized with glial fibrillary acidic protein (GFAP). Below is an image of GFAP staining for astrocytes.
Other groups of glia:
- Oligodendrocytes: Provide myelin sheath in neurons present in the central nervous system (CNS). Each oligodendrocyte can myelinate multiple axons.
- Schwann Cells: Myelinate axons of neurons present in the peripheral nervous system (PNS). Schwan cells, however, only myelinate one axon.
- Microglia: Derived from bone marrow and function as antigen presenting cells. Microglia have phagocytic activity, which means they “eat up” (or clear) cellular debris and their roles are predominantly host defense.
- Regulation of brain extracellular pH via secretion of acid into the extracellular space (aka potassium buffering). Other regulatory functions of astrocytes include limiting the rise of both extracellular potassium (K+) and pH during neural activity. In addition, astrocytes can take up potassium in a variety of ways: Na+-K+ exchange, K+-Cl- cotransport and other K+ channels characterized by distinct properties.
- Regulating the uptake of glutamate near the synaptic cleft.
- Astrocytes can serve as signaling elements within an astrocyte network, between astrocytes and blood vessels, and/or between astrocytes and neurons. For example, astrocytes can signal to other neurons via Ca+2 oscillations (otherwise known as calcium waves). These calcium waves can come about in two ways: they are either triggered by neural activity (such as activation of astrocyte glutamate receptors) or spontaneoulsy via calcium release from internal stores and activation of IP3 receptors. Astrocytes may also serve as neurotransmitter transporters and receptors as well as aiding in neurotransmitter catabolism.
- Modulate synaptic and neural activity via “gliotransmission”. Known gliotransmitters (chemicals that can act on neighboring neurons, glial cells or vessels) include glutamate, cytokines, ATP, and D-serine. As illustrated below, astrocyte processes govern the amount of neurotransmitter spillage around synapse, thus controlling lateral spread of excitation.
- Modulation of brain vascular tone (i.e. vasodilation/vasoconstriction) and promotion of neurovascular coupling. Basically, astrocytes regulate cerebral blood flow. Moreover, vascular tone depends on the release of vascular agents into the perivascular space.
- Control of synapse formation, stabilization and function as well as neurogenesis. These roles have been predominantly explored in the context of brain pathology and psychiatric disorders like ALS, Alzheimer’s, brain tumors, traumatic brain injury and ischemia.
Chesler, Mitch. Properties of the brain, extracellular space and astrocyte function. Lecture given as part of the cellular neuroscience course. Fall 2009.
After Brain Injury, New Astrocytes Play Unexpected Role in Healing
DURHAM, N.C. – The production of a certain kind of brain cell that had been considered an impediment to healing may actually be needed to staunch bleeding and promote repair after a stroke or head trauma, researchers at Duke Medicine report.
These cells, known as astrocytes, can be produced from stem cells in the brain after injury. They migrate to the site of damage where they are much more effective in promoting recovery than previously thought. This insight from studies in mice, reported online April 24, 2013, in the journal Nature, may help researchers develop treatments that foster brain repair.
“The injury recovery process is complex,” said senior author Chay T. Kuo, M.D., PhD, George W. Brumley Assistant Professor of Cell Biology, Pediatrics and Neurobiology at Duke University. “There is a lot of interest in how new neurons can stimulate functional recovery, but if you make neurons without stopping the bleeding, the neurons don’t even get a chance. The brain somehow knows this, so we believe that’s why it produces these unique astrocytes in response to injury.”
Each year, more than 1.7 million people in the United States suffer a traumatic brain injury, according to the Centers for Disease Control and Prevention. Another 795,000 people a year suffer a stroke. Few therapies are available to treat the damage that often results from such injuries.
Kuo and colleagues at Duke are interested in replacing lost neurons after a brain injury as a way to restore function. Once damaged, mature neurons cannot multiply, so most research efforts have focused on inducing brain stem cells to produce more immature neurons to replace them.
This strategy has proved difficult, because in addition to making neurons, neural stem cells also produce astrocytes and oligodendrocytes, known as glial cells. Although glial cells are important for maintaining the normal function of neurons in the brain, the increased production of astrocytes from neural stem cell has been considered an unwanted byproduct, causing more harm than good. Proliferating astrocytes secrete proteins that can induce tissue inflammation and undergo gene mutations that can lead to aggressive brain tumors.
In their study of mice, the Duke team found an unexpected insight about the astrocytes produced from stem cells after injury. Stem cells live in a special area or “niche” in the postnatal/adult brain called the subventricular zone, and churn out neurons and glia in the right proportions based on cues from the surrounding tissue.
After an injury, however, the subventricular niche pumps out more astrocytes. Significantly, the Duke team found they are different from astrocytes produced in most other regions of the brain. These cells make their way to the injured area to help make an organized scar, which stops the bleeding and allows tissue recovery.
When the generation of these astrocytes in the subventricular niche was experimentally blocked after a brain injury, hemorrhaging occurred around the injured areas and the region did not heal. Kuo said the finding was made possible by insights about astrocytes from Cagla Eroglu, PhD, whose laboratory next door to Kuo’s conducts research on astrocyte interactions with neurons.
“Cagla and I started at Duke together and have known each other since our postdoctoral days,” Kuo said. “To have these stem cell-made astrocytes express a unique protein that Cagla understands more than anyone else, it’s just a wonderful example of scientific serendipity and collaboration.”
Additionally, Kuo said first author Eric J. Benner, M.D., PhD, a former postdoctoral fellow who now has his own laboratory at Duke, provided key clinical correlations on brain injury as a physician-scientist and practicing neonatologist in the Jean and George Brumley Jr. Neonatal-Perinatal Research Institute.
“We are very excited about this innate flexibility in neural stem cell behavior to know just what to do to help the brain after injury,” Kuo said. “Since bleeding in the brain after injury is a common and serious problem for patients, further research into this area may lead to effective therapies for accelerated brain recovery after injury.”
In addition to Kuo, Eroglu and Benner, authors include Dominic Luciano, Rebecca Jo, Khadar Abdi, Patricia Paez-Gonzalez, Huaxin Sheng, David Warner and Chunlei Liu.
The research was supported by the National Biomedical Technology Resource Center (P41 RR005959); the George and Jean Brumley Endowment; the Sontag Foundation; the David & Lucile Packard Foundation; the March of Dimes; and the National Institutes of Health (DP2 OD004453-01).
IMAGE: Artist rendition of a special astrocyte. Courtesy of Andrew Swift.