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scienceblogtumbler · 4 years
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Implanted Neural Stem Cell Grafts Show Functionality in Spinal Cord Injuries
Using stem cells to restore lost functions due to spinal cord injury (SCI) has long been an ambition of scientists and doctors. Nearly 18,000 people in the United States suffer SCIs each year, with another 294,000 persons living with an SCI, usually involving some degree of permanent paralysis or diminished physical function, such as bladder control or difficulty breathing.
In a new study, published August 5, 2020 in Cell Stem Cell, researchers at University of California San Diego School of Medicine report successfully implanting highly specialized grafts of neural stem cells directly into spinal cord injuries in mice, then documenting how the grafts grew and filled the injury sites, integrating with and mimicking the animals’ existing neuronal network.
Until this study, said the study’s first author Steven Ceto, a postdoctoral fellow in the lab of Mark H. Tuszynski, MD, PhD, professor of neurosciences and director of the Translational Neuroscience Institute at UC San Diego School of Medicine, neural stem cell grafts being developed in the lab were sort of a black box.
Although previous research, including published work by Tuszynski and colleagues, had shown improved functioning in SCI animal models after neural stem cell grafts, scientists did not know exactly what was happening.
“We knew that damaged host axons grew extensively into (injury sites), and that graft neurons in turn extended large numbers of axons into the spinal cord, but we had no idea what kind of activity was actually occurring inside the graft itself,” said Ceto. “We didn’t know if host and graft axons were actually making functional connections, or if they just looked like they could be.”
Ceto, Tuszynski and colleagues took advantage of recent technological advances that allow researchers to both stimulate and record the activity of genetically and anatomically defined neuron populations with light rather than electricity. This ensured they knew exactly which host and graft neurons were in play, without having to worry about electric currents spreading through tissue and giving potentially misleading results.
They discovered that even in the absence of a specific stimulus, graft neurons fired spontaneously in distinct clusters of neurons with highly correlated activity, much like in the neural networks of the normal spinal cord. When researchers stimulated regenerating axons coming from the animals’ brain, they found that some of the same spontaneously active clusters of graft neurons responded robustly, indicating that these networks receive functional synaptic connections from inputs that typically drive movement. Sensory stimuli, such as a light touch and pinch, also activated graft neurons.
“We showed that we could turn on spinal cord neurons below the injury site by stimulating graft axons extending into these areas,” said Ceto. “Putting all these results together, it turns out that neural stem cell grafts have a remarkable ability to self-assemble into spinal cord-like neural networks that functionally integrate with the host nervous system. After years of speculation and inference, we showed directly that each of the building blocks of a neuronal relay across spinal cord injury are in fact functional.”
Tuszynski said his team is now working on several avenues to enhance the functional connectivity of stem cell grafts, such as organizing the topology of grafts to mimic that of the normal spinal cord with scaffolds and using electrical stimulation to strengthen the synapses between host and graft neurons.
“While the perfect combination of stem cells, stimulation, rehabilitation and other interventions may be years off, patients are living with spinal cord injury right now,” Tuszynski said. “Therefore, we are currently working with regulatory authorities to move our stem cell graft approach into clinical trials as soon as possible. If everything goes well, we could have a therapy within the decade.”
Co-authors of the study are Kohel J. Sekiguchi and Axel Nimmerjahn, Salk Institute for Biological Studies and Yoshio Takashima, UC San Diego and Veterans Administration Medical Center, San Diego.
Funding for this research came, in part, from Wings for Life, the University of California Frontiers of Innovation Scholars Program, the Veterans Administration (Gordon Mansfield Spinal Cord Injury Collaborative Consortium, RR&D B7332R), the National Institutes of Health (grants NS104442 and NS108034), The Craig H. Neilsen Foundation, the Kakajima Foundation, the Bernard and Anne Spitzer Charitable Trust and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.
source https://scienceblog.com/517790/implanted-neural-stem-cell-grafts-show-functionality-in-spinal-cord-injuries/
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kathleenseiber · 4 years
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Transplanted brain cells repair MS damage in mice
When researchers transplanted specific human brain cells into animal models of multiple sclerosis and other white matter diseases, the cells repaired damage and restored function, according to a new study.
The study provides one of the final pieces of scientific evidence necessary to advance this treatment strategy to clinical trials.
“These findings demonstrate that through the transplantation of human glial cells, we can effectively achieve remyelination in the adult brain,” says lead author Steve Goldman, professor of neurology and neuroscience at the University of Rochester Medical Center and co-director of the Center for Translational Neuromedicine.
“These findings have significant therapeutics implications and represent a proof-of-concept for future clinical trials for multiple sclerosis and potential other neurodegenerative diseases.”
As reported in Cell Reports, the findings represent the culmination of more than 15 years of research understanding support cells found in the brain called glia, how the cells develop and function, and their role in neurological disorders.
Goldman’s lab has developed techniques to manipulate the chemical signaling of embryonic and induced pluripotent stem cells to create glia. A subtype of these, called glial progenitor cells, gives rise to the brain’s main support cells, astrocytes and oligodendrocytes, which play important roles in the health and signaling function of nerve cells.
In multiple sclerosis, an autoimmune disorder, glial cells are lost during the course of the disease. Specifically, the immune system attacks oligodendrocytes. These cells make a substance called myelin, which, in turn, produce the “insulation” that allows neighboring nerve cells to communicate with one another.
As myelin is lost during disease, signals between nerve cells become disrupted, which results in the loss of function reflected in the sensory, motor, and cognitive deficits.
In the early stages of the disease, referred to as relapsing multiple sclerosis, oligodendrocytes replenish the lost myelin. However, over time these cells become exhausted, can no longer serve this function, and the disease becomes progressive and irreversible.
In the new study, Goldman’s lab showed that when researchers transplanted human glia progenitor cells into adult mouse models of progressive multiple sclerosis, the cells migrated to where the brain needed them, created new oligodendrocytes, and replaced the lost myelin.
The study also shows that this process of remyelination restored motor function in the mice. The researchers believe this approach could also apply to other neurological disorders, such as pediatric leukodystrophies—childhood hereditary diseases in which myelin fails to develop—and certain types of stroke affecting the white matter in adults.
A University of Rochester start-up company Oscine Therapeutics, is in the process of developing the research. The company’s experimental transplant therapy for multiple sclerosis and other glial diseases, such as Huntington’s disease, is currently under early FDA review for clinical trials. Goldman is the scientific founder, an officer, and holds equity in the company.
The National Institute of Neurological Disorders and Stroke, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Mathers Charitable Foundation, the New York Stem Cell Research Program, the Oscine Corporation, and Sana Biotechnology funded the work.
Goldman also holds an appointment at the University of Copenhagen. The Novo Nordisk Foundation and the Lundbeck Foundation supports his work there.
Source: University of Rochester
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kathleenseiber · 4 years
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Brain tumor organoids hint at how to best treat glioblastoma
Lab-grown brain tumor organoids developed from a patient’s own glioblastoma, the most aggressive and common form of brain cancer, may hold the answers on how to best treat it, researchers report.
A new study in Cell shows how glioblastoma organoids could serve as effective models to rapidly test personalized treatment strategies.
Glioblastoma multiforme (GBM) remains the most difficult of all brain cancers to study and treat, largely because of tumor heterogeneity. Treatment approaches, like surgery, radiation, and chemotherapy, along with newer personalized cellular therapies, have proven to slow tumor growth and keep patients disease-free for some period of time. However, a cure remains elusive.
“While we’ve made important strides in glioblastoma research, preclinical and clinical challenges persist, keeping us from getting closer to more effective treatments,” says senior author Hongjun Song, professor of neuroscience in the Perelman School of Medicine at the University of Pennsylvania.
“One hurdle is the ability to recapitulate the tumor to not only better understand its complex characteristics, but also to determine what therapies post-surgery can fight it in a timelier manner.”
Faster growth
Lab-grown brain organoids—derived from human pluripotent stem cells or patient tissues and grown to a size no bigger than a pea—can recapitulate important genetic composition, brain cell type heterogeneity, and architecture, for example.
These models allow researchers to recreate key features of patients’ diseased brains to help paint a clearer picture of their cancer, and then allow them to explore ways to best attack it. What makes organoids so attractive in GBM is timing and the ability to maintain cell type and genetic heterogeneity.
While existing in vitro models have added to researchers’ understanding of the biological mechanisms underlying the cancer, they have limitations. Unlike other models, which need more time to exhibit gene expression and other histological features that more closely represent the tumor, brain tumor organoids the research group developed grow into use much more rapidly.
That’s important because current treatment regimens are typically initiated one month following surgery, so having a road map sooner offers more advantages.
Personalized treatments for glioblastoma
In the new study, the researchers removed fresh tumor specimens from 52 patients to “grow” corresponding tumor organoids in the lab. The overall success rate for generating glioblastoma organoids (GBOs) was 91.4%, with 66.7% of tumors expressing the IDH1 mutation, and 75% for recurrent tumors, within two weeks. Researchers can also biobank these tumor glioblastoma organoids and recover them later for analyses.
The researchers also performed genetic, histological, molecular analyses in 12 patients to establish that these new GBOs had largely retained features from the primary tumor in the patient.
They then successfully transplanted eight GBO samples into adult mouse brains, which displayed rapid and aggressive infiltration of cancer cells and maintained key mutation expression up to three months later. Importantly, they observed a major hallmark of GBM—the infiltration of tumor cells into the surrounding brain tissue—in the mouse models.
To mimic post-surgery treatments, the researchers subjected GBOs to standard-of-care and targeted therapies, including drugs from clinical trials and chimeric antigen receptor T (CAR-T) cell immunotherapy.
For each treatment, researchers showed that the organoid responses are different and effectiveness correlates to their genetic mutations in patient tumors. This model opens the possibility for future clinical trials for personalized treatment based on individual patient tumor responses to various different drugs.
Notably, the researchers observed a benefit in the organoids treated with CAR T therapies, which they had used in ongoing clinical trials to target the EGFRvIII mutation, a driver of the disease. In six GBOs, the researchers showed specific effect to patient GBOs with the EGFRvIII mutation with an expansion of CAR T cells and reduction in EGFRvIII expressing cells.
Looking to the future
“These results highlight the potential for testing and treating glioblastomas with a personalized approach. The ultimate goal is to work towards a future where we can study a patient’s organoid and test which CAR T cell is going to be the best against their tumor, in real time,” O’Rourke says.
“A shorter-term goal, given the heterogeneity of glioblastomas, is that in vitro testing of various therapeutic options may also help refine patient enrollment in clinical trials, by more accurately defining mutations and selecting the appropriate, available targeted therapies for each.”
Support for this work came partially from the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center, the National Institutes of Health, the Sheldon G. Adelson Medical Research Foundation, a Blavatnik Family Fellowship in Biomedical Research, and a Hearst Foundation Fellowship.
Source: University of Pennsylvania
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