Pioneering models of human brains have been created to bring first-of-its-kind analysis of stem cell dysregulation in people living with Multiple Sclerosis (MS).
Through the creation of ‘mini brains’, dervied from cells of patients with MS, it can be shown in a novel way how a patient’s genetic makeup impacts neural cell functions.
These organoids – created by the Tisch Multiple Sclerosis Research Center of New York – allow researchers, for the first time ever, to analyse the role of an individual’s genetic background in MS in a new non-immune-based human model.
The study revealed novel insights into MS cellular dysregulation and found that a patient’s genetic background can directly alter stem cell function and result in differences in the development of myelin-producing oligodendrocyte cells.
Additionally, researchers have identified the p21 pathway as a new potential target, for future MS treatment strategies.
Until now, the relative inaccessibility of human brain tissues has been a significant barrier to advancing research into the origin and evolution of MS.
Researchers at the Tisch MSRCNY developed induced pluripotent stem cells from healthy human controls, as well as from patients with PPMS, SPMS, and RRMS, to grow cerebral organoids that are free of immune system interaction and function within a controlled microenvironment.
“Our innovative cerebral organoids address a persistent challenge for MS researchers worldwide, and represent a major step forwarding in advancing our knowledge of cellular dysregulation,” said Dr Saud A. Sadiq, director and chief research scientist at the Tisch MS Research Center of New York.
“With our novel mini-brain models, we’re taking a critical step toward understanding how a patient’s genetic background influences MS pathogenesis – and to ultimately discovering the origin of MS.
“We look forward to applying this novel technology to upcoming research and one day, toward a long-awaited cure for MS patients.”
The cerebral organoids allowed researchers to recapitulate early human neurodevelopment, including the generation, proliferation, and differentiation of neural progenitors into glial cells and neurons.
Within these models, researchers observed dysregulation of the neural progenitor proliferation and differentiation capacity, leading to increased neuronal differentiation and decreased glial cell development.
The study also analysed the expression of the protein p21, which is key for the regulation of the cell cycle, as well as the maintenance of proper proliferation and differentiation of stem cells.
It found that, particularly within PPMS organoids, P21 expression was decreased, resulting in disruptions to the development of oligodendrocyte cells.
“Since MS is a human-specific disease, this application of our cerebral organoids is absolutely critical in giving MS research the ability to conduct analysis on human tissue,” said Tisch MSRCNY research scientist Nicolas Daviaud.
“We look forward to building on the findings of this research to study the mechanisms and various pathways leading to the differences we observed, allowing us to develop an improved understanding of the pathogenesis of MS.”
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