Multiple Sclerosis Models Clarify Role of Glia, Hint at New Targets

A team of scientists from the New York Stem Cell Foundation (NYSCF) Research Institute and Case Western Reserve University has created the largest reported collection of stem cell models from multiple sclerosis (MS) patients. The researchers used the stem cells to identify unique ways in which glia—integral support cells in the brain—contribute to the disease. They suggest their study is the first to report that glial cells from MS patients have intrinsic hallmarks of disease, independent of immune system influences. The results point to the power of stem cell research to provide new insights into disease biology.

The study’s findings also open up new possibilities for treating MS. By identifying specific glial cell behaviors that contribute to the disease researchers can explore potential therapies that target these cells directly. This could lead to more effective treatments that go beyond simply suppressing the immune system, and so offer new hope for patients.

“Our findings represent a significant leap forward in our understanding of MS and underscore the vast potential in glia as a target for therapeutic intervention that could transform the treatment landscape for many patients,” commented research co-lead Paul Tesar, PhD, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and director of the Institute for Glial Sciences at Case Western Reserve University School of Medicine, and NYSCF—Robertson Stem Cell Investigator Alumnus.

Tesar, together with co-lead Valentina Fossati, PhD, NYSCF senior research investigator, and colleagues reported on their studies in Cell Stem Cell, in a paper titled “Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis.” In their report, the team concluded: “iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.”

MS is an autoimmune disease that occurs when the body’s immune system mistakenly attacks the protective myelin sheaths that surround the nerves in the brain and spinal cord, resulting in significant neurological disability. “Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time,” the authors wrote. “While progress has been made in defining the immune system’s role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear.”

“Most research and therapeutic strategies have so far focused on blocking the overactive immune system, but how cells in the brain itself, especially glia, contribute to the initiation and progression of MS remained a mystery,” added Fossati. “The mechanisms behind chronic MS progression are only partially understood, highlighting an urgent unmet need,” the team continued. “Human models based on induced pluripotent stem cell (iPSC) technology are increasingly used to investigate complex CNS disorders and provide the opportunity to investigate glial dysfunction in MS.”

For their study the researchers harnessed NYSCF’s automation platforms to create induced pluripotent stem cells from skin biopsies of individuals with MS, resulting in the largest collection of MS patient stem cell lines to date, spanning diverse clinical subtypes. The scientists then converted the iPSCs into glial cells—which include oligodendrocytes and astrocytes—to investigate their role in the disease. “… we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures,” they noted. Fossati added, “By generating glia-enriched cultures from stem cells, we have been able to study their role in MS independently of the complex environment in the body, which is constantly altered by the presence of immune cells and inflammatory signals.”

Using single-cell gene expression profiling, the scientists found that stem cell-derived glia cultures from people with primary progressive MS (PPMS, a particularly severe form of the disease) contained fewer oligodendrocytes. Oligodendrocytes are responsible for producing myelin, the protective sheath around nerve fibers that is lost in MS. “This observation challenges the conventional understanding of MS as being purely driven by immune system dysfunction, suggesting that the disease may also be fueled by processes originating within the brain itself,” noted Tesar.

The team also observed that a set of genes associated with immune and inflammatory functions were particularly active in stem cell-derived glia cultures from MS patients, matching what they see in brain samples from deceased individuals with MS. “Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms,” the authors stated. “We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains.”

The NYSCF scientists in addition leveraged their latest advances in artificial intelligence to detect differences in astrocytes that are not easily seen by the human eye. “… our morphological analysis supports the hypothesis that inflammatory clusters in MS astrocytes make them distinguishable from their healthy counterpart,” they commented. Fossati further noted, “The fact that glia created from stem cells show similar features to glia in MS patient brains shows us that stem cell models provide a pretty accurate reflection of what happens in the brains of living patients, and that we can use them to gain important insights into this disease.”

Because of the autoimmune activity in MS, many current therapies target the immune system. These drugs help reduce the frequency of immune attacks, but they, unfortunately, fall short of preventing the neurodegeneration that drives disease progression. In their paper, the team concluded, “… our study demonstrates that iPSC-derived glial-enriched cultures from people with MS are a powerful model to identify CNS-intrinsic phenotypes in MS. Future studies using human iPSC-derived models are necessary to fully understand glial contributions to MS pathogenesis. These findings could unveil novel glia-specific therapeutic targets to halt or reverse MS progression.” Added Jennifer J. Raab, PhD NYSCF’s president and CEO: “This study is a remarkable example of team science … It is through unique collaborations like these that we can move even faster toward new treatments for the major diseases of our time that patients urgently need.”