Glial cells implicated in MS disease progression, development
Study shows cells could be potential therapeutic target
Glial cells, which mostly support the function of nerve cells, play key roles in multiple sclerosis (MS) disease progression and development, according to a stem cell-based study.
“Most research and therapeutic strategies have so far focused on blocking the overactive immune system, but how cells in the brain itself, especially glia [glial cells], contribute to the initiation and progression of MS remained a mystery,” Valentina Fossati, PhD, the study’s co-senior author and senior research investigator at the New York Stem Cell Foundation (NYSCF) Research Institute, said in a foundation press release.
The results “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,” said Paul Tesar, PhD, the study’s co-senior author and director of the Institute for Glial Sciences at Case Western Reserve University School of Medicine.
Details of the discovery were published in Cell Stem Cell in the study “Patient iPSC models reveal glia-intrinsic phenotypes in multiple sclerosis.”
In MS, the body’s immune system mistakenly attacks the protective coating around nerve fibers called the myelin sheath. The resulting inflammation damages nerve cells and oligodendrocytes, a type of glial cell that produces the myelin sheath, in the brain and spinal cord, leading to significant disability.
Glia’s role in disease progression
“While progress has been made in defining the immune system’s role in MS … the contribution of intrinsic [brain and spinal cord] cell dysfunction remains unclear,” the researchers wrote.
To investigate the role of glia in MS, the researchers analyzed glial cells derived from patients and healthy people through the use of induced pluripotent stem cells (iPSCs). Derived from adult skin or blood cells that are reprogrammed back into a stem cell-like state, iPSCs can mature into almost any type of human cell.
Glial cells were derived from six people with relapsing-remitting MS (RRMS), five with primary progressive MS (PPMS), and six with secondary progressive MS (SPMS), as well as five healthy people.
“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,” Fossati said.
The researchers found that iPSCs derived from people with PPMS, a severe form of the disease, generated fewer oligodendrocytes.
“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,” said Tesar, who is also the Dr. Donald and Ruth Weber Goodman professor of innovative therapeutics at Case Western.
The activity of immune and inflammatory genes was increased in patient-derived oligodendrocytes and astrocytes, star-shaped glial cells that serve a wide range of roles in maintaining a healthy nervous system. These findings were consistent with those of glia from brain samples collected from deceased MS patients, the team 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,” Fossati said.
MS models derived from iPSCs “provide a unique platform for dissecting glial contributions to disease [features] independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention,” the researchers wrote.
The study combined NYSCF’s large-scale stem cell-based disease modeling capabilities with Tesar’s team’s expertise studying glia in neurological conditions, the foundation said.
“This study is a remarkable example of team science,” said Jennifer J. Raab, NYSCF’s president and CEO. “It is through unique collaborations like these that we can move even faster towards new treatments for the major diseases of our time that patients urgently need.”
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