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Impaired myelination in multiple sclerosis organoids: p21 links oligodendrocyte dysfunction to disease subtype
Saud A Sadiq1, Tanmay Mehta1, William Holzman1
1Tisch Multiple Sclerosis Research Center of New York, New York, NY, United States.
Abstract:
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are strongly involved in its pathogenesis. We derived cerebral and spinal cord organoids from induced pluripotent stem cells (iPSC) from healthy controls as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients to investigate and compare oligodendrocyte differentiation and myelination capacity. In MS organoids, particularly in PPMS, we observed a decrease in p21 expression associated with a dysregulation of PAK1 and E2F1 expression. In parallel, a decrease in oligodendrocyte maturation was detected in long-term cultured cerebral and spinal cord organoids, especially in PPMS, leading to a reduced myelination capacity. Disruption of astrocyte and neuronal populations was also observed. Our findings demonstrate that in MS, inherent deficits in the p21 pathway may alter glial and neuronal cell populations and may contribute to the disease pathogenesis by reducing the capacity for myelin repair.
Insights
Multiple sclerosis organoids show reduced oligodendrocyte maturation and myelination capacity, particularly in primary progressive MS. This suggests p21 pathway deficits may impair myelin repair in multiple sclerosis.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Multiple sclerosis (MS) is a central nervous system autoimmune inflammatory disease.
- Its pathogenesis involves complex genetic and environmental factors.
- Oligodendrocyte dysfunction and impaired myelination are key features of MS.
Purpose of the Study:
- To investigate and compare oligodendrocyte differentiation and myelination capacity in cerebral and spinal cord organoids derived from healthy controls and MS patients.
- To explore the role of the p21 pathway in MS pathogenesis.
Main Methods:
- Generation of cerebral and spinal cord organoids from induced pluripotent stem cells (iPSCs) of healthy controls and patients with primary progressive MS (PPMS), secondary progressive MS (SPMS), and relapsing-remitting MS (RRMS).
- Analysis of oligodendrocyte differentiation, myelination capacity, and gene expression (p21, PAK1, E2F1).
- Assessment of astrocyte and neuronal populations in long-term cultured organoids.
Main Results:
- MS organoids, especially PPMS, exhibited decreased p21 expression and dysregulated PAK1 and E2F1.
- A reduction in oligodendrocyte maturation and myelination capacity was observed in long-term cultured MS organoids, most notably in PPMS.
- Disruption of astrocyte and neuronal populations was evident in MS organoids.
Conclusions:
- Inherent deficits in the p21 pathway in MS may contribute to altered glial and neuronal populations.
- Reduced myelination capacity and impaired myelin repair are linked to p21 pathway alterations in MS.
- These findings highlight potential therapeutic targets for myelin repair in multiple sclerosis.
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