Extracellular Vesicles as Potential Drivers of Myelin Health and Myelin Repair in Pregnant MS Patients
Abstract
Oligodendrocytes are brain cells that generate a specialized membrane termed myelin, which wraps around neuronal connections to form a protective coating. In MS, oligodendrocytes are attacked by the immune system, leading to myelin loss, which triggers a cascade of neuronal dysfunction. Without myelin neurons do not communicate effectively and their metabolism is altered, which, if unresolved, can lead to neuronal death. Fortunately, oligodendrocytes are capable of regenerating and restoring the myelin coat, which can lead to functional recovery of the damaged neuronal communication network. Yet, myelin regeneration does not always occur, and even within the same patient can be effective in some brain regions but not in others. In addition, bouts of regeneration can occur for years, or even decades, in MS, which results in remission periods and periods of improved neuronal function, but the disease can then transition to a progressive phase in which regeneration fails and disability steadily increases. It remains unclear, however, why this spontaneous oligodendrocyte regeneration either does or does not occur, and what leads to its failure. Given that endogenous repair exists and can sometimes be quite robust, it is essential to uncover the molecular mechanisms that contribute to oligodendrocyte health and regenerative capacity, as these mechanisms may reveal key targets for the development of myelin-targeted MS therapies. The proposed study seeks to discover factors that contribute to the improved regenerative capacity of oligodendrocytes. We propose to follow up on a clue provided by examining what happens to MS during pregnancy. MS remission is highly influenced by pregnancy, with disease activity being robustly suppressed, particularly in the last 2-3 trimesters, followed by a postpartum spike. Substantial changes in the immune system and in hormone levels occur during pregnancy, but attempts to mimic these changes as potential MS therapies have not been successful. We now propose to explore the possibility that the molecular "cargo" delivered by circulating extracellular vesicles (EVs) influences the regenerative capacity of oligodendrocytes during pregnancy. Cells throughout the body use EVs as communication tools, as they can both act in the short range by fusing with nearby cells and delivering molecules that signal cells to change their behavior or function, as well as travel throughout the body in the bloodstream to distant organs. EVs can cross into the brain from the circulation and are known to undergo changes in cargo content during pregnancy, making it possible that changes in circulating EVs could impart benefits to oligodendrocytes and myelin during pregnancy. Intriguingly, we have found that circulating EVs from pregnant rodents contain a type of RNA that is known to influence oligodendrocytes. If we identify and characterize ways in which EVs improve the oligodendrocyte regenerative potential during pregnancy, this will open the door for identifying new ways to therapeutically target oligodendrocytes to improve outcomes in MS. The proposed experiments to assess cargoes and other molecular characteristics of pregnancy-EVs in particular could lead in the short term to a better understanding of the molecular signals that control oligodendrocyte health and capacity for myelin repair in MS. The impact of the proposed experiments will be to uncover new effectors that promote MS remission during pregnancy, which could then can be applied to any MS patient, pregnant or otherwise. By learning more about cellular signals that can influence oligodendrocytes and enhance myelin repair, our long-term goal will be to translate these findings into drug discovery in which we investigate ways to harness these signals to help repair myelin, first in animal models of myelin damage, then in MS patients. The approach is exploratory but will greatly improve our currently limited understanding of how effec
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010741
Entities
People
- Holly Colognato
Organizations
- Stony Brook University
- United States Army