Myelin is repaired by constitutive differentiation of oligodendrocyte progenitors.
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| Title: | Myelin is repaired by constitutive differentiation of oligodendrocyte progenitors. |
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| Authors: | Mironova, Yevgeniya A. (AUTHOR), Dang, Brendan (AUTHOR), Heo, Dongeun (AUTHOR), Xu, Yu Kang T. (AUTHOR), Hsu, Angela Yu-Huey (AUTHOR), Eugenin von Bernhardi, Jaime (AUTHOR), Molina-Castro, Gian Carlo (AUTHOR), Kim, Anya A. (AUTHOR), Lin, Jing-Ping (AUTHOR), Reich, Daniel S. (AUTHOR), Bergles, Dwight E. (AUTHOR) |
| Source: | Science. 1/22/2026, Vol. 391 Issue 6783, p1-17. 17p. |
| Subjects: | Myelin, Oligodendroglia, Inflammation, Myelination, Biological evolution, Nerve tissue, Aging, Neuroglia |
| Abstract: | Oligodendrocytes form myelin sheaths around axons to enable rapid signaling within neural circuits. The generation of new oligodendrocytes through differentiation of oligodendrocyte precursor cells (OPCs) promotes myelin plasticity and repair in the adult brain. Here, we performed genetic interrogation and in vivo analysis of OPCs in the mouse brain to determine their differentiation dynamics. Our results show that OPCs attempt to differentiate throughout the adult central nervous system with spatial and temporal regularity. The differentiation rate was not influenced by myelin demand or oligodendrocyte loss and declined with age and in response to acute inflammation. The results suggest that OPC differentiation is governed primarily by constitutive processes and might be negatively influenced by aging and inflammation. Editor's summary: Oligodendrocyte precursor cells (OPCs) are glial progenitor cells responsible for differentiating into oligodendrocytes that produce new myelin during learning (adaptive myelination) and also regenerate myelin lost through injury or disease. Mironova et al. studied OPC differentiation dynamics in mice during normal development and aging, as well as after demyelination and inflammation (see the Perspective by Macklin and Allen). The authors showed that OPCs attempt to differentiate continuously throughout the central nervous system at a constant rate independently of myelin demand. Moreover, demyelination did not alter the OPC differentiation rate, indicating that OPC differentiation is cell autonomous. —Mattia Maroso INTRODUCTION: Insulating sheaths of myelin around nerve axons allow rapid signal propagation in the mammalian central nervous system (CNS) that is crucial for processing sensory information, coordinating movement, and enabling higher-order cognitive functions. In the brain, myelin is exclusively produced by oligodendrocytes that are formed through differentiation of resident progenitor cells. These oligodendrocyte precursor cells (OPCs) remain abundant and widely distributed in the CNS throughout life, enabling prolonged production of new myelin to establish, modify, and repair damage to oligodendrocytes that results from trauma or disease. However, the mechanisms that control differentiation of these endogenous progenitors are not well understood. RATIONALE: Understanding the differentiation potential of OPCs and the effects of environmental changes such as brain aging and inflammation on the process of differentiation may help develop new strategies for repairing and replacing myelin. However, tracking OPC differentiation in the CNS is challenging, because most OPCs that initiate lineage progression die before they mature into myelin-producing oligodendrocytes. Thus, recording the emergence of new oligodendrocytes alone underestimates the extent of OPC differentiation. OPC differentiation is also frequently inferred by monitoring their proliferation, as they maintain a constant density throughout life by replacing cells that attempt to differentiate; however, OPCs can directly differentiate into oligodendrocytes without proliferation and are vulnerable to various insults, which confound the interpretation of proliferation as an indirect indication of differentiation. RESULTS: Using transcriptional profiling in mouse, marmoset, and human, we found that OPCs exhibit a characteristic change in gene expression during the initial stages of differentiation that selectively modifies the surrounding extracellular matrix (ECM). This modified ECM persists for up to 10 days, allowing detection of OPC differentiation attempts, even when they are unsuccessful and result in death and removal of the transitioning cell. Leveraging this new insight provided improved resolution of oligodendrogenesis in the brain. We used immunostaining and in vivo longitudinal time-lapse imaging over weeks in the adult mouse brain to define the spatial and temporal dynamics of OPC lineage progression and assessed the effects of aging, demyelination, and inflammation on this process. These studies revealed that OPC differentiation was not correlated with the eventual pattern of oligodendrocytes achieved, occurred in areas devoid of oligodendrocytes and myelin, and was notably insensitive to oligodendrocyte loss and demyelination. CONCLUSION: The generation of new oligodendrocytes in the adult brain is governed predominantly by widespread, constitutive lineage progression of OPCs that is uncoupled from myelin demand. This process appears to be an extension of their behavior in the developing CNS, designed to extend the period of myelination rather than replace myelin lost through injury or disease. The production of new oligodendrocytes is therefore constrained by this occasional, constitutive lineage progression of OPCs, which declines with aging and is further suppressed by inflammation and homeostatic proliferation of these progenitors when they are damaged. Defining the factors that influence this constitutive behavior of OPCs may provide additional means to accelerate lineage progression of these ubiquitous progenitors to enhance remyelination in diseases such as multiple sclerosis. ECM modification allows tracking of OPC differentiation attempts.: OPCs alter the sulfation pattern on aggrecan as they differentiate. This change in aggrecan sulfation is recognized by the CS56 antibody, revealing immunoreactive dandelion clock–like structures (DACS). Because this modified aggrecan in the ECM persists whether differentiation is successful or fails, DACS reveal each OPC differentiation attempt. Retrospective analysis of DACS revealed that extensive demyelination does not alter OPC differentiation, but that these transitions decline with aging and brain inflammation. CREDIT: J. FAIRMAN/JOHNS HOPKINS DEPARTMENT OF ART AS APPLIED TO MEDICINE [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Oligodendrocytes form myelin sheaths around axons to enable rapid signaling within neural circuits. The generation of new oligodendrocytes through differentiation of oligodendrocyte precursor cells (OPCs) promotes myelin plasticity and repair in the adult brain. Here, we performed genetic interrogation and in vivo analysis of OPCs in the mouse brain to determine their differentiation dynamics. Our results show that OPCs attempt to differentiate throughout the adult central nervous system with spatial and temporal regularity. The differentiation rate was not influenced by myelin demand or oligodendrocyte loss and declined with age and in response to acute inflammation. The results suggest that OPC differentiation is governed primarily by constitutive processes and might be negatively influenced by aging and inflammation. Editor's summary: Oligodendrocyte precursor cells (OPCs) are glial progenitor cells responsible for differentiating into oligodendrocytes that produce new myelin during learning (adaptive myelination) and also regenerate myelin lost through injury or disease. Mironova et al. studied OPC differentiation dynamics in mice during normal development and aging, as well as after demyelination and inflammation (see the Perspective by Macklin and Allen). The authors showed that OPCs attempt to differentiate continuously throughout the central nervous system at a constant rate independently of myelin demand. Moreover, demyelination did not alter the OPC differentiation rate, indicating that OPC differentiation is cell autonomous. —Mattia Maroso INTRODUCTION: Insulating sheaths of myelin around nerve axons allow rapid signal propagation in the mammalian central nervous system (CNS) that is crucial for processing sensory information, coordinating movement, and enabling higher-order cognitive functions. In the brain, myelin is exclusively produced by oligodendrocytes that are formed through differentiation of resident progenitor cells. These oligodendrocyte precursor cells (OPCs) remain abundant and widely distributed in the CNS throughout life, enabling prolonged production of new myelin to establish, modify, and repair damage to oligodendrocytes that results from trauma or disease. However, the mechanisms that control differentiation of these endogenous progenitors are not well understood. RATIONALE: Understanding the differentiation potential of OPCs and the effects of environmental changes such as brain aging and inflammation on the process of differentiation may help develop new strategies for repairing and replacing myelin. However, tracking OPC differentiation in the CNS is challenging, because most OPCs that initiate lineage progression die before they mature into myelin-producing oligodendrocytes. Thus, recording the emergence of new oligodendrocytes alone underestimates the extent of OPC differentiation. OPC differentiation is also frequently inferred by monitoring their proliferation, as they maintain a constant density throughout life by replacing cells that attempt to differentiate; however, OPCs can directly differentiate into oligodendrocytes without proliferation and are vulnerable to various insults, which confound the interpretation of proliferation as an indirect indication of differentiation. RESULTS: Using transcriptional profiling in mouse, marmoset, and human, we found that OPCs exhibit a characteristic change in gene expression during the initial stages of differentiation that selectively modifies the surrounding extracellular matrix (ECM). This modified ECM persists for up to 10 days, allowing detection of OPC differentiation attempts, even when they are unsuccessful and result in death and removal of the transitioning cell. Leveraging this new insight provided improved resolution of oligodendrogenesis in the brain. We used immunostaining and in vivo longitudinal time-lapse imaging over weeks in the adult mouse brain to define the spatial and temporal dynamics of OPC lineage progression and assessed the effects of aging, demyelination, and inflammation on this process. These studies revealed that OPC differentiation was not correlated with the eventual pattern of oligodendrocytes achieved, occurred in areas devoid of oligodendrocytes and myelin, and was notably insensitive to oligodendrocyte loss and demyelination. CONCLUSION: The generation of new oligodendrocytes in the adult brain is governed predominantly by widespread, constitutive lineage progression of OPCs that is uncoupled from myelin demand. This process appears to be an extension of their behavior in the developing CNS, designed to extend the period of myelination rather than replace myelin lost through injury or disease. The production of new oligodendrocytes is therefore constrained by this occasional, constitutive lineage progression of OPCs, which declines with aging and is further suppressed by inflammation and homeostatic proliferation of these progenitors when they are damaged. Defining the factors that influence this constitutive behavior of OPCs may provide additional means to accelerate lineage progression of these ubiquitous progenitors to enhance remyelination in diseases such as multiple sclerosis. ECM modification allows tracking of OPC differentiation attempts.: OPCs alter the sulfation pattern on aggrecan as they differentiate. This change in aggrecan sulfation is recognized by the CS56 antibody, revealing immunoreactive dandelion clock–like structures (DACS). Because this modified aggrecan in the ECM persists whether differentiation is successful or fails, DACS reveal each OPC differentiation attempt. Retrospective analysis of DACS revealed that extensive demyelination does not alter OPC differentiation, but that these transitions decline with aging and brain inflammation. CREDIT: J. FAIRMAN/JOHNS HOPKINS DEPARTMENT OF ART AS APPLIED TO MEDICINE [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adu2896 |
