Microglial Activation Induces Generation of Oligodendrocyte Progenitor Cells from the Subventricular Zone after Focal Demyelination in the Corpus Callosum

2018 ◽  
Vol 40 (1) ◽  
pp. 54-63 ◽  
Author(s):  
Masae Naruse ◽  
Koji Shibasaki ◽  
Hiroya Shimauchi-Ohtaki ◽  
Yasuki Ishizaki
Keyword(s):  
Corpus Callosum ◽  
Progenitor Cells ◽  
Subventricular Zone ◽  
Microglial Activation ◽  
Neural Progenitor Cells ◽  
Internal Capsule ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Demyelinating Lesions ◽  
Focal Demyelination

Neuroblasts derived from neural stem cells (NSCs) in the subventricular zone (SVZ) migrate along the rostral migratory stream into the olfactory bulb to generate interneurons under normal physiological conditions. When demyelination occurs, NSCs or neural progenitor cells (NPCs) in the SVZ provide newly formed oligodendrocytes to demyelinated lesions. The plasticity of NSC/NPC lineages may tend to oligodendrogenesis under the influence of demyelinated lesions. The mechanisms, however, still remain unknown. This study revealed that focal demyelination in the corpus callosum caused activation of the microglia, not only at the site of demyelination but also in the SVZ, and dramatically increased the generation of oligodendrocyte progenitor cells (OPCs) in the SVZ. Furthermore, the inhibition of microglial activation by minocycline treatment decreased OPC generation in the SVZ, suggesting that microglial activation in the SVZ, induced by the focal demyelination in the corpus callosum, regulates NSC/NPC lineage plasticity in situ. In contrast to the findings regarding demyelination in the corpus callosum, inducing focal demyelination in the internal capsule did not induce either microglial activation or OPC generation in the SVZ. These results suggest that the mechanism of OPC generation in the SVZ after inducing demyelinating lesions could be different across the demyelinated regions.

scholarly journals An Extract of Chinpi, the Dried Peel of the Citrus Fruit Unshiu, Enhances Axonal Remyelination via Promoting the Proliferation of Oligodendrocyte Progenitor Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Hideaki Tokunaga ◽  
Chika Seiwa ◽  
Nozomu Yoshioka ◽  
Kazushige Mizoguchi ◽  
Masahiro Yamamoto ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Progenitor Cells ◽  
Ventricular Zone ◽  
Therapeutic Option ◽  
Herbal Medicines ◽  
Protein Isoforms ◽  
Oligodendrocyte Progenitor Cells ◽  
Rna Helicases ◽  
Oligodendrocyte Progenitor

The aging-induced decrease in axonal myelination/remyelination is due to impaired recruitment and differentiation of oligodendrocyte progenitor cells (OPCs). Our previous studies have shown that a monoclonal antibody to DEAD (Asp-Glu-Ala-Asp) box polypeptide 54 (Ddx54), a member of the DEAD box family of RNA helicases, (1) specifically labels oligodendrocyte lineages, (2) binds to mRNA and protein isoforms of myelin basic proteins (MBP), and (3) regulates migration of OPCs from ventricular zone to corpus callosum in mice. It has also been demonstrated that specific loss of a 21.5 kDa MBP isoform (MBP21.5) reflects demyelination status, and oral administration of an extract of Chinpi, citrus unshiu peel, reversed the aging-induced demyelination. Here, we report that Chinpi treatment induced a specific increase in the MBP21.5, led to the reappearance of Ddx54-expressing cells in ventricular-subventricular zone and corpus callosum of aged mice, and promoted remyelination. Treatment ofin vitroOPC cultures with Chinpi constituents, hesperidin plus narirutin, led to an increase in 5-bromo-2′-deoxyuridine incorporation in Ddx54-expressing OPCs, but not in NG2- or Olig2-expressing cell populations. The present study suggests that Ddx54 plays crucial role in remyelination. Furthermore, Chinpi and Chinpi-containing herbal medicines may be a therapeutic option for the aging-induced demyelination diseases.

scholarly journals Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Darpan Saraswat ◽  
Hani J. Shayya ◽  
Jessie J. Polanco ◽  
Ajai Tripathi ◽  
R. Ross Welliver ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progenitor Cells ◽  
Demyelinating Disease ◽  
Heparan Sulfate Proteoglycans ◽  
Oligodendrocyte Progenitor Cells ◽  
Subsequent Generation ◽  
Oligodendrocyte Progenitor ◽  
Demyelinating Lesions ◽  
Experimental Demyelination

AbstractChronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.

scholarly journals Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following demyelination

2020 ◽  
Author(s):  
Darpan Saraswat ◽  
Hani J. Shayya ◽  
Jessie J. Polanco ◽  
Ajai Tripathi ◽  
R. Ross Welliver ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progenitor Cells ◽  
Demyelinating Disease ◽  
Heparan Sulfate Proteoglycans ◽  
Oligodendrocyte Progenitor Cells ◽  
Subsequent Generation ◽  
Oligodendrocyte Progenitor ◽  
Demyelinating Lesions ◽  
Experimental Demyelination

Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.

scholarly journals mTORC2 loss in oligodendrocyte progenitor cells results in regional hypomyelination in the central nervous system

2022 ◽  
Author(s):  
Kristin D Dahl ◽  
Hannah A Hathaway ◽  
Adam R Almeida ◽  
Jennifer Bourne ◽  
Tanya L Brown ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Corpus Callosum ◽  
Signaling Pathways ◽  
Progenitor Cells ◽  
Myelin Proteins ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
The Central Nervous System

In the central nervous system (CNS), oligodendrocyte progenitor cells (OPCs) differentiate into mature oligodendrocytes to generate myelin, which is essential for normal nervous system function. OPC differentiation is driven by signaling pathways such as mTOR (Mechanistic Target of Rapamycin), which functions in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), containing Raptor or Rictor respectively. In the current studies, mTORC2 signaling was selectively deleted from OPCs in PDGFRα-Cre X Rictorfl/fl mice. This study examined developmental myelination in male and female mice, comparing the impact of mTORC2 deletion in the corpus callosum and spinal cord. In both corpus callosum and spinal cord, Rictor loss in OPCs resulted in early reduction in myelin RNAs and some myelin proteins. However, these deficits rapidly recovered in spinal cord, where normal myelin abundance and thickness was noted at post-natal day 21 and 1.5 months. By contrast, the losses in corpus callosum resulted in severe hypomyelination, and increased unmyelinated axons. The current studies focus on uniquely altered signaling pathways following mTORC2 loss in developing oligodendrocytes. A major mTORC2 substrate is phospho-Akt-S473, which was significantly reduced throughout development in both corpus callosum and spinal cord at all ages measured, yet this had little impact in spinal cord. Loss of mTORC2 signaling resulted in decreased expression of actin regulators such as gelsolin in corpus callosum, but only minimal loss in spinal cord. The current study establishes a regionally-specific role for mTORC2 signaling in OPCs, particularly in the corpus callosum.

scholarly journals Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

2021 ◽  
Vol 22 (10) ◽  
pp. 5192
Author(s):  
Ulises Gómez-Pinedo ◽  
Yolanda García-Ávila ◽  
Lucía Gallego-Villarejo ◽  
Jordi A. Matías-Guiu ◽  
María Soledad Benito-Martín ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Progenitor Cells ◽  
Neuromyelitis Optica ◽  
Subventricular Zone ◽  
Precursor Cells ◽  
Oligodendrocyte Progenitor Cells ◽  
Oligodendrocyte Progenitor ◽  
Differentiation Capacity ◽  
The Central Nervous System

Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

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