Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following 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.

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Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following demyelination

10.1101/2020.01.21.906073 ◽

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.

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

Developmental Neuroscience ◽

10.1159/000486332 ◽

2018 ◽

Vol 40 (1) ◽

pp. 54-63 ◽

Cited By ~ 8

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.

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NG2-Glia, a New Player in Energy Balance

Neuroendocrinology ◽

10.1159/000488111 ◽

2018 ◽

Vol 107 (3) ◽

pp. 305-312 ◽

Cited By ~ 2

Author(s):

Sarah C. Robins ◽

Maia V. Kokoeva

Keyword(s):

Radiation Therapy ◽

Energy Balance ◽

Progenitor Cells ◽

Clinical Implication ◽

Energy Homeostasis ◽

Neural Circuits ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

Physiological Outcomes

There is increasing evidence that glia act not only as neuronal support cells, but that they can also influence physiological outcomes via effects on neural signalling. The role of NG2-glia in this regard is especially enigmatic, as they are known to interact with neural circuits but their precise functions other than as oligodendrocyte progenitor cells remain elusive. Here, we summarise recent evidence suggesting that NG2-glia play a role in the maintenance of energy homeostasis, most notably via the support of leptin-sensing neural circuits. We also discuss the potential clinical implication of these findings specifically in the context of cranial radiation therapy.

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