Dataset Information

PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation.

ABSTRACT:

Background

Promotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs. It is also unknown whether astrocytes or microglia play a functional role in IgM-mediated lesion repair.

Methods

We assessed the effect of rHIgM22 on cell proliferation in mixed CNS glial and OPC cultures by tritiated-thymidine uptake and by double-label immunocytochemistry using the proliferation marker, Ki-67. Antibody-mediated signaling events, OPC differentiation and OPC survival were investigated and quantified by Western blots.

Results

rHIgM22 stimulates OPC proliferation in mixed glial cultures but not in purified OPCs. There is no proliferative response in astrocytes or microglia. rHIgM22 activates PDGF?R in OPCs in mixed glial cultures. Blocking PDGFR-kinase inhibits rHIgM22-mediated OPC proliferation in mixed glia. We confirm in isolated OPCs that rHIgM22-mediated anti-apoptotic signaling and inhibition of OPC differentiation requires PDGF and FGF-2. We observed no IgM-mediated effect in mature OLs in the absence of PDGF and FGF-2.

Conclusion

Stimulation of OPC proliferation by rHIgM22 depends on co-stimulatory astrocytic and/or microglial factors. We demonstrate that rHIgM22-mediated activation of PDGF?R is required for stimulation of OPC proliferation. We propose that rHIgM22 lowers the PDGF threshold required for OPC proliferation and protection, which can result in remyelination of CNS lesions.

SUBMITTER: Watzlawik JO

PROVIDER: S-EPMC3562326 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation.

Watzlawik Jens O JO Warrington Arthur E AE Rodriguez Moses M

PloS one 20130201 2

<h4>Background</h4>Promotion of remyelination is a major goal in treating demyelinating diseases such as multiple sclerosis (MS). The recombinant human monoclonal IgM, rHIgM22, targets myelin and oligodendrocytes (OLs) and promotes remyelination in animal models of MS. It is unclear whether rHIgM22-mediated stimulation of lesion repair is due to promotion of oligodendrocyte progenitor cell (OPC) proliferation and survival, OPC differentiation into myelinating OLs or protection of mature OLs. It ...[more]

PMID: 23383310

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Project description:HMGB1 is a highly conserved, ubiquitous protein in eukaryotic cells. HMGB1 is normally localized to the nucleus, where it acts as a chromatin associated non-histone binding protein. In contrast, extracellular HMGB1 is an alarmin released by stressed cells to act as a danger associated molecular pattern (DAMP). We have recently determined that progenitor cells from multiple sclerosis patients exhibit a cellular senescent phenotype and release extracellular HMGB1 which directly impaired the maturation of oligodendrocyte progenitor cells (OPCs) to myelinating oligodendrocytes (OLs). Herein, we report that administration of recombinant HMGB1 into the spinal cord at the time of lysolecithin administration resulted in arrest of OPC differentiation in vivo, and a profound impairment of remyelination. To define the receptor by which extracellular HMGB1 mediates its inhibitory influence on OPCs to impair OL differentiation, we tested selective inhibitors against the four primary receptors known to mediate the effects of HMGB1, the toll-like receptors (TLRs)-2, -4, -9 or the receptor for advanced glycation end-products (RAGE). We found that inhibition of neither TLR9 nor RAGE increased OL differentiation in the presence of HMGB1, while inhibition of TLR4 resulted in partial restoration of OL differentiation and inhibiting TLR2 fully restored differentiation of OLs in the presence of HMGB1. Analysis of transcriptomic data (RNAseq) from OPCs identified an overrepresentation of NFκB regulated genes in OPCs when in the presence of HMGB1. We found that application of HMGB1 to OPCs in culture resulted in a rapid and concentration dependent shift in NFκB nuclear translocation which was also attenuated with coincident TLR2 inhibition. These data provide new information on how extracellular HMGB1 directly affects the differentiation potential of OPCs. Recent and past evidence for elevated HMGB1 released from senescent progenitor cells within demyelinated lesions in the MS brain suggests that a greater understanding of how this molecule acts on OPCs may unfetter the endogenous remyelination potential in MS.

Dataset Information

PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation.

Background

Methods

Results

Conclusion

Publications

PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation.

Similar Datasets

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