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The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination
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 patt...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095917/ https://www.ncbi.nlm.nih.gov/pubmed/35573828 http://dx.doi.org/10.3389/fncel.2022.833186 |
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author | Rouillard, Megan E. Hu, Jingwen Sutter, Pearl A. Kim, Hee Won Huang, Jeffrey K. Crocker, Stephen J. |
author_facet | Rouillard, Megan E. Hu, Jingwen Sutter, Pearl A. Kim, Hee Won Huang, Jeffrey K. Crocker, Stephen J. |
author_sort | Rouillard, Megan E. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9095917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90959172022-05-13 The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination Rouillard, Megan E. Hu, Jingwen Sutter, Pearl A. Kim, Hee Won Huang, Jeffrey K. Crocker, Stephen J. Front Cell Neurosci Cellular Neuroscience 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. Frontiers Media S.A. 2022-04-28 /pmc/articles/PMC9095917/ /pubmed/35573828 http://dx.doi.org/10.3389/fncel.2022.833186 Text en Copyright © 2022 Rouillard, Hu, Sutter, Kim, Huang and Crocker. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cellular Neuroscience Rouillard, Megan E. Hu, Jingwen Sutter, Pearl A. Kim, Hee Won Huang, Jeffrey K. Crocker, Stephen J. The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination |
title | The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination |
title_full | The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination |
title_fullStr | The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination |
title_full_unstemmed | The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination |
title_short | The Cellular Senescence Factor Extracellular HMGB1 Directly Inhibits Oligodendrocyte Progenitor Cell Differentiation and Impairs CNS Remyelination |
title_sort | cellular senescence factor extracellular hmgb1 directly inhibits oligodendrocyte progenitor cell differentiation and impairs cns remyelination |
topic | Cellular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095917/ https://www.ncbi.nlm.nih.gov/pubmed/35573828 http://dx.doi.org/10.3389/fncel.2022.833186 |
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