Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Rouillard, Megan E., Hu, Jingwen, Sutter, Pearl A., Kim, Hee Won, Huang, Jeffrey K., Crocker, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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
_version_ 1784705857729069056
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
work_keys_str_mv AT rouillardmegane thecellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT hujingwen thecellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT sutterpearla thecellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT kimheewon thecellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT huangjeffreyk thecellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT crockerstephenj thecellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT rouillardmegane cellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT hujingwen cellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT sutterpearla cellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT kimheewon cellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT huangjeffreyk cellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination
AT crockerstephenj cellularsenescencefactorextracellularhmgb1directlyinhibitsoligodendrocyteprogenitorcelldifferentiationandimpairscnsremyelination