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 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.

Astrocyte-Derived Extracellular Vesicles (ADEVs): Deciphering their Influences in Aging.

Astrocytes are an abundant and dynamic glial cell exclusive to the central nervous system (CNS). In the context of injury, inflammation, and/or diseases of the nervous system, astrocyte responses, termed reactive astrogliosis, are a recognized pathological feature across a range of conditions and diseases. However, the impact of reactive astrogliosis is not uniform and varies by context and duration (time). In recent years, extracellular communication between glial cells via extracellular vesicles (EVs) has garnered interest as a process connected with reactive astrogliosis. In this review, we relate recent findings on astrocyte-derived extracellular vesicles (ADEVs) with a focus on factors that can influence the effects of ADEVs and identified age related changes in the function of ADEVs. Additionally, we will discuss the current limitations of existing experimental approaches and identify questions that highlight areas for growth in this field, which will continue to enhance our understanding of ADEVs in age-associated processes.

Extracellular matrix influences astrocytic extracellular vesicle function in wound repair.

Astrocytic injury responses are known to be influenced by the extracellular matrix (ECM). Astrocytes are also recognized as a source of extracellular vesicles (EVs) that can impact the activity and function of other astrocytes and cell types. Whether the ECM influences the function of astrocytic EVs in the context of wound recovery has not been previously studied. We report EVs from astrocytes cultured on varied ECM substrates are sufficient to elicit distinct injury responses in naive astrocytes that recapitulate the effects of the ECM of origin. When compared with wound recovery on control substrates, EVs from ECM-exposed astrocytes elicited accelerated rates of wound recovery that varied based on each ECM. When EVs were collected from IL-1ß treated and ECM-exposed astrocyte cultures, we found that IL-1ß arrested wound recovery in naive astrocytes treated with EVs from astrocytes cultured on ECM but adding EVs from IL-1ß treated Tenascin-c-cultured astrocytes increased wound recovery. To confirm that ECM was a primary influence on these astrocytic EV functions, we tested the contribution of ß1-integrin, a major integrin receptor for the ECM molecules tested in this study. We found that the ß1-integrin inhibitor Ha2/5, resulted in EVs that significantly attenuated the wound recovery of naive astrocytes. This provides new information on the importance of culture substrates on astrocytic responses, EV functions and injury responses that may impact the understanding of astroglial responses related to ECM compositional differences in diverse physiological states.