Zandee, S. E. J. | bioRxiv Science

bioRxiv2024

The functional and pathogenic consequences of fibrinogen on human oligodendroglia

Fibrinogen is a blood-derived protein involved in coagulation, and can make its way into the central nervous system (CNS) following breakdown of the blood-brain barrier. This molecule has been implicated in multiple sclerosis (MS), a disease marked by inflammation and demyelination in the CNS, as well as other neurological disorders. However, the effect of this molecule has not been studied on human myelinating cells. This study examines how fibrinogen influences human oligodendrocyte (OL) lineage cells at various stages of development. Using induced pluripotent stem cell-derived (iPSC) OL precursors and human primary OLs, we examined the effects of fibrinogen on cell differentiation, viability and myelination-related function. Here we show that fibrinogen induces an aberrant differentiation of early lineage OLs, by inhibiting their maturation and inducing an astrocytic phenotype, as seen in previous studies. On mature OLs, fibrinogen was found to promote myelination capacity as shown by ensheathment assays as well as on the RNA level. These effects were associated with the activation of BMP signalling, both in early and mature OLs. Transcriptomic analysis of human MS brain tissue shows similar pro-myelination changes in a subset of OLs, suggesting in vivo relevance. These findings indicate that fibrinogen has a lineage-dependent effect, where it may be inhibitory earlier in the lineage while promoting OL function in later stages. Understanding this dual role will provide insight into remyelination failure in MS and highlights the importance of timing and target in future therapeutic strategies. Significance StatementIn multiple sclerosis (MS), the blood protein fibrinogen leaks into the brain and has been shown to interfere with myelin repair. This study demonstrates that fibrinogen has opposite effects on human oligodendrocyte-lineage cells depending on their stage of maturation. While it blocks the differentiation of early-stage cells, it enhances the functional capacity of mature oligodendrocytes. These findings help explain why remyelination may fail in MS and suggest that fibrinogen could both hinder and support repair, depending on the cell context. This dual role has important implications for developing stage-specific therapies for MS.

neuroscience↗

bioRxiv2024

Disease-associated astrocyte epigenetic memory promotes CNS pathology

Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE)1-8. However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges. Here, we describe the identification of an epigenetically controlled memory astrocyte subset which exhibits exacerbated pro-inflammatory responses upon re-challenge. Specifically, using a combination of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), and cell-specific in vivo CRISPR/Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) used by the histone acetyltransferase p300 to control chromatin accessibility. ACLY+p300+ memory astrocytes are increased in acute and chronic EAE models; the genetic targeting of ACLY+ p300+ astrocytes using CRISPR/Cas9 ameliorated EAE. We also detected responses consistent with a pro-inflammatory memory phenotype in human astrocytes in vitro; scRNA-seq and immunohistochemistry studies detected increased ACLY+ p300+ astrocytes in chronic MS lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, MS. These findings may guide novel therapeutic approaches for MS and other neurologic diseases.

immunology↗