Age and Maturation Stage Linked Consequences of Fibrinogen on Human Oligodendroglia

Abstract

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. 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 the differential effect of fibrinogen, based on OL-lineage stage. While fibrinogen induced aberrant differentiation of early lineage OLs, by inhibiting their maturation and inducing an astrocytic phenotype, 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 bone morphogenetic protein (BMP) signaling, both in early and mature OLs. We further found BMP signaling enrichment in OLs to be correlated with the inflammatory activity of an MS lesion and confirmed fibrinogen deposition on OLs in situ. Unlike previous rodent studies, 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.