The functional and pathogenic consequences of fibrinogen on human oligodendroglia

Abstract

ObjectiveMultiple sclerosis is an inflammatory demyelinating disorder associated with blood-brain-barrier breakdown, where myelin repair is reduced and ultimately fails. Our aim was to investigate the effect of a systemically circulating molecule fibrinogen, which is abnormally present in the central nervous system as a result of blood-brain barrier breakdown on human oligodendrocyte lineage cells.MethodsIn situ immunofluorescence was performed using anti-fibrinogen and anti-SOX10 antibodies. Mature oligodendrocytes and late progenitors were derived from brain tissue from pediatric and adult donors. Early progenitors were generated from human induced pluripotent stem cells. Following fibrinogen addition to each of these cultures, cell viability and functional capacity was evaluated. Downstream signalling following fibrinogen exposure was confirmed by immunofluorescence microscopy and bulk RNA sequencing.ResultsIn situ studies showed fibrinogen on SOX10-positive oligodendrocytes in multiple sclerosis, both in plaques and normal-appearing white matter, and white matter in amyotrophic lateral sclerosis. In response to in vitro exposure to fibrinogen, mature oligodendrocytes showed increased ensheathment capacity and upregulation of lipid synthesis, whereas pediatric-age late oligodendrocyte precursors showed a decrease. Early precursors were unable to differentiate but expressed astrocytic markers and increased proliferation. Fibrinogen-exposed cells show bone morphogenetic protein signalling, more prominently in mature oligodendrocytes.InterpretationWe demonstrate that fibrinogen is deposited on oligodendrocytes in multiple sclerosis and has distinct functional consequences dependent on cell lineage stage. Our findings derived using human OL lineage cells suggest fibrinogen may be beneficial for myelin maintenance by mature oligodendrocytes, while preventing earlier lineage cells from differentiating and repairing multiple sclerosis lesions.