# Age and Maturation Stage Linked Consequences of Fibrinogen on Human Oligodendroglia

## TL;DR

Fibrinogen, a blood protein, affects human brain cells differently depending on their maturity, potentially impacting multiple sclerosis.

## Contribution

This study reveals fibrinogen's dual effect on human oligodendroglia, showing lineage-dependent outcomes on differentiation and myelination.

## Key findings

- Fibrinogen inhibits maturation of early oligodendroglia and promotes astrocytic differentiation.
- Fibrinogen enhances myelination in mature oligodendroglia.
- BMP signaling is activated by fibrinogen in both early and mature 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.

Fibrinogen induces aberrant differentiation of human early lineage oligodendroglia, by inhibiting their maturation and inducing an astrocytic phenotype.Fibrinogen promotes myelination capacity in mature human oligodendroglia.These effects were associated with the activation of bone morphogenetic protein (BMP) signaling, both in early and mature oligodendroglia.There is BMP signaling enrichment in oligodendroglia evident in chronic active multiple sclerosis plaques.Fibrinogen deposition is evident on oligodendroglia in MS plaques and normal‐appearing white mater.

Fibrinogen induces aberrant differentiation of human early lineage oligodendroglia, by inhibiting their maturation and inducing an astrocytic phenotype.

Fibrinogen promotes myelination capacity in mature human oligodendroglia.

These effects were associated with the activation of bone morphogenetic protein (BMP) signaling, both in early and mature oligodendroglia.

There is BMP signaling enrichment in oligodendroglia evident in chronic active multiple sclerosis plaques.

Fibrinogen deposition is evident on oligodendroglia in MS plaques and normal‐appearing white mater.

This study shows that the blood‐derived molecule, Fibrinogen, has a differential effect on human Oligodendroglial (OL) cells. Fibrinogen, when added in vitro, leads to aberrant differentiation of OL‐precursors towards an astrocytic fate. On the other hand, when added into the culture of mature OLs, fibrinogen increases myelination capacity. Fibrinogen acts through the bone morphogenetic protein (BMP) pathway across the OL lineage, which is confirmed via fluorescence imaging and on the RNA level. This BMP pathway signature was found in situ on OLs derived from chronic active lesions, and fibrinogen was found to be in contact with OL‐lineage cells in both MS lesions and normal appearing white matter. This figure was created in BioRender. Durcan, T. (2026) https://BioRender.com/b0d3fb4
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