Tissue-type plasminogen activator expression by endothelial cells and oligodendrocytes is required for proper CNS myelination.

Oligodendrocytes form myelin sheaths, a process regulated by intrinsic and extrinsic signals. Endothelial derived-tissue-type plasminogen activator (tPA) has been previously recognized for its role in aiding oligodendrocyte migration during (re)myelination. Moreover, it is well established that oligodendrocytes express de novo tPA following myelin damage, possibly reflecting the initiation of a regenerative program. However, its role in differentiation and myelination has remained unclear. This study aims to uncover the role of endothelial- and oligodendrocytes-derived tPA in developmental myelination. It appears that tPA is transiently expressed in myelinating oligodendrocytes in mice and humans. tPA deficiency delays oligodendrocyte maturation and causes persistent myelin defects, leading to motor impairments. Endothelial-derived tPA promotes myelin compaction, while oligodendrocyte-derived tPA supports myelin growth. These findings, along with previous research, highlight shared molecular mechanisms between developmental myelination and remyelination. Moreover, we highlight tPA’s dual roles in myelination. Thus, tPA-deficient mice could serve as a valuable model to study dysmyelinating diseases and to explore potential avenues for future therapeutic strategies.