Tissue-type plasminogen activator exerts EGF-like chemokinetic effects on oligodendrocytes in white matter (re)myelination

Camille Leonetti,Mathilde Pruvost,Antoine Fournier,Isabel Machin,Fernando De Castro,Richard Macrez,Jérémie Bronsard,Denis Vivien,Fabian Docagne,Yannick Hommet,Eric Maubert,Diego Clemente,Maxime Perrigault

doi:10.1186/s13024-017-0160-5

Abstract

BackgroundThe ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Tissue plasminogen activator (tPA) is a serine protease expressed in the central nervous system (CNS), where it regulates cell fate. In particular, tPA has been reported to protect oligodendrocytes from apoptosis and to facilitate the migration of neurons. Here, we investigated whether tPA can also participate in the migration of OPCs during CNS development and during remyelination after focal white matter lesion.MethodsOPC migration was estimated by immunohistological analysis in spinal cord and corpus callosum during development in mice embryos (E13 to P0) and after white matter lesion induced by the stereotactic injection of lysolecithin in adult mice (1 to 21 days post injection). Migration was compared in these conditions between wild type and tPA knock-out animals. The action of tPA was further investigated in an in vitro chemokinesis assay.ResultsOPC migration along vessels is delayed in tPA knock-out mice during development and during remyelination. tPA enhances OPC migration via an effect dependent on the activation of epidermal growth factor receptor.ConclusionEndogenous tPA facilitates the migration of OPCs during development and during remyelination after white matter lesion by the virtue of its epidermal growth factor-like domain.

Highlights

The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation
The ventral OPCs originate from the motor neuron progenitor domain that first produces motor neurons followed by OPCs [20]
A higher number of Olig2+ OPCs remained in the Motor neuron progenitor (pMN) domain, in Tissue plasminogen activator (tPA)−/− mice than in wild type mice at E13

Summary

Introduction

The ability of oligodendrocyte progenitor cells (OPCs) to give raise to myelin forming cells during developmental myelination, normal adult physiology and post-lesion remyelination in white matter depends on factors which govern their proliferation, migration and differentiation. Spontaneous remyelination enables regeneration of white matter after lesions This process is possible thanks to the presence, in the adult central nervous system (CNS), of oligodendrocyte precursor cells (OPCs) which have the capacity to replace dead oligodendrocytes and to. There is great interest in understanding the endogenous factors which govern spontaneous remyelination in order to explain why this process fails in the different forms of MS. This better knowledge could help designing new therapeutic strategies aiming at boosting the capacity of remyelination in MS and other demyelinating diseases [5, 6]

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Conclusion