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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0160-5) contains supplementary material, which is available to authorized users.

Tissue plasminogen activator promotes white matter integrity and functional recovery in a murine model of traumatic brain injury

“…tPA is naturally expressed in both gray and white matter, including within oligodendrocytes of the CC, but tPA expression in the CC declines with age, perhaps reducing the regeneration potential of white matter (35). After lysolecithin-induced white matter demyelination, endogenous tPA accelerates the migration of oligodendrocyte precursors to the lesion site through its EGFlike domain (36). Furthermore, endogenous tPA protects neurons against ischemic injury, and exogenous tPA mitigates white matter damage 24 h poststroke (17,18,35).…”

“…Although tPA treatment has shown neuroprotective effects and promotes neurovascular remodeling or regeneration (17,18,27,(36)(37)(38), the use of tPA is not currently indicated in head trauma due to somewhat contradictory perceptions of an increased risk of brain hemorrhage and edema (42). Intravascular delivery of the free form, but not of erythrocyte-bound tPA, was reported to increase cortical tissue injury and hemorrhage after TBI (43).…”

Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses

“…On the other hand, it has been shown that tPA can act via non-proteolytic "growth factor-like" effects [30], some of them mediated by its EGF-like domain [4,14] The addition of the EGFR blocking agent AG1478 decreased MHC-II + expression on MHC-II + APCs as compared to the condition with tPA (DCs: 55.49% ±20.64; M : 77.76%±18.82; P < 0.001, Fig. 7C and D).…”

“…In addition to its protease activity, tPA exerts various functions due to its ve distinct functional domains: nger domain, Epidermal Growth Factor (EGF)-like domain, kringle 1, kringle 2 and protease domain [13]. We have previously shown that tPA, by activating the EGF receptor (EGFR), has an anti-apoptotic effect over oligodendrocytes [4] and a chemotactic effect on their progenitors that helps remyelination after chemically-induced white matter lesions [14]. tPA is also able to increase blood brain barrier (BBB) permeability and helps leukocyte diapedesis [15] by several mechanisms, including the potentiation of endothelial N-Methyl-D-Aspartate receptors (NMDAR) [16] or tight junction disruption by the modi cation of occludin phosphorylation [17].…”

Extrinsic Factors Driving Oligodendrocyte Lineage Cell Progression in CNS Development and Injury

“…Mice lacking NG2 fail to expand their OPC population [113,114]. The epidermal growth factor (EGF) and vascular endothelial growth factor A (VEGFA) bind to their receptors on OPCs, EGFR, and VEGFR, respectively, and activate intracellular signaling, driving OPC migration [115][116][117][118]. Interestingly, there is a mutually beneficial relationship between OPCs and the vascular/perivascular population: OPCs regulate angiogenesis and pericyte colonization of the vasculature, while blood vessels and their associated cells support OPC proliferation, survival, and migration [97,104,117].…”