Laminin α2, α4, and α5 Chains Positively Regulate Migration and Survival of Oligodendrocyte Precursor Cells

Abstract

In the developing central nervous system (CNS), oligodendrocyte precursor cells (OPCs) migrate along blood vessels and are widely distributed in the CNS. Meanwhile, OPCs require survival factors from the extracellular microenvironment. In other tissues, laminins, heterotrimetric (αβγ) extracellular matrix proteins, promote cell migration and survival. However, the expression pattern and functions of laminins in OPC development remain poorly understood. In the present study, we first investigated the expression of laminin α chains, which bind to cell surface receptors such as integrins, in the postnatal murine brain. We found that laminin α1, α2, α4, and α5 chains were expressed around blood vessels and OPCs attached the laminin α chain-positive vessels. We then evaluated the effect of these laminins on OPCs activity using recombinant laminin E8s (LME8s) that are minimally active fragments of the laminin isoforms. OPCs attached on LM211E8, LM411E8, and LM511E8, containing laminin α2, α4, and α5 chains, respectively, through integrin β1. Further, these three LME8s promoted migration of OPCs, and OPC survival was prolonged on either LM411E8 or LM511E8 via the activation of focal adhesion kinase. Together, our findings suggest that laminins expressed surrounding blood vessels positively regulate migration and survival of OPCs through the integrin β1-FAK pathway.

Laminin regulates oligodendrocyte development and myelination

“…Survival Laminin-α2 on axons Increased survival (Colognato et al, 2002) Laminin-α2 knockout Fewer OPCs and increased cell death (Relucio et al, 2012) Laminin-411 and À 511 Increased survival (Suzuki et al, 2019) Laminin-211 with PDGF Increased survival (Colognato et al, 2004;Decker, 2004;Frost et al, 1999) Laminin substrate Decreased OPC death (Hu et al, 2009) Integrin-α6β1 blockage Reduced survival (Corley et al, 2001;Frost et al, 1999) Lipid raft depletion Increased apoptosis (Decker, 2004) Integrin-α6 knockout Increased cell death (Colognato et al, 2002) Integrin-αv/α6 chimera Increased survival (Colognato et al, 2002) Integrin-β1 CKO a (CNP-Cre) Increased cell death (Benninger et al, 2006) Laminin with dystroglycan blockage No significant change (Colognato et al, 2007) Migration Laminin substrate Increased migration (Milner et al, 1996;Schmidt et al, 1997) Laminin-211 Increased migration (Frost et al, 1996) Laminin-211, À411 and À 511 Increased migration (Suzuki et al, 2019) Laminin Increased migration (Fok-Seang et al, 1995) Integrin-β1 blockage Reduced migration (Milner et al, 1996) Integrin-α6 blockage No significant change (Milner et al, 1996) Integrin…”

“…Consistent with this result, laminin‐α2 knockout mice have fewer OPCs and increased perinatal death of newborn OPCs at the subventricular zone (SVZ) (Relucio et al, 2012). Additionally, laminin in the basal lamina also contributes to the survival of OPCs (Suzuki et al, 2019). It has been shown that laminin‐411 and ‐511 enhance OPC survival by binding to integrin‐β1 and activating FAK, whereas laminin‐211 fails to do so (Suzuki et al, 2019).…”

“…Additionally, laminin in the basal lamina also contributes to the survival of OPCs (Suzuki et al, 2019). It has been shown that laminin‐411 and ‐511 enhance OPC survival by binding to integrin‐β1 and activating FAK, whereas laminin‐211 fails to do so (Suzuki et al, 2019). Interestingly, laminin‐211 but not fibronectin significantly enhances OL survival in the presence of PDGF (Decker, 2004; Frost et al, 1999).…”

Mechanisms of oligodendrocyte progenitor developmental migration

“…Wnt signaling in OPCs has critical function in this process, as it mediates association of OPCs with vessels by driving OPC expression of the chemokine receptor Cxcr4, which interacts with its ligand Sdf1 on the endothelial surface (Tsai et al., 2016). A recent study suggests that laminins expressed surrounding blood vessels positively regulate migration and survival of OPCs through the integrin β1‐FAK pathway (Suzuki et al., 2019). Vascular endothelial growth factor (VEGF‐A) secreted from cerebral endothelial cells has also been suggested to promote the migration but not the proliferation of OPCs (Hayakawa et al., 2011, 2012).…”

A Novel Three-Dimensional Culture Device Favors a Myelinating Morphology of Neural Stem Cell-Derived Oligodendrocytes

“…Laminin matrices enhanced NSPC migration, expansion, differentiation into neurons and astrocytes, and elongation of neurites from NSPC-derived neurons (Liu et al, 2020), an effect possibly mediated by the α6 integrin subunit (Flanagan et al, 2006), thus confirming the importance of cellmatrix interaction in a microenvironment mimicking the NSPC niche. In addition, laminins expressed around blood vessels positively regulated the migration and survival of OPCs through the integrin β1-FAK pathway (Suzuki et al, 2019). Moreover, laminin is the most used coating for neurosphere-derived and primary OPCs (Chen et al, 2007;Lourenço et al, 2016), as the main extracellular matrix mediator of their adhesion and differentiation (Liu et al, 2020).…”