Schwann cell migration is integrin‐dependent and inhibited by astrocyte‐produced aggrecan

Abstract

Schwann cells transplantation has considerable promise in spinal cord trauma to bridge the site of injury and for remyelination in demyelinating conditions. They support axonal regeneration and sprouting by secreting growth factors and providing a permissive surface and matrix molecules while shielding axons from the inhibitory environment of the central nervous system. However, following transplantation Schwann cells show limited migratory ability and they are unable to intermingle with the host astrocytes. This in turn leads to formation of a sharp boundary and an abrupt transition between the Schwann cell graft and the host tissue astrocytes, therefore preventing regenerating axons from exiting the graft. The objective of this study was to identify inhibitory elements on astrocytes involved in restricting Schwann cell migration. Using in vitro assays of cell migration, we show that aggrecan produced by astrocytes is involved in the inhibition of Schwann cell motility on astrocytic monolayers. Knockdown of this proteoglycan in astrocytes using RNAi or digestion of glycosaminglycan chains on aggrecan improves Schwann cell migration. We further show aggrecan mediates its effect by disruption of integrin function in Schwann cells, and that the inhibitory effects of aggrecan can overcome by activation of Schwann cell integrins.

Kindlin-1 Enhances Axon Growth on Inhibitory Chondroitin Sulfate Proteoglycans and Promotes Sensory Axon Regeneration

“…The fact that kindlin-1 expression only enhances axon growth in the presence of inhibitory aggrecan is consistent with the idea that aggrecan impairs integrin signaling, which can be restored by integrin activation (Tan et al, 2011). This is important in axon regeneration, since CSPG upregulation usually follows a CNS injury (Jaworski et al, 1999;McKeon et al, 1999;Asher et al, 2000;Afshari et al, 2010).…”

“…These results are consistent with several earlier reports that integrin activation could enhance axon growth from neurons in vitro, even when cultured in the presence of inhibitory molecules such as amino-Nogo or aggrecan (Ivins et al, 2000;Lein et al, 2000;Hu and Strittmatter, 2008;Tan et al, 2011), and also with our demonstration that expression of a tenascin-binding integrin can promote axon regeneration (Andrews et al, 2009). CNS injuries cause an upregulation of myelin-related inhibitors (e.g., Nogo, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein) (McKerracher et al, 1994;Mukhopadhyay et al, 1994;GrandPré et al, 2000GrandPré et al, , 2002Prinjha et al, 2000;Kottis et al, 2002;Wang et al, 2002) and CSPGs (e.g., aggrecan, brevican, phosphacan, versican), which impair regenerative responses (Jaworski et al, 1999;McKeon et al, 1999;Asher et al, 2000;Afshari et al, 2010). Our experiment suggests that integrin activation might be a general method to overcome these inhibitory effects and promote axon regeneration in vivo.…”

Manipulation of Schwann cell migration across the astrocyte boundary by polysialyltransferase-loaded superparamagnetic nanoparticles under magnetic field

“…5 Briefly, the brains were removed carefully and placed under a dissecting microscope in Hank's balanced salt solution (HBSS) before removing the meningeal membranes and being chopped into small pieces, digested in 0.125% trypsin for 30 min at 37°C. Cells were plated on poly-d-lysine (PLL)-coated T75 flasks and incubated in DMEM containing 10% FCS (Thermo Fisher Scientific Inc.) and antibiotics (penicillin and streptomycin solution).…”

“…5 The SCs were trypsinized with 0.1% trypsin and then resuspended at a density of 2×10 6 cells/mL. SCs, PEISPIONs/DNA/SCs, or PEI-SPIONs/PST/SCs were plated onto coverslip fragments (~5 mm 2 ) pre-coated with PLL.…”

Stem Cell Therapy: A Promising Therapeutic Approach for Multiple Sclerosis

“…Modifying SC-intrinsic properties, like boosting expression of neurotrophins (e.g., BDNF and NT3), promote SC migration and myelinating potentials (180,181). Also, SC-mediated myelination and axonal regeneration increased when the environment of the SC was modified (182).…”