Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord

Abstract

Olfactory ensheathing cell (OEC) transplantation emerged some years ago as a promising therapeutic strategy to repair injured spinal cord. However, inhibitory molecules are present for long periods of time in lesioned spinal cord, inhibiting both OEC migration and axonal regrowth. Two families of these molecules, chondroitin sulphate proteoglycans (CSPG) and myelin-derived inhibitors (MAIs), are able to trigger inhibitory responses in lesioned axons. Mounting evidence suggests that OEC migration is inhibited by myelin. Here we demonstrate that OEC migration is largely inhibited by CSPGs and that inhibition can be overcome by the bacterial enzyme Chondroitinase ABC. In parallel, we have generated a stable OEC cell line overexpressing the Nogo receptor (NgR) ectodomain to reduce MAI-associated inhibition in vitro and in vivo. Results indicate that engineered cells migrate longer distances than unmodified OECs over myelin or oligodendrocyte-myelin glycoprotein (OMgp)-coated substrates. In addition, they also show improved migration in lesioned spinal cord. Our results provide new insights toward the improvement of the mechanisms of action and optimization of OEC-based cell therapy for spinal cord lesion.

Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs)

“…In addition, the acquisition of different morphologies and markers by clonal OECs in response to the culture conditions must be considered (Alexander et al, ; Franceschini & Barnett, ; Moreno‐Flores et al, ; Moreno‐Flores et al, ; Moreno‐Flores et al, ; Pixley, ; Vincent et al, ). Furthermore, OECs are migratory cells (Huang et al, ; Nocentini et al, ; Reginensi et al, ; Windus, Claxton, Allen, Key, & St John, ) and dynamic lamellipodal waves are crucial for cell migration (Windus et al, ). Through the re‐organization of the cytoskeleton, different phenotypes with flattened and spindle‐shaped morphologies can be generated (the morphological characteristics of astrocytes and SchCs, respectively), producing unique OEC subpopulations that can spontaneously transform from one to the other (Huang et al, ).…”

“…OECs not only express factors that promote neuroregeneration but they also express some inhibitory factors (Table b and Figure ), although the significance of this is not yet well understood. OECs express Nogo and their NgR receptor (Nocentini et al, ; Su et al, ; Woodhall, West, Vickers, & Chuah, ), and the latter has a direct effect on the capacity of OECs to migrate on myelin or myelin‐derived substrates in vitro (Nocentini et al, ; Reginensi et al, ). Significantly, this phenomenon may affect their ability to penetrate the glial scar.…”

Brain-derived Neurotrophic Factor Promotes the Migration of Olfactory Ensheathing Cells Through TRPC Channels

“…In OEC transplantations, OECs have to face a more complex environment during their migration from transplanted sites to injury sites, as they interact with a great variety of cell types such as reactive astrocytes and with the factors produced through injury (Chuah et al, 2011;Pearse et al, 2007;Su et al, 2009). Although some factors have been identified to regulate OEC migration (Cao et al, 2006;Ekberg et al, 2012;Huang et al, 2011a;Ingram et al, 2016;Reginensi et al, 2015;Su et al, 2007;Wang and Huang, 2012;Yan et al, 2003), it remains unclear the molecular mechanism of OEC migration. Although some factors have been identified to regulate OEC migration (Cao et al, 2006;Ekberg et al, 2012;Huang et al, 2011a;Ingram et al, 2016;Reginensi et al, 2015;Su et al, 2007;Wang and Huang, 2012;Yan et al, 2003), it remains unclear the molecular mechanism of OEC migration.…”

Ginsenoside Rg1 Promotes the Migration of Olfactory Ensheathing Cells <i>via</i> the PI3K/Akt Pathway to Repair Rat Spinal Cord Injury

“…21) However, inhibitory molecules were persistently present in the spinal cord lesion, which inhibited OEC migration. 22) Thus, it is urgently necessary to improve the migration ability of OECs. The aim of our experiments was to develop a feasible and effective method of improving OEC migration.…”