Improving the regenerative potential of olfactory ensheathing cells by overexpressing prostacyclin synthetase and its application in spinal cord repair

Abstract

BackgroundOlfactory ensheathing cells (OEC), specialized glia that ensheathe bundles of olfactory nerves, have been reported as a favorable substrate for axonal regeneration. Grafting OEC to injured spinal cord appears to facilitate axonal regeneration although the functional recovery is limited. In an attempt to improve the growth-promoting properties of OEC, we transduced prostacyclin synthase (PGIS) to OEC via adenoviral (Ad) gene transfer and examined the effect of OEC with enhanced prostacyclin synthesis in co-culture and in vivo. Prostacyclin is a vasodilator, platelet anti-aggregatory and cytoprotective agent.ResultsCultured OEC expressed high level of cyclooxygneases, but not PGIS. Infection of AdPGIS to OEC could selectively augument prostacyclin synthesis. When cocultured with either OEC or AdPGIS-OEC, neuronal cells were resistant to OGD-induced damage. The resulted OEC were further transplanted to the transected cavity of thoracic spinal cord injured (SCI) rats. By 6 weeks post-surgery, significant functional recovery in hind limbs occurred in OEC or AdPGIS-OEC transplanted SCI rats compared with nontreated SCI rats. At 10–12 weeks postgraft, AdPGIS-OEC transplanted SCI rats showed significantly better motor restoration than OEC transplanted SCI rats. Futhermore, regenerating fiber tracts in the distal spinal cord stump were found in 40–60% of AdPGIS-OEC transplanted SCI rats.ConclusionsEnhanced synthesis of prostacyclin in grafted OEC improved fiber tract regeneration and functional restoration in spinal cord injured rats. These results suggest an important potential of prostacyclin in stimulating OEC therapeutic properties that are relevant for neural transplant therapies.

Exogenous FGF-1 Differently Regulates Oligodendrocyte Replenishment in an SCI Repair Model and Cultured Cells

“…Mixed neuronal/glial cell cultures were prepared from the spinal cord regions of embryonic SD rat fetus at gestation 14–16 days as described in our published articles [ 47 ]. Briefly, cells were dissociated with mixtures of papain/protease/deoxyribonuclease I (0.1%:0.1%:0.03%) and plated onto poly-D-lysine coated dishes at a density of 1–2 × 10 5 cells/cm 2 .…”

Spinal cord injury: Olfactory ensheathing cell‐based therapeutic strategies

“…This genetically engineered cellular and molecular approach is a feasible combination therapy demonstrated in rat SCI models (Prager et al., 2021). OECs modified with the prostacyclin gene were shown to enhance and significantly promote functional recovery and fibroblast regeneration in rats with SCI, as prostacyclin has a protective effect on cells (Tsai et al., 2017).…”

Olfactory Ensheathing Cells for Spinal Cord Injury: The Cellular Superpowers for Nerve Repair

“…The recent advances in genetic modifications, transgenics and our understanding of developmental cell fate open a new avenue to enhance the functions, utility, and efficacy of the OECs for nerve repair. Research has been conducted to genetically improve the therapeutic potential of OECs by overexpressing prostacyclin synthetase [14], Nogo receptors and Chondroitinase ABC enzyme [15], for example. Additionally, recent development of techniques into the cell fate specifications of fibroblasts [16] and glial cell reprogramming [17] provide novel ways to purify OECs in culture and improve the cell yield, as well as enhancing the transplantation outcomes using OECs.…”