Visual Abstract

Schwann cell (SC) grafts promote axon regeneration in the injured spinal cord, but transplant efficacy is diminished by a high death rate in the first 2–3 days postimplantation. Both hypoxic preconditioning and pharmacological induction of the cellular hypoxic response can drive cellular adaptations and improve transplant survival in a number of disease/injury models. Hypoxia‐inducible factor 1 alpha (HIF‐1α), a regulator of the cellular response to hypoxia, is implicated in preconditioning‐associated protection. HIF‐1α cellular levels are regulated by the HIF‐prolyl hydroxylases (HIF‐PHDs). Pharmacological inhibition of the HIF‐PHDs mimics hypoxic preconditioning and provides a method to induce adaptive hypoxic responses without direct exposure to hypoxia. In this study, we show that hypoxia‐mimetics, deferoxamine (DFO) and adaptaquin (AQ), enhance HIF‐1α stability and HIF‐1α target gene expression. Expression profiling of hypoxia‐related genes demonstrates that HIF‐dependent and HIF‐independent expression changes occur. Analyses of transcription factor binding sites identify several candidate transcriptional co‐regulators that vary in SCs along with HIF‐1α. Using an in vitro model system, we show that hypoxia‐mimetics are potent blockers of oxidative stress‐induced death in SCs. In contrast, traditional hypoxic preconditioning was not protective. The robust protection induced by pharmacological preconditioning, particularly with DFO, indicates that pharmacological induction of hypoxic adaptations could be useful for promoting transplanted SC survival. These agents may also be more broadly useful for protecting SCs, as oxidative stress is a major pathway that drives cellular damage in the context of neurological injury and disease, including demyelinating diseases and peripheral neuropathies.

Transplanted olfactory ensheathing cells (OECs) contribute to functional recovery in a range of CNS injuries by several mechanisms, one of which is potentially their ability to form myelin sheaths. OECs sourced from donors of different ages have been shown to remyelinate in several in vitro and in vivo models. However, the optimal donor age for OEC associated remyelination is unclear. This project directly compared the remyelinating potential of p75 purified OEC transplants from three donor ages. OECs were sourced from the olfactory bulbs of embryonic, neonatal, and adult rats and purified by immunopanning, and their remyelinating potential was directly compared by transplantation into the same adult rat toxin-induced model of spinal cord demyelination. Remyelination efficiency 3 weeks after transplantation was assessed morphologically and by immunostaining. Our results indicate that all donor ages remyelinate; however, this process is most efficiently achieved by embryonic-derived OECs.

This study shows that OLs are relatively resistant to EtOH, even at a concentration more than 4 times the typical blood EtOH concentrations associated with social drinking (10 to 30 mM). In contrast, OLs are much more sensitive to ACD than EtOH, particularly with long-term exposure. This suggests that part of white matter loss in response to EtOH, especially during high rates of myelin formation, may be due in part to the effects of its principal metabolite ACD.