Journal
GLIA
Volume 69, Issue 9, Pages 2215-2234Publisher
WILEY
DOI: 10.1002/glia.24019
Keywords
adaptaquin; cell death; cell survival; deferoxamine; H2O2; hypoxia adaptations; hypoxia inducible factor (HIF); preconditioning; prolyl hydroxylase inhibition; reporter assay
Categories
Funding
- National Institute of Neurological Disorders and Stroke [NS075375]
- Spinal Cord Injury Trust Fund through New York State Department of Health [C029128, C030081]
- Burke Foundation
- Regenerative Research Foundation
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Schwann cell grafts in the injured spinal cord can benefit from pharmacological induction of adaptive hypoxic responses, which enhance cell survival and promote axon regeneration. By stabilizing HIF-1 alpha and its target gene expression, pharmacological preconditioning with hypoxia-mimetics like DFO can protect cells from oxidative stress-induced death, offering a potential therapeutic strategy for neurological injuries and diseases involving SC damage.
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-1 alpha), a regulator of the cellular response to hypoxia, is implicated in preconditioning-associated protection. HIF-1 alpha 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-1 alpha stability and HIF-1 alpha 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-1 alpha. 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.
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