Hypoxic preconditioning (HP) is a novel strategy to make stem cells resistant to the ischemic environment they encounter after transplantation into injured tissue; this strategy improves survival of both the transplanted cells and the host cells at the injury site. Using both in vitro and in vivo injury models, we confirmed that HP-treated adipose tissue-derived mesenchymal stem cells (HP-AT-MSCs) increased cell survival and enhanced the expression of marker genes in DsRed-engineered neural stem cells (NSCs-DsRed). Similar to untreated AT-MSCs, HP-AT-MSCs had normal morphology and were positive for the cell surface markers CD90, CD105, and CD29, but not CD31. In three in vitro ischemic-mimicking injury models, HP-AT-MSCs significantly increased both the viability of NSCs-DsRed and the expression of DsRed and clearly reduced the number of annexin-V-positive apoptotic NSCs-DsRed and the expression of the apoptotic factor Bax. Consistent with the in vitro assay, co-transplantation of NSCs-DsRed with HP-AT-MSCs significantly improved the survival of the NSCs-DsRed, resulting in an increased expression of the DsRed reporter gene at the transplantation site in a rat spinal cord injury (SCI) model. These findings suggest that the co-transplantation of HP-AT-MSCs with engineered NSCs can improve both the cell survival and the gene expression of the engineered NSCs, indicating that this novel strategy can be used to augment the therapeutic efficacy of combined stem cell and gene therapies for SCI.
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