Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation

Traumatic brain injury (TBI), a complicated form of brain damage, is a major cause of mortality in adults. Following mechanical and structural primary insults, a battery of secondary insults, including neurotransmitter-mediated cytotoxicity, dysregulation of calcium and macromolecule homeostasis, and increased oxidative stress, exacerbate brain injury and functional deficits. Although stem cell therapy is considered to be an alternative treatment for brain injuries, such as TBI and stroke, many obstacles remain. In particular, the time window for TBI treatment with either drugs or stem cells and their efficacy is still vague. Human placenta-derived mesenchymal stem cells (hpMSCs) have received extensive attention in stem cell therapy because they can be acquired in large numbers without ethical issues and because of their immune-modulating capacity and effectiveness in several diseases, such as Alzheimer's disease and stroke. Here, we tested the feasibility of hpMSCs for TBI treatment with an animal model and attempted to identify appropriate time points for cell treatments. Double injections at 4 and 24 h post-injury significantly reduced the infarct size and suppressed astrocyte and microglial activation around the injury. With reduced damage, double-injected mice showed enhanced anti-inflammatory- and TNF-alpha receptor 2 (TNFR2)-associated survival signals and suppressed pro-inflammatory and oxidative responses. In addition, double-treated TBI mice displayed restored sensory motor functions and reduced neurotoxic A beta(42) plaque formation around the damaged areas. In this study, we showed the extended therapeutic potentials of hpMSCs and concluded that treatment within an appropriate time window is critical for TBI recovery.