Persistent hypersomnia following repetitive mild experimental traumatic brain injury: Roles of chronic stress and sex differences.

Traumatic brain injury (TBI) is often more complicated than a single head injury. An extreme example of this point may be military service members who experience a spectrum of exposures over a prolonged period under stressful conditions. Understanding the effects of complex exposures can inform evaluation and care to prevent persistent symptoms. We designed a longitudinal series of non-invasive procedures in adult mice to evaluate the effects of prolonged mild stress and head injury exposures. We assessed anxiety, depression, and sleep-wake dysfunction as symptoms that impact long-term outcomes after mild TBI. Unpredictable chronic mild stress (UCMS) was generated from a varied sequence of environmental stressors distributed within each of 21 days. Subsequently, mice received a mild blast combined with closed-head mild TBI on 5 days at 24-h intervals. In males and females, UCMS induced anxiety without depressive behavior. A major finding was reproducible sleep-wake dysfunction through 6- to 12-month time points in male mice that received UCMS with repetitive blast plus TBI events, or surprisingly after just UCMS alone. Specifically, male mice exhibited hypersomnia with increased sleep during the active/dark phase and fragmentation of longer wake bouts. Sleep-wake dysfunction was not found with TBI events alone, and hypersomnia was not found in females under any conditions. These results identify prolonged stress and sex differences as important considerations for sleep-wake dysfunction. Furthermore, this reproducible hypersomnia with impaired wakefulness is similar to the excessive daytime sleepiness reported in patients, including patients with TBI, which warrants further clinical screening, care, and treatment development.

World-Wide Efficacy of Bone Marrow Derived Mesenchymal Stromal Cells in Preclinical Ischemic Stroke Models: Systematic Review and Meta-Analysis.

Background: Following extensive, positive results in pre-clinical experiments, Bone Marrow Derived-Mesenchymal Stromal Cells (BM-MSCs) are now being tested as a novel therapy for ischemic stroke in ongoing clinical trials. However, multiple critical questions relating to their translational application remain to be clarified. We performed a comprehensive, systematic review and meta-analysis of pre-clinical studies to evaluate the efficacy of BM-MSCs on functional outcomes after ischemic stroke, as well as the independent role of translational factors on their effect size. Methods: We systematically reviewed the literature and identified articles using BM-MSCs in animal models of focal ischemic stroke. After abstraction of all relevant data, we performed a meta-analysis to estimate the combined effect size of behavioral endpoints after BM-MSC administration. To describe the effect size across many behavioral outcomes, we divided these outcomes into four categories: (1) Composite scores, (2) Motor Tests, (3) Sensorimotor Tests, and (4) Cognitive Tests. We also performed a meta-regression analysis for measuring the effect of individual characteristics of BM-MSC administration on the effect size. Results: Our results from 141 articles indicate a significant beneficial effect on composite, motor, and sensorimotor outcomes after treatment with BM-MSCs compared to control groups. We found no major differences in treatment effect based on delivery route, dose, fresh vs. frozen preparation, or passage number. There were no consistent findings supporting a difference in treatment effect based on time windows from acute periods (0-6 h) vs. later windows (2-7 days). Furthermore, these positive treatment effects on functional outcome were consistent across different labs in different parts of the world as well as over the last 18 years. There was a negative correlation between publication year and impact factor. Conclusions: Our results show worldwide efficacy of BM-MSCs in improving functional outcomes in pre-clinical animal models of stroke and support testing these cells in clinical trials in various ranges of time windows using different delivery routes. The continued growing number of publications showing functional benefit of BM-MSCs are now adding limited value to an oversaturated literature spanning 18 years. Researchers should focus on identifying definitive mechanisms on how BM-MSCs lead to benefit in stroke models.

Multipotent Adult Progenitor Cells Enhance Recovery After Stroke by Modulating the Immune Response from the Spleen.

Stem cell therapy modulates not only the local microenvironment of the brain but also the systemic immune responses. We explored the impact of human multipotent adult progenitor cells (MAPC) modulating splenic activation and peripheral immune responses after ischemic stroke. Hundred twenty-six Long-Evans adult male rats underwent middle cerebral artery occlusion. Twenty-four hours later, they received IV MAPC or saline treatment. At 3 days after infusion, RNA was isolated from the injured cortex and spleen for microarray analysis. Spleen mass, splenocyte phenotype, and releasing cytokines were measured. Serum cytokines, MAPC biodistribution, brain lesion sizes and neurofunctional deficits were compared in rats treated with MAPC or saline with and without spleens. Stroked animals treated with MAPC exhibited genes that more closely resembled animals with sham surgery. Gene categories downregulated by MAPC included leukocyte activation, antigen presentation, and immune effector processing, associated with the signaling pathways regulated by TNF-α, IL-1ß, IL-6, and IFN-γ within the brain. MAPC treatment restored spleen mass reduction caused by stroke, elevated Treg cells within the spleen, increased IL-10 and decreased IL-1ß released by splenocytes. MAPC reduced IL-6 and IL-1ß and upregulated IL-10 serum levels. Compared with saline, MAPC enhance stroke recovery in rats with intact spleens but had no effects in rats without spleens. MAPC restores expression of multiple genes and pathways involved in immune and inflammatory responses after stroke. Immunomodulation of the splenic response by the intravenous administration of MAPC may create a more favorable environment for brain repair after stroke. Stem Cells 2017;35:1290-1302.