MESENCHYMAL STROMAL CELLS PROTECT THE BLOOD-BRAIN BARRIER, REDUCE ASTROGLIOSIS, AND PREVENT COGNITIVE AND BEHAVIORAL IMPAIRMENTS IN EXPERIMENTAL SEPSIS

Abstract

<h3>Background</h3> Sepsis is a systemic inflammatory host-response against a pathogen; it is the largest cause of admission to intensive care units (ICUs) in the United States. Sepsis-associated encephalopathies (SAEs) are neurological complications that occur during or after sepsis events. SAE causes long-term neurological consequences affecting memory, cognition and mood. Currently, there is no prevention or treatment for neurological damage resulting from SAEs. Thus, investigating new therapies is necessary. Both clinical and experimental studies have been show the effects of cell therapy in neurodegenerative diseases. Indeed, the immunomodulatory capacity of mesenchymal stromal cells (MSCs) is well established. Considering that, the aim of the present study was to evaluate the effects of MSC therapy on blood-brain barrier (BBB) maintenance, astrocyte activation, cognitive and behavioral damage in an experimental model of sepsis. <h3>Methods</h3> Male adult Swiss mice underwent cecal ligation and puncture (CLP) surgery for sepsis induction and sham-operated animals were used as control. Six hours after surgery, mice were treated with MSC intravenously (1 × 10⁵ cells in 0.05 mL of saline/mouse) or saline. For in vitro, analysis cultured astrocytes were stimulated with lipopolysaccharide (LPS) (1μg/ ml). After 24 hours, cells were washed to eliminated residual LPS and then treated with conditioned media from MSCs (CM-MSCs). <h3>Results</h3> MSC therapy led to a reduction in systemic levels of IL-1β, IL-6, and MCP-1, a decrease in cortical and hippocampal cytokine levels, a reduction in astrogliosis (evaluated by immunofluorescence) and BBB protection (evaluated by Evans Blue Dye Assay). In cultured astrocytes stimulated with LPS, CM-MSCs reduced astrogliosis at 24h, suggesting a paracrine mechanism of action. These results might be associated with an improvement in spatial memory (Morris Water Maze test), aversive memory (fear-conditioned test) and anxiety-like behavior (Elevated plus maze test). <h3>Conclusion</h3> A single dose- therapy with MSC led to an improvement in cognitive damage, behavioral impairments, protection of the BBB, reduction in local levels of cytokines and astrogliosis and these effects might be associated with a decrease in systemic levels of inflammatory mediators.