• Adriano Y O Silva, Érica A Amorim, Maria C Barbosa-Silva, Maiara N Lima, Helena A Oliveira, Marcelo G Granja, Karina S Oliveira, Paula M Fagundes, Rômulo L S Neris, Raquel M P Campos, Carolina A Moraes, Adriana L Vallochi, RoccoPatricia R MPRMLaboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Br, Fernando A Bozza, Hugo C Castro-Faria-Neto, and Tatiana Maron-Gutierrez.
• Laboratory of Immunopharmacology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Fiocruz, Rio de Janeiro, Brazil.
• Crit. Care Med. 2020 Apr 1; 48 (4): e290e298e290-e298.

ObjectivesSurvivors of sepsis are frequently left with significant cognitive and behavioral impairments. These complications derive from nonresolving inflammation that persists following hospital discharge. To date, no study has investigated the effects of mesenchymal stromal cell therapy on the blood-brain barrier, astrocyte activation, neuroinflammation, and cognitive and behavioral alterations in experimental sepsis.DesignProspective, randomized, controlled experimental study.SettingGovernment-affiliated research laboratory.SubjectsMale Swiss Webster mice (n = 309).InterventionsSepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. All animals received volume resuscitation (1 mL saline/mouse subcutaneously) and antibiotics (meropenem 10 mg/kg intraperitoneally at 6, 24, and 48 hours). Six hours after surgery, mice were treated with mesenchymal stromal cells IV (1 × 10 cells in 0.05 mL of saline/mouse) or saline (0.05 mL IV).Measurements And Main ResultsAt day 1, clinical score and plasma levels of inflammatory mediators were increased in cecal ligation and puncture mice. Mesenchymal stromal cells did not alter clinical score or survival rate, but reduced levels of systemic interleukin-1β, interleukin-6, and monocyte chemoattractant protein-1. At day 15, survivor mice completed a battery of cognitive and behavioral tasks. Cecal ligation and puncture mice exhibited spatial and aversive memory deficits and anxiety-like behavior. These effects may be related to increased blood-brain barrier permeability, with altered tight-junction messenger RNA expression, increased brain levels of inflammatory mediators, and astrogliosis (induced at day 3). Mesenchymal stromal cells mitigated these cognitive and behavioral alterations, as well as reduced blood-brain barrier dysfunction, astrocyte activation, and interleukin-1β, interleukin-6, tumor necrosis factor-α, and interleukin-10 levels in vivo. In cultured primary astrocytes stimulated with lipopolysaccharide, conditioned media from mesenchymal stromal cells reduced astrogliosis, interleukin-1β, and monocyte chemoattractant protein-1, suggesting a paracrine mechanism of action.ConclusionsIn mice who survived experimental sepsis, mesenchymal stromal cell therapy protected blood-brain barrier integrity, reduced astrogliosis and neuroinflammation, as well as improved cognition and behavior.

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