Mesenchymal Stromal Cells Protect the Blood-Brain Barrier, Reduce Astrogliosis, and Prevent Cognitive and Behavioral Alterations in Surviving Septic Mice
| Autor: | Raquel Maria Pereira Campos, Adriano Y. O. Silva, Rômulo L. S. Neris, Hugo C. Castro-Faria-Neto, Carolina A. Moraes, Patricia R. M. Rocco, Tatiana Maron-Gutierrez, Adriana Lima Vallochi, Helena A. Oliveira, Maiara N. Lima, Paula M. Fagundes, Maria C Barbosa-Silva, Fernando A. Bozza, Karina S. Oliveira, Marcelo Gomes Granja, Erica Amorim |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Stromal cell business.industry Mesenchymal stem cell 030208 emergency & critical care medicine Inflammation Critical Care and Intensive Care Medicine medicine.disease Blood–brain barrier Astrogliosis Sepsis 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Endocrinology 030228 respiratory system Internal medicine medicine medicine.symptom business Neuroinflammation Astrocyte |
| Zdroj: | Critical Care Medicine. 48:e290-e298 |
| ISSN: | 0090-3493 |
| DOI: | 10.1097/ccm.0000000000004219 |
| Popis: | Objectives Survivors 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. Design Prospective, randomized, controlled experimental study. Setting Government-affiliated research laboratory. Subjects Male Swiss Webster mice (n = 309). Interventions Sepsis 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 results At 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. Conclusions In 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|