Mesenchymal stem cell-derived small extracellular vesicles alleviate the immunometabolic dysfunction in murine septic encephalopathy
Ioannis Koutroulis,
Panagiotis Kratimenos,
Claire Hoptay,
Wade N. O’Brien,
Georgios Sanidas,
Chad Byrd,
Maria Triantafyllou,
Evan Goldstein,
Beata Jablonska,
Manish Bharadwaj,
Vittorio Gallo,
Robert Freishtat
Affiliations
Ioannis Koutroulis
Department of Pediatrics, Division of Emergency Medicine, Children’s National Hospital, Washington, DC 20010, USA; George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA; Children’s National Research Institute, Washington, DC 20010, USA; Corresponding author
Panagiotis Kratimenos
George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA; Department of Pediatrics, Division of Neonatology, Children’s National Hospital, Washington, DC 20010, USA; Children’s National Research Institute, Washington, DC 20010, USA
Claire Hoptay
Children’s National Research Institute, Washington, DC 20010, USA
Wade N. O’Brien
Dartmouth College Geisel School of Medicine, Hanover, NH 03755, USA
Georgios Sanidas
Children’s National Research Institute, Washington, DC 20010, USA
Chad Byrd
Children’s National Research Institute, Washington, DC 20010, USA
Maria Triantafyllou
Children’s National Research Institute, Washington, DC 20010, USA
Evan Goldstein
Augusta University Medical College of Georgia, Augusta, GA 30912, USA
Beata Jablonska
Children’s National Research Institute, Washington, DC 20010, USA
Manish Bharadwaj
Agilent Inc, Santa Clara, CA 95051, USA
Vittorio Gallo
George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA; Children’s National Research Institute, Washington, DC 20010, USA
Robert Freishtat
Department of Pediatrics, Division of Emergency Medicine, Children’s National Hospital, Washington, DC 20010, USA; George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA; Children’s National Research Institute, Washington, DC 20010, USA
Summary: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that results in high mortality and long-term sequela. The central nervous system (CNS) is susceptible to injury from infectious processes, which can lead to clinical symptoms of septic encephalopathy (SE). SE is linked to a profound energetic deficit associated with immune dysregulation. Here, we show that intravenous administration of adipose tissue mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) in septic mice improved disease outcomes by reducing SE clinical severity, restoring aerobic metabolism, and lowering pro-inflammatory cytokines in the cerebellum, a key region affected by SE. Our high throughput analysis showed that MSC-derived sEVs partially reversed sepsis-induced transcriptomic changes, highlighting the potential association of miRNA regulators in the cerebellum of MSC-derived sEV-treated mice with miRNAs identified in sEV cargo. MSC-derived sEVs could serve as a promising therapeutic agent in SE through their favorable immunometabolic properties.
