Exosomal miRNA Following Severe Trauma: Role in Bone Marrow Dysfunction

Abstract

ABSTRACT Introduction Severe trauma disrupts bone marrow function and is associated with persistent anemia and altered hematopoiesis. Previously, plasma-derived exosomes isolated after trauma have been shown to suppress in vitro bone marrow function. However, the cargo contained in these vesicles has not been examined. We hypothesized that trauma plasma-derived exosomes exhibit microRNA (miR) changes that impact bone marrow function after severe injury. Methods Plasma was collected from a prospective, cohort study of trauma patients (n = 15; 7 males, 8 females) with hip and/or femur fractures and an injury severity score (ISS) ≥ 15; elective total hip arthroplasty (THA) patients (n = 8; 4 males, 4 females) served as operative controls. Exosomes were isolated from plasma with the Invitrogen Total Exosome Isolation Kit and RNA was isolated using a miRNeasy Mini Kit. Direct quantification of miRNA was performed by NanoString Technologies on a human miRNA gene panel and analyzed with nSolver with significance defined as p < 0.05. Results There were no differences in age or sex distribution between trauma and THA groups; the average ISS was 23. Trauma plasma-derived exosomes had 60 miR identities that were significantly downregulated and 3 miR upregulated when compared to THA (p < 0.05). Twelve of the downregulated miR have a direct role in hematopoiesis regulation. Further, male trauma plasma-derived exosomes demonstrated downregulation of 150 miR compared to male THA (p < 0.05). Female trauma plasma-derived exosomes demonstrated downregulation of only four miR and upregulation of two miR compared to female THA (p < 0.05). Conclusions We observed downregulation of 12 miRNA linked to hematopoiesis along with sexual dimorphism in miR expression from plasma-derived exosomes following severe trauma. Understanding sexually dimorphic miR expression provides new insight into sex-based changes in postinjury systemic inflammation, immune system dysregulation, and bone marrow dysfunction and will aid us in more precise future potential therapeutic strategies. Level of Evidence II, Prognostic and Epidemiological