β-Blockade reprograms trauma-induced changes in bone marrow exosomal microRNAs

BACKGROUND: Severe trauma produces sustained sympathetic activation that contributes to bone marrow dysfunction, impaired hematopoiesis, and persistent injury-associated anemia. Although β-adrenergic blockade improves bone marrow recovery after injury, the downstream mechanisms remain incompletely defined. We hypothesized that propranolol reprograms trauma-induced bone marrow extracellular vesicle (EV) microRNA (miRNA) expression toward restoration of hematopoietic homeostasis. METHODS: Sprague-Dawley rats were randomized to naïve, polytrauma (PT), PT plus propranolol (PT+BB), PT with chronic restraint stress (PTRS), or PTRS plus propranolol (PTRS+BB) groups (n=6-8 per group). Propranolol (10 mg/kg intraperitoneally) was administered daily. On day 7, complete blood counts were obtained, and bone marrow-derived EV miRNAs were profiled using the NanoString nCounter platform. Differentially expressed miRNAs were identified using an absolute log2 fold change ≥1.5 and p<0.05. Predicted pathways were assessed using Ingenuity Pathway Analysis, and miR-125b-5p was validated by quantitative PCR. RESULTS: PT altered 45 EV miRNAs compared with naïve animals, including suppression of miRNAs involved in hematopoietic stem cell maintenance and erythropoiesis. Chronic restraint stress amplified this response, with 93 differentially expressed miRNAs following PTRS. Propranolol altered 12 miRNAs after PT and 43 after PTRS, increasing hematopoietic regulatory miRNAs, including miR-125b-5p, while suppressing several stress- and inflammation-associated miRNAs. Pathway analysis identified alterations in NOTCH, RUNX1, PTEN, thyroid receptor/retinoid X receptor, and histone modification signaling. Quantitative PCR confirmed a 2.4-fold increase in EV miR-125b-5p following propranolol in PTRS animals (p=0.018). CONCLUSIONS: Trauma and persistent adrenergic stress broadly remodel bone marrow EV miRNA signaling. β-Adrenergic blockade selectively reprograms these networks toward pathways associated with hematopoietic recovery, identifying EV miRNAs as potential mediators of posttraumatic bone marrow dysfunction. LEVEL OF EVIDENCE: Not applicable-Animal research.