Extracellular vesicles as stress signals: Identifying novel systemic mechanisms of trauma programming
Tracy L. Bale1, Kathleen E. Morrison2, Anaïs Stenson3, Sierra Carter4, Vasiliki Michopoulos3, Tanja Jovanovic3
1University of Maryland School of Medicine, 2West Virginia University, 3Wayne State University, 4Georgia State University
Exposure to traumatic events and adversity during specific windows of development is a risk factor for negative physical and mental health outcomes, but the underlying mechanisms that perpetuate these lasting effects or our ability to identify at-risk populations are not known. Extracellular vesicles (EVs) are a novel signaling mechanism involved in numerous biological processes and the systemic transmission of stress. The protein and sncRNA content of EVs is altered by stress and can impact the function of target tissues, including the brain and immune system. However, how or if EVs function in humans as stress signals is not known. We investigated the impact and timing of trauma experienced during key developmental windows of childhood, adolescence, or adulthood on adult health outcomes and associated biomarkers, including extracellular vesicles (EV), in a cohort of adult women. Our results revealed that stress reactivity related to PTSD risk was uniquely observed when trauma was experienced during adolescence. Further, in an unbiased proteomics assessment we identified a novel and robust EV signature comprised of a significant number of keratin-related proteins encoded in a 17q21 gene cluster related to Piezo2 Merkel cells. Dramatic increases in these proteins were positively associated with changes in the skin conductance response (SCR) and fear-potentiated startle. We developed a mouse model in which multimodal sensory stress experienced during puberty produced similar changes in EV proteins associated with the corresponding mouse keratin I gene cluster, 11qD, and increased adult fear-potentiated startle responses and freezing behaviors. Taken together, these results support EVs as novel biomarkers and potential stress signals relevant to disease risk.
Support or Funding Information NIH MH108286, HD097093, MH104184, ES028202, HD091376, MH111682, MH110364, MH098212
