Plasma extracellular vesicles in chronic stress and functional link to epithelial cell migration and wound repair

Authors

• SK Abey
• Y Yuana
• ND Kenea
• PV Joseph
• NH Fourie
• LB Sherwin
• GE Gonye
• PA Smyser
• ES Stempinski
• WA Henderson

Abstract

Wound repair and chronic stress response are related processes with poorly understood mechanisms and limited therapies. We investigated whether circulating RNA and extracellular vesicles (EVs) from patients with chronic stress-induced gastrointestinal dysfunction contained stress response signals with functional roles in wound repair. Blood transcriptomes (Affymetrix) from patients with chronic stress (Irritable Bowel Syndrome, IBS) and healthy controls were used to identify signaling network related to wound repair and network membrane effectors. Based on this network, plasma EVs were isolated and EV membrane proteins, CD9, mucins, and lysozyme, were characterized using immunogold labeling-electron microscopy. Lysozyme effects on post-wound migration response were investigated in human fetal colon epithelial cells and compared to the effects of CXCL12 (a CXCR4 ligand). Lysozyme effects on altered cellular levels of immune-related mRNAs and proteins in response to wound were quantitated using NanoString. Results: Blood transcriptomes from patients with chronic stress versus controls revealed pyridoxal 5’phosphate salvage, cellular movement, and assembly and organization network driven by membrane-associated CD9 and CXCR4. This network revealed a link to extracellular lysozyme via ubiquitin and akt. Plasma EVs from patients and controls showed labeling with CD9, lysozyme, and mucins. Lysozyme induced post-wound cell migration to the same extent as CXCL12. NanoString analyses of mRNAs and proteins in cells which survived wound in the presence or absence of lysozyme showed altered levels of immune and wound repair-related mRNAs and proteins. We concluded that signals for wound repair and cell migration were associated with plasma EVs in chronic stress.

Scientific Focus Area: Immunology

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