The toxic effects of neutrophil extracellular traps on mesenchymal stem cells

Sepsis, a systemic inflammatory response syndrome resulting from an uncontrolled inflammatory reaction to infection, remains without a definitive cure despite therapeutic advancements. Mesenchymal stem cells (MSCs), renowned for their capacity to alleviate inflammation and modulate the immune system, have emerged as a potential treatment avenue for sepsis. In sepsis pathophysiology, hyperactivated neutrophils release extracellular neutrophil traps (NETs). NETs are essential for eradicating pathogens; however, excessive formation leads to tissue damage. Given the limited knowledge regarding the impact of NETs on MSCs used in sepsis therapy and the established interaction between MSCs and NETs, this study investigates the effects of NETs on MSCs in vitro. NETs were isolated from stimulated neutrophils, and MSCs were sourced from umbilical cord blood. After co-culturing MSCs with isolated NETs, MSCs' viability, migration, intracellular antioxidant capacity, and changes in gene expression were analyzed. Following exposure to NETs, MSCs exhibited obvious apoptosis and necrosis. NETs disrupt MSCs' mitochondrial activity. Also, NETs upregulate the pro-apoptotic gene BAX and downregulate the anti-apoptotic gene BCL2 in MSCs. Additionally, NETs reduce MSCs' intracellular antioxidant capacity. Furthermore, MSC migration is significantly impaired by NETs. This study collectively demonstrates that NETs have toxic and detrimental effects on MSCs. These effects on MSCs indicate a potential barrier to their functionality and therapeutic efficacy. Therefore, it appears that reducing the undesirable effects of NETs could serve as a novel target to enhance the therapeutic efficacy of MSCs in septic patients.