Apoptotic bodies derived from hypoxic bone marrow mesenchymal stem cells reverse LPS-induced apoptosis delay in neutrophils.

Immune system disorders underlie numerous chronic inflammatory diseases. Functional status and normal apoptosis of neutrophils are of great significance in the regulation and outcome of inflammation. Excessive activation and delayed apoptosis of neutrophils can lead to additional tissue damage, which may be an important cause of delayed disease recovery. Stem cells have immunomodulatory effects, but transplanted stem cells are prone to apoptosis in the hypoxic-inflammatory microenvironment. However, the capacity of stem cell-derived apoptotic bodies (ApoBDs) to regulate neutrophil functions, along with the specific components and mechanisms involved, is still unclear. Our study revealed that ApoBDs stemming from hypoxia-induced apoptosis in bone marrow mesenchymal stem cells reversed Lipopolysaccharide (LPS)-induced delayed neutrophil apoptosis, without notable effects on neutrophil apoptosis under physiological conditions. This functional shift was attributed to the phagocytosis of miR-125b-5p within ApoBDs by neutrophils, which inhibited the activation of the PI3K-AKT signaling pathway. In a mouse skin wound healing model, ApoBDs and the miR-125b-5p they contain also promoted neutrophils apoptosis around the wound and early wound closure. In summary, we demonstrated that hypoxia-induced apoptosis of bone marrow mesenchymal stem cells produced ApoBDs by transferring miR-125b-5p to neutrophils to reduce the expression of PI3 Kinase p110α and inhibit the activation of the PI3K-AKT signaling pathway, thereby reversing the delay of neutrophil apoptosis induced by LPS, which may be a novel option for the treatment of diseases associated with abnormalities in neutrophil apoptosis.