The Role And Mechanism Of Human Bone Marrow Mesenchymal Stem Cell-derived Exosomes In Acute Myeloid Leukemia

Background: Acute myeloid leukemia(AML)is a kind of malignant clonal disease derived from the hematopoietic stem cells and progenitor cells.The proliferation of abnormal progenitor cells and leukemia cells in bone marrow is characterized by inhibition of normal hematopoiesis.Exosomes are bilayer lipid vesicles with a diameter of 30～200nm,secreted by cells and containing active substances such as proteins or nucleic acids.Exosomes are primarily involved in cell-to-cell communication and are emerging as key modulators of hematopoiesis.Micro RNAs(miRNAs)are a class of 22 nt long single-stranded non-coding RNAs that have repeatedly been shown to be enriched in exosomes and play a role in the treatment of disease.Objective: This study aims to explore the role and mechanism of exosomes derived from human bone marrow mesenchymal stem cells(h BM-MSCs-Exo)in regulating proliferation and apoptosis of acute myeloid leukemia cell line THP-1.Methods:1.hBM-MSCs-Exo was isolated by ultra-centrifugation and administered into THP-1 cells to elucidate the effects of exosomes in THP-1 cells.The proliferation of THP-1 cells was detected by CCK-8,and the apoptosis was detected by flow cytometry.The expression of miR-222-3p,IRF2,and INPP4 B were measured by q RT-PCR and western blot.2.The interaction between miR-222-3p and IRF2 was analyzed by luciferase reporter assay.Results: 1.Lower cell viability rate,higher apoptosis ratio,higher miR-222-3p expression,and lower IRF2/INPP4 B expression were observed in THP-1 cells exposed to BM-MSCs-Exo.2.The proliferation-inhibitory and pro-apoptotic effects of BM-MSCs-Exo on THP-1cells were markedly compromised when miR-222-3p expression in BM-MSCs-Exo was inhibited.Furthermore,miR-222-3p directly targeted IRF2 and negatively regulated IRF2/INPP4 B signaling in THP-1 cells.Moreover,overexpression of either IRF2 or INPP4 B counteracted the proliferation-inhibitory and pro-apoptotic effects mediated by BM-MSCs-Exo.Conclusion:BM-MSCs delivered miR-222-3p via exosomes to inhibit cell proliferation and promote cell apoptosis by targeting IRF2 and negatively regulating IRF2/INPP4 B signaling in THP-1 cells.