Extracellular Vesicles Derived from Human Bone Marrow Stem Cells Inhibit Acute Lymphoblastic Leukemia Cell Growth by Inhibiting MAPK Pathway via the miR-29b-3p/GDF15 Axis

Abstract

Introduction: Acute lymphoblastic leukemia (ALL) is a common hematologic neoplastic disease. This study discussed the effect of extracellular vesicles (EVs) released from bone marrow mesenchymal stem cells (BMSCs) on ALL cells and the mechanism. Methods: BMSCs-EVs were isolated by differential centrifugation and identified. The effect of BMSCs-EVs on ALL cell proliferation and apoptosis was evaluated. The expression of miR-29b-3p in ALL cells and EVs was detected. The uptake of EVs by ALL cells was observed. The effect of miR-29b-3p on ALL cell proliferation and apoptosis was assessed after silencing miR-29b-3p. The targeting relation of miR-29b-3p and GDF15 was analyzed by bioinformatics website and dual-luciferase assay. The role of GDF15 in proliferation and apoptosis of ALL cells was further confirmed, and Western blot assay was performed to measure MAPK pathway-related protein levels. Results: BMSC-derived EVs inhibited proliferation and promoted apoptosis of ALL cells, as shown by the up-regulation of caspase-3 and Bax expressions and down-regulation of Bcl-2 expression. EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p expression in ALL cells, and inhibited GDF15 expression. Silencing of miR-29b-3p or overexpression of GDF15 partially reversed the effect of EVs. EVs inhibited the MAPK pathway through the miR-29b-3p/GDF15 axis. Conclusion: BMSCs-EVs carried miR-29b-3p into ALL cells, upregulated miR-29b-3p, and inhibited GDF15 to suppress the MAPK pathway and further inhibit proliferation and promote apoptosis of ALL cells.