MicroRNAs of bone marrow mesenchymal stem cell-derived exosomes regulate acute myeloid leukemia cell proliferation and apoptosis

Abstract

Background: Acute myeloid leukemia (AML) is a malignant hematological disease, originating from hematopoiesis stem cell differentiation obstruction and clonal proliferation. New reagents or biologicals for the treatment of AML are urgently needed, and exosomes have been identified as candidate biomarkers for disease diagnosis and prognosis. This study aimed to investigate the effects of exosomes from bone marrow mesenchymal stem cells (BMSCs) on AML cells as well as the underlying microRNA (miRNA)-mediated mechanisms. Methods: Exosomes were isolated using a precipitation method, followed by validation using marker protein expression and nanoparticle tracking analysis. Differentially expressed miRNAs were identified by deep RNA sequencing and confirmed by quantitative real-time polymerase chain reaction (qPCR). Cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt method, and cell cycle progression and apoptosis were detected by flow cytometry. Functional gene expression was analyzed by qPCR and Western blotting (WB). Significant differences were determined using Student's t test or analysis of variance. Results: BMSCs-derived exosomes effectively suppressed cell proliferation (both P < 0.0001 at 10 and 20 μg/mL) and cell cycle progression (P < 0.01 at G0–G1 stage), and also significantly enhanced cell apoptosis (P < 0.001) in KG-1a cells. There were 1167 differentially expressed miRNAs obtained from BMSCs-derived exosomes compared with KG-1a cell-derived exosomes (P < 0.05). Knockdown of hsa-miR-124-5p in BMSCs abrogated the effects of BMSCs-derived exosomes in regulating KG-1a such as the change in cell proliferation (both P < 0.0001 vs. normal KG-1a cell [NC] at 48 and 72 h). KG-1a cells treated with BMSCs-derived exosomes suppressed expression of structural maintenance of chromosomes 4 (P < 0.001 vs. NC by qPCR and P < 0.0001 vs. NC by WB), which is associated with the progression of various cancers. This BMSCs-derived exosomes effect was significantly reversed with knockdown of hsa-miR-124-5p (P < 0.0001 vs. NC by WB). Conclusions: BMSCs-derived exosomes suppress cell proliferation and cycle progression and promote cell apoptosis in KG-1a cells, likely acting through hsa-miR-124-5p. Our study establishes a basis for a BMSCs-derived exosomes-based AML treatment.

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

“…By contrast, EVs derived from healthy MSCs (HD-MSC-EVs) suppress cell proliferation and promote apoptosis in KG-1a cells, likely acting through miR-124-5p [ 49 ]. HD-MSC-EVs transfer miR-222-3p to THP-1 cells and exert pro-apoptotic effects targeting the IRF2/INPP4B signaling pathway [ 50 ]. However, in another study HD-MSC-EVs promote resistance to cytarabine via the upregulation of S100A4, a calcium-binding protein with a prominent role in tumorigenesis [ 51 ].…”

Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11

“…BMSCs are used as important seed cells for tissue engineering because of their multipotency, immunomodulatory, and differentiative functions [ 39 ]. BMSCs regulate the bone marrow microenvironment of AML through the paracrine pathway, with exosomes being the main paracrine substances in BMSCs [ 40 ]. Exosomes are considered a novel intercellular signaling modality harboring miRNAs that can be transferred to recipient cells, which in turn regulate the expression of targeted genes in the cells [ 41 ].…”

“…In another study, exosomal miR-139-5p derived from BMSCs inhibited bladder carcinogenesis by targeting PRC1 [ 34 ]. Similarly, exosome-secreted miR-124-5p promoted apoptosis in AML by inhibiting the expression of BMSCs [ 40 ].…”

Human Bone Marrow-Derived Mesenchymal Stem Cell-Secreted Exosomes Overexpressing Microrna-124-3p Inhibit DLBCL Progression By Downregulating  NFATc1

“…In recent years, MSC-derived exosomes transfected with miRNAs have been shown to play essential roles in tumorigenesis and can serve as mediators in human cancers. Several studies have reported that exosomes released from bone marrow mesenchymal stem cells (MSCs) can carry microRNAs (miRNAs), which are involved in cancer cell proliferation, differentiation, and apoptosis [26][27][28]. However, the effect of human BMSC (hBMSC)-derived exosomes on the occurrence and progression of DLBCL remains poorly understood.…”