Microvesicles derived from normal and multiple myeloma bone marrow mesenchymal stem cells differentially modulate myeloma cells’ phenotype and translation initiation

Abstract

Multiple myeloma (MM) cells' interaction with the bone marrow (BM) microenvironment critically hinders disease therapy. Previously, we showed that MM co-culture with BM-mesenchymal stem cells (MSCs) caused co-modulation of translation initiation (TI) and cell phenotype and implicated secreted components, specifically microvesicles (MVs). Here, we studied the role of the BM-MSCs [normal donors (ND) and MM] secreted MVs in design of MM cells' phenotype, TI and signaling. BM-MSCs' MVs collected from BM-MSCs (MM/ND) cultures were applied to MM cell lines. After MVs uptake confirmation, the MM cells were assayed for viability, cell count and death, proliferation, migration, invasion, autophagy, TI status (factors, regulators, targets) and MAPKs activation. The interdependence of MAPKs, TI and autophagy was determined (inhibitors). ND-MSCs MVs' treated MM cells demonstrated a rapid (5 min) activation of MAPKs followed by a persistent decrease (1-24 h), while MM-MSCs MVs' treated cells demonstrated a rapid and continued (5 min-24 h) activation of MAPKs and TI (↑25-200%, P < 0.05). Within 24 h, BM-MSCs MVs were internalized by MM cells evoking opposite responses according to MVs origin. ND-MSCs' MVs decreased viability, proliferation, migration and TI (↓15-80%; P < 0.05), whereas MM-MSCs' MVs increased them (↑10-250%, P < 0.05). Inhibition of MAPKs in MM-MSCs MVs treated MM cells decreased TI and inhibition of autophagy elevated cell death. These data demonstrate that BM-MSCs MVs have a fundamental effect on MM cells phenotype in accordance with normal or pathological source implemented via TI modulation. Future studies will aim to elucidate the involvement of MVs-MM receptor ligand interactions and cargo transfer in our model.

The effect of simultaneous administration of arsenic trioxide and microvesicles derived from human bone marrow mesenchymal stem cells on cell proliferation and apoptosis of acute myeloid leukemia cell line

“…Therefore, conveying of mRNA and microRNA of MSCs-MV induces dynamic regulation in recipient cells, subsequently the transferred mRNA is translated into protein in target cells [36,37]. In another study, Dabbah et al [38] In this study, we investigated the effect of ATO in combination with MSCs-MV on NB4 cells compared to the treatment with each agent alone. The cell viability rates were completely dose-dependent.…”

A Novel Positive Feedback Loop Between NTSR1 and Wnt/β-Catenin Contributes to Tumor Growth of Glioblastoma

“…For instance, β-catenin and Tcf mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/Ephrin-B [18]. In human colonic adenomas, NTSR1 gene activation was perfectly correlated with nuclear or cytoplasmic beta-catenin localization [14]. Recently, Kim et al demonstrated that NTS itself was a direct target for Wnt/β-catenin signaling in neuroendocrine tumor cells in addition to NTSR1.…”

“…Activation of Wnt/β-catenin signaling leads to stabilization and nuclear translocation of β-catenin, which further activates T-cell factor/lymphoid enhancer-binding factor (TCF/LEF)-dependent transcription of downstream target genes. Recently, it has been demostrated that NTSR1 is a direct target of the Wnt/APC oncogenic pathways connected with the β-catenin/Tcf transcriptional complex [14]. And excitingly, NTS is also a direct target of the Wnt/β-catenin pathway and may be a mediator for neuroendocrine tumor cell growth [4].…”

The role of microvesicles and its active molecules in regulating cellular biology

“…Different environmental stimuli can not only change the number of particles, but also change the active ingredients carried by particles. An interesting study revealed that the co‐culture of normal bone marrow mesenchymal cell–derived MVs with multiple myeloma cells can reduce the viability, proliferation and migration of multiple myeloma cells, while MVs from multiple myeloma patients can enhance these biological effects . This shows that MVs produced in diseases are not only different in number from the normal state, but also have different biological effects.…”

“…14 An interesting study revealed that the co-culture of normal bone marrow mesenchymal cell-derived MVs with multiple myeloma cells can reduce the viability, proliferation and migration of multiple myeloma cells, while MVs from multiple myeloma patients can enhance these biological effects. 15 This shows that MVs produced in diseases are not only different in number from the normal state, but also have different biological effects. The main reason for these different effects is correlated to the changes in bioactive components carried by MVs.…”