Multiple Myeloma-Derived Exosomes Regulate the Functions of Mesenchymal Stem Cells Partially via Modulating miR-21 and miR-146a

Abstract

Exosomes derived from cancer cells can affect various functions of mesenchymal stem cells (MSCs) via conveying microRNAs (miRs). miR-21 and miR-146a have been demonstrated to regulate MSC proliferation and transformation. Interleukin-6 (IL-6) secreted from transformed MSCs in turn favors the survival of multiple myeloma (MM) cells. However, the effects of MM exosomes on MSC functions remain largely unclear. In this study, we investigated the effects of OPM2 (a MM cell line) exosomes (OPM2-exo) on regulating the proliferation, cancer-associated fibroblast (CAF) transformation, and IL-6 secretion of MSCs and determined the role of miR-21 and miR-146a in these effects. We found that OPM2-exo harbored high levels of miR-21 and miR-146a and that OPM2-exo coculture significantly increased MSC proliferation with upregulation of miR-21 and miR-146a. Moreover, OPM2-exo induced CAF transformation of MSCs, which was evidenced by increased fibroblast-activated protein (FAP), α-smooth muscle actin (α-SMA), and stromal-derived factor 1 (SDF-1) expressions and IL-6 secretion. Inhibition of miR-21 or miR-146a reduced these effects of OPM2-exo on MSCs. In conclusion, MM could promote the proliferation, CAF transformation, and IL-6 secretion of MSCs partially through regulating miR21 and miR146a.

miR‐146a‐5p: Expression, regulation, and functions in cancer

“…Coculture of OPM2 cells with MSCs resulted in both upregulation of miR‐146a and higher proliferation rates in MSCs. MSC transformation into CAFs was also induced by this coculture (Cheng et al, ).…”

Intranasal delivery of mesenchymal stem cell‐derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post‐deprivation relapse drinking.

“…The pellets were washed with PBS and ultracentrifuged again as previously described (Cheng et al . ). Exosome pellets were diluted in filtered saline, and exosome protein concentration was determined by a MicroBCA Protein Assay kit (Thermo Scientific, Rockford, IL).…”

Approaches to mimic the complexity of the skeletal mesenchymal stem/stromal cell niche in vitro

“…Increased megakaryocyte numbers in the BM are associated with elevated BMP-2, -4, and -6 in mice and are followed by stimulation of MSC osteogenesis (Garimella et al, 2007). While osteoblast maturation and skeletal homeostasis might be supported by megakaryocyte (Alvarez et al, 2018;Kacena et al, 2006), data regarding the effects on osteoclastogenesis suggest inhibitory effects of megakaryocyte on osteoclast development and functions (Beeton et al, 2006;Ciovacco et al, 2010;Kim et al, 2018). In vitro studies show that www.ecmjournal.org monocytes can induce osteogenesis in MSCs through cell contact, which leads to the activation of STAT3 signaling followed by upregulation of Runx2, ALP, and Oncostatin M and downregulation of DKK1 in MSCs (Nicolaidou et al, 2012).…”

“…MSCs can facilitate monocyte to macrophage transition, but attenuate (Vasandan et al, 2016) or favor their pro-inflammatory and osteoclastic activities (Gamblin et al, 2014). MSCs induce a M2 phenotype in BM-Mɸ, increasing their expression of arginase-1, IL-10, IL-4, and CD206 and decreasing the expression of IL-6, MCP-1, and iNOS (Cho et al, 2014;Takizawa et al, 2017). Through the production of major osteoclastogenic [e.g., RANKL (Biswas et al, 2018) and M-CSF (Cappellen et al, 2002)] and anti-osteoclastogenic factors [e.g., OPG (Oshita et al, 2011)], MSCs control bone resorption and remodeling (Sharaf-Eldin et al, 2016).…”

“…Exosomal transfer of miRNAs from MSCs to breast DCCs (Ono et al, 2014) induces MSCs dormancy in the BM niche. Moreover, multiple-myeloma-cell-derived exosome miRNA promotes a phenotype switch of MSCs towards a cancer-associated fibroblast state (Cheng et al, 2017). Concerning tumor persistence, there is a complex bidirectional crosstalk of MSCs and cancer cells involving various mechanisms which are still unclear but important for the understanding of peculiarities of normal and stem cell niche in tumors.…”