Bone marrow stromal cell-derived exosomes facilitate multiple myeloma cell survival through inhibition of the jnk pathway

Jinheng Wang, An Hendrix, Elke De Bruyne, Els Van Valckenborgh, Eddy Himpe, Nathan De Beule, Olivier De Wever, Karin Vanderkerken, Eline Menu

Onderzoeksoutput: Meeting abstract (Journal)

Samenvatting

Interplay between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells plays a crucial role in MM pathogenesis by exchanging growth factors, cytokines, and other functional components. Exosomes are 30–100nm diameter membranous vesicles and mediate local cell-cell communication by transferring mRNAs, miRNAs, and proteins. Although the promotion of MM survival induced by BMSCs has been studied, the role of BMSC-derived exosomes in this action remains unclear. Here, we investigated the effect and mechanisms of murine BMSC-derived exosomes on the proliferation and survival of MM cells using the murine 5T33MM model.

Exosomes were isolated from conditioned medium after culture of primary BMSCs obtained from naïve C57BL/KaLwRij mice or 5T33MM diseased mice. The size of exosomes derived from naïve BMSCs, 5T33 BMSCs or 5T33MMvt cells were confirmed using a NanoSight LM10. Several exosomal markers such as CD63, Flotillin-1, heat shock protein 90 (HSP90), and HSP70 were detected. Both naïve and 5T33 BMSC-derived exosomes could fuse with 5T33MMvt cells. Several cytokines were found to be present in BMSC- and MMvt cell-derived exosomes. Both naïve and 5T33 BMSC-derived exosomes increased 5T33MMvt and MMvv cell viability and BrdU uptake. Significantly reduced apoptosis of 5T33 MMvt and MMvv cells were observed after exosomes’ treatment. Bcl-2 was increased and activated (cleaved) caspase-3 was reduced after co-culture with BMSC-derived exosomes. Reduced phosphorylation of p53, p38MAPK and JNK were detected after naïve BMSC-derived exosomes treatment, whereas 5T33 BMSC-derived exosomes didn’t change the activation of p53 and p38MAPK. 5T33 BMSC-derived exosomes further decreased the activation of JNK, Bim expression and phosphorylated Bim compared to naïve BMSC-derived exosomes. As Bim is a pro-apoptosis protein and mainly regulated by the JNK pathway, promotion of MM cell survival likely results from the inhibition of the JNK pathway by BMSC-derived exosomes. In summary, our results demonstrate a positive role for BMSC-derived exosomes in induction of MM cell proliferation and survival. BMSC-derived exosomes could inhibit the JNK pathway, thereby reducing caspase-3 activation and protecting MM cells from apoptosis.
Originele taal-2English
Pagina's (van-tot)27-28
Aantal pagina's2
TijdschriftBelg. J. Hematol.
StatusPublished - jan 2014

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