Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications

Abstract

Interactions between chronic lymphocytic leukemia (CLL) B cells and the bone marrow (BM) microenvironment play a major function in the physiopathology of CLL. Extracellular vesicles (EVs), which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in CLL / microenvironment interactions. In the present study, EVs purified by ultracentrifugation from BM mesenchymal stromal cell (BM-MSC) cultures were added to CLL B cells. After their integration into CLL B cells, we observed a decrease of leukemic cell spontaneous apoptosis and an increase in their chemoresistance to several drugs, including fludarabine, ibrutinib, idelalisib and venetoclax after 24 hours. Spontaneous (P=0.0078) and stromal cell-derived factor 1α -induced migration capacities of CLL B cells were also enhanced (P=0.0020). A microarray study highlighted 805 differentially expressed genes between leukemic cells cultured with or without EVs. Of these, genes involved in the B-cell receptor pathway such as CCL3/4, EGR1/2/3, and MYC were increased. Interestingly, this signature presents important overlaps with other microenvironment stimuli such as B-cell receptor stimulation, CLL/nurse-like cells co-culture or those provided by a lymph node microenvironment. Finally, we showed that EVs from MSCs of leukemic patients also rescue leukemic cells from spontaneous or drug-induced apoptosis. However, they induce a higher migration and also a stronger gene modification compared to EVs of healthy MSCs. In conclusion, we show that EVs play a crucial role in CLL B cells/BM microenvironment communication.

Amorphous polyphosphate, a smart bioinspired nano-/bio-material for bone and cartilage regeneration: towards a new paradigm in tissue engineering

“…Furthermore, both direct cell-cell contact through nurse cells 212 and even extracellular vesicles affect the differentiation direction of the MSC. 213 Those vesicles are abundantly present around SaOS-2 and HUVEC cells. 214 In addition, it has been shown that the topology of the surrounding matrices controls the gene expression systems within MSCs and in turn also the phenotype of the differentiated cells.…”

Biology and therapeutic potential of mesenchymal stem cell‐derived exosomes

“…Bone marrow mesenchymal stem cell‐derived exosomes are reported to act as communicators during drug treatment. Transcriptomic profiles further demonstrated that the underlying mechanism was through the enhancement of cell migration and induction of relevant gene expression, such as Ccl3/4 , Ccl4 and Cxcr4 59 . In addition, it was found that exosomes were able to promote breast cancer cell metastasis through the transfer of miRNA‐23b and to suppress target Marcks mRNA expression 60 .…”

miR-221-3p Delivered by BMMSC-Derived Microvesicles Promotes the Development of Acute Myelocytic Leukemia

“…In the present study, we found that miR-221-3p was highly expressed in BMMSC-derived MVs. Besides, it has been reported that bone marrow stromal cell-derived MVs can attenuate the B cell apoptosis in chronic lymphocytic leukemia, also promote cell migration and induce gene expression and modification (Crompot et al, 2017). Hence, this study focused attention on the BMMSC MVs-derived miR-221-3p.…”

“…Studies have found that tumor-derived MVs (TMV) can interact directly with tumor cells and play a macro-messenger role to promote the transfer of molecular substances between tumor cells to facilitate tumor growth (Stec et al, 2015a,b). MVs derived from bone marrow mesenchymal stem cell (BMMSC) can promote tumorigenesis and development (Crompot et al, 2017;Boyiadzis and Whiteside, 2018). miRNAs in MVs, as post-transcriptional regulatory elements, directly regulate gene expression, target mRNA expression and translation or induce mRNA degradation to reduce protein synthesis by directly binding with the 3 ′ -untranslation region (3 ′ -UTR) of specific mRNA targets (Braicu et al, 2015;Jerez et al, 2019), ultimately induce multiple pathophysiological processes, such as leukemia stem cell formation, regulation of tumor cell proliferation, angiogenesis, invasion, metastasis, and immune escape to modulate leukemia development (Braicu et al, 2015;Del Principe et al, 2017).…”