Extracellular Vesicles and MicroRNA in Myelodysplastic Syndromes

Abstract

The bone marrow niche plays an increasing role in the pathophysiogenesis of myelodysplastic syndromes. More specifically, mesenchymal stromal cells, which can secrete extracellular vesicles and their miRNA contents, modulate the fate of hematopoietic stem cells leading to leukemogenesis. Extracellular vesicles can mediate their miRNA and protein contents between nearby cells but also in the plasma of the patients, being potent tools for diagnosis and prognostic markers in MDS. They can be targeted by antisense miRNA or by modulators of the secretion of extracellular vesicles and could lead to future therapeutic directions in MDS.

Keywords: bone marrow niche; exosomes; extracellular vesicles; miRNA; microvesicles; myelodysplastic syndromes; non-coding RNA.

Figure 1

Definition of exosomes and microvesicles in the context of MSC to HSC communication. Large EVs or microvesicles are released during cell-surface budding, while smaller EVs or exosomes are derived from the endosomal pathway. All cells produce EVs. Here, we show the example of EV production by mesenchymal cells because they play an important role in hematopoiesis and are in close interaction with hematopoietic stem cells (HSC). EVs are an important means of communication between cells and deliver signals in the form of nucleic acids, including miRNAs, lipids, proteins, or metabolites. The mechanisms of non-viral EV transfer are not yet fully elucidated. EVs may have ligands capable of binding to corresponding receptors on target cells. These trigger signaling cascades and can induce receptor-mediated endocytosis. Despite the fact that the mechanisms by which receptor cells take up exosomes have not been fully elucidated, there are some studies demonstrating that integrins, lectins/proteoglycans, T cell immunoglobulin, and mucin structural domain protein 4 (Tim4) may contribute to cellular targeting specificity [25,26]. EV entry may also involve endocytosis mediated by clathrin-coated pits, lipid rafts, phagocytosis, caveolae, and micropinocytosis [27]. Finally, the entry of EV contents may also involve membrane fusion or macropinocytosis to spill their contents into the cytoplasm. Thus, bioactive molecules contained in EVs can also be transferred into the cytoplasm of the target cell and exert activity there. EVs can also simply be degraded, thus, becoming a source of nutrients for the recipient cells [28]. Moreover, EVs can mediate the interaction of secretory cells with the surrounding extracellular matrix (ECM). In mainly tumor contexts, EVs were shown to function also in long-distance communication.

Figure 2

Schema of the role of EVs and miRNA in the physiopathology of MDS. The hematopoietic niche is a complex structure that contains a number of different cell types: multipotent mesenchymal stem cells (MSCs) and their progeny, a complex vascular network, nerve fibers, mature blood cells, etc. These cell types modulate HSC function and are frequently disrupted or even abnormal in the context of malignancies. It was shown that the components of the bone marrow niche and the HSC communicate in different ways, including: intercellular communication, cytokines, growth factors, mitochondria, and extracellular vesicles. In the context of the evolution of hematopoiesis during MDS development, the exchange/communication delivered by EVs and their miRNA content may influence genetic remodeling.