Emerging roles of extracellular vesicles in normal and malignant hematopoiesis

Abstract

Hematopoietic stem cells, regulated by their microenvironment (or “niche”), sustain the production of mature blood and immune cells. Leukemia cells remodel the microenvironment to enhance their survival, which is accompanied by the loss of support for normal hematopoiesis in hematologic malignancies. Extracellular vesicles (EVs) mediate intercellular communication in physiological and pathological conditions, and deciphering their functions in cell-cell interactions in the ecosystem can highlight potential therapeutic targets. In this Review, we illustrate the utility of EVs derived from various cell types, focusing on the biological molecules they contain and the behavioral alterations they can induce in recipient cells. We also discuss the potential for clinical application in hematologic malignancies, including EV-based therapeutic regimens, drug delivery via EVs, and the use of EVs (or their cargoes) as biomarkers.

Leukemogenesis occurs in a microenvironment enriched by extracellular microvesicles/exosomes: recent discoveries and questions to be answered

“…By analogy to physiological hematopoiesis, we learned that ExMVs also play an essential role in leukemia, and we will focus on this topic in this review. Briefly, ExMVs can affect the proliferation and survival of leukemic cells, modulate the hematopoietic microenvironment to support leukemia cell expansion, contribute to immune escape by malignant cells, and promote chemotherapy resistance [ 12 , 24 – 27 , 30 , 31 ]. On the other hand, they could play a role in diagnosing hematopoietic malignancies as they express potential biomarkers and even be modified as drug carriers for therapy [ 22 , 32 – 34 ].…”

“…These effects are mediated by surface-expressed ligands or the content of fused or internalized inside cargo. Accordingly, ExMVs may (i) interact with cell surface receptors, (ii) fuse with target cells to release their cargo into the cytosol, or (iii) they can be internalized [ 8 , 27 , 29 , 30 , 33 , 34 , 45 ]. The first two mechanisms are the most important, as internalization may lead to lysosomal degradation of ExMVs content.…”

Non-Classical Intercellular Communications: Basic Mechanisms and Roles in Biology and Medicine

“…Although the roles of paracrine signaling and adhesive interactions in HSC-niche intercellular interactions are firmly established (see, for example [ 83 , 87 , 88 , 89 ]), the roles of various types of non-classical communications remain to be elucidated. Nevertheless, it has been reliably established that a significant role in the modulation of the bone marrow niche is played by extracellular vesicles that can change the biology of HSCs and progenitor cells [ 90 , 91 ]. Ex vivo studies show that MSC microvesicles contain effector molecules, including Wnt and Hedgehog morphogens, which regulate SC self-renewal, proliferation and differentiation [ 92 , 93 ].…”

The Role of Extracellular Vesicles in the Pathogenesis of Hematological Malignancies: Interaction with Tumor Microenvironment; a Potential Biomarker and Targeted Therapy

“…More often, tumor-EVs have been shown to activate the endothelial cells, contributing to tumor angiogenesis, whereas endothelial EVs in the TME induce tumor cells to remodel ECM components, thereby providing supplements for the growth of the tumor [ 157 ]. For example, EV-mediated transfer of VEGF and VEGF receptor from AML to endothelial cells promotes endothelial glycolysis, leading to vascular remodeling and chemoresistance [ 158 , 159 ]. Multiple signaling pathways appear to be regulated in MM, leading to increased viability of a bone marrow endothelial cell line (STR10), enhanced, angiogenesis and immunosuppression, further facilitating the progression of MM [ 120 , 159 ].…”