Extracellular vesicles in the hematopoietic microenvironment

Self-renewal and differentiation are defining characteristics of hematopoietic stem and progenitor cells, and their balanced regulation is central to lifelong function of both blood and immune systems. In addition to cell intrinsic programs, hematopoietic stem and progenitor cells fate decisions are subject to extrinsic cues from within the bone marrow microenvironment and systemically. Yet, many of the paracrine and endocrine mediators that shape hematopoietic function remain to be discovered. Extracellular vesicles serve as evolutionarily conserved, constitutive regulators of cell and tissue homeostasis, with several recent reports supporting a role for extracellular vesicles in the regulation of hematopoiesis. Researchers from the Papé Family Pediatric Research Institute discuss the physiological and pathophysiological effects that extracellular vesicles have on bone marrow compartmental function while highlighting progress in understanding vesicle biogenesis, cargo incorporation, differential uptake and downstream effects of vesicle internalization. This review further touches on the role of extracellular vesicles in hematopoietic stem and progenitor cells fate regulation and recent advances in therapeutic and diagnostic applications of extracellular vesicles in hematological disorders.

Unresolved aspects of extracellular vesicle biology in the regulation of hematopoiesis

(A) EVs have been proposed to enter recipient cells through lipid raft-mediated internalization, endocytosis, phagocytosis, membrane fusion, caveolin-mediated endocytosis and macropinocytosis. (B) Exosome-mediated crosstalk may explain the intercellular competition of neighboring cells where the “winner” HSPC outcompetes the less fit HSPC through a P53-dependent mechanism. (C) Vesicles contain cargo comprised of uniquely packaged proteins, miRNAs and RNAs which serve as promising biomarkers for disease detection. (D) Vesicles from HSPCs and other cells of the bone marrow niche have been shown to exhibit preferential targeting to specific recipient cells for entry. (E) Cytonemes (filopodia, invadopodia, tunneling nanotubes) are cytoplasmic extensions that serve as modes of exosomal transfer to adjacent bystander cells. EVs: extracellular vesicles; HSPC: hematopoietic stem and progenitor cell.