Page 22 - Haematologica3

Correspondence:
kurrepe@ohsu.edu
Received: November13,2017. Accepted: January 18, 2018. Pre-published: February 8, 2018.
doi:10.3324/haematol.2017.183335
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Extracellular vesicles in the hematopoietic microenvironment
John T. Butler,1,2 Sherif Abdelhamed1 and Peter Kurre1,3
1Department of Pediatrics, Papé Family Pediatric Research Institute, Pediatric
Blood & Cancer Biology Program, Oregon Health & Science University; 2Department of Biomedical Engineering, Oregon Health & Science University and 3OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
ABSTRACT
Self-renewal and differentiation are defining characteristics of hematopoietic stem and progenitor cells, and their balanced regula- tion is central to lifelong function of both blood and immune sys- tems. In addition to cell-intrinsic programs, hematopoietic stem and pro- genitor cell 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 con- served, constitutive regulators of cell and tissue homeostasis, with several recent reports supporting a role for extracellular vesicles in the regulation of hematopoiesis. We review 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 vesi- cle internalization. This review also touches on the role of extracellular vesicles in hematopoietic stem and progenitor cell fate regulation and recent advances in therapeutic and diagnostic applications of extracellular vesicles in hematologic disorders.
Introduction
To fulfill its critical systemic functions in oxygen delivery, coagulation and immune defense, hematopoiesis is regulated via integration of cell-intrinsic pro- grams with extrinsic cues from the surrounding bone marrow (BM) microenviron- ment.1,2 Recent studies from infectious diseases, cardiovascular, and cancer fields demonstrate the existence of systemic crosstalk with BM cells which adds to the complexity of compartmental signaling, especially during injury responses.1,3 Cytokines, chemokines and other growth factors act as important mediators in a reasonably well-understood system by which the extrinsic ligands act on cells expressing the cognate receptor (Figure 1A). These in turn transmit signals to a net- work of cellular signaling pathways regulating hematopoiesis, including Wnt, Notch, transforming growth factor beta (TGF-β), phosphatidylinositol-3 kinase, and the mammalian target of rapamycin.4-7 Signaling by extrinsic mediators through any one of these pathways triggers activation of quiescent long-lived hematopoietic stem cells (HSCs). More recent studies of the leukemic microenvironment have revealed that tumor-derived paracrine factors also act on mesenchymal stromal cells, osteoprogenitors and endothelial cells within the BM, indirectly suppressing hematopoietic stem and progenitor cells (HSPCs).1,3,8 Thus, dynamic compartmental interactions shape physiological and pathophysiological regulation of BM function.
Extracellular vesicle (EV) biogenesis is a constitutive cellular process, broadly con- served across evolution, with a role in development, homeostatic organismal func- tion and tissue regeneration.9-11 EVs of various shapes and sizes have been demon- strated in every biofluid tested to date, with substantial variation in their structure, content and function.12 Protein, lipid and RNA components contribute to cell-cell crosstalk at a short distance, in a paracrine or endocrine manner via the blood-
Haematologica 2018 Volume 103(3):382-394
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