Page 32 - Haematologica3

392
J.T. Butler et al.
relying on “free” vesicle exchange (Figure 4E).46,95 Clearly, the development of experimental approaches that more closely resemble the physiological context should be a pri- ority for future studies.
In addition to hematopoietic regulation, the vesicles released by BM cells may play a central role in the estab- lishment and propagation of pathophysiological events outside the medullary space, ranging from promoting metastatic dissemination of melanoma cells, to priming inflammatory responses after cardiac injury.73,96 A mecha- nistic understanding of the EV-mediated crosstalk between tissues is currently lacking, and EV as carriers of cytokines, bioactive lipids and several classes of RNA may deserve greater consideration when systemic conditions affect BM function. For example, given the EV-mediated crosstalk between lymphocytes and antigen-presenting cells,11 or priming of an inflammatory phenotype in the BM by EV miRNA,97 it is not inconceivable that systemic inflammatory effects after cardiovascular injury or chronic stress conditions are similarly induced by EVs and their cargo.96 Such a systemic communication model finds fur- ther support in reports of BM-derived EV trafficking to the brain during experimentally induced systemic inflamma- tion.98
Finally, it is now widely accepted that EVs contribute to pathophysiological regulation, and the suppression of EV release in disease states may offer therapeutic benefit. However, while several of the molecular mechanisms involved in EV release have been described,24,99 broad sup- pression of EV release is an unlikely therapeutic goal given the role EVs play in maintaining homeostasis. Rather, a nuanced understanding of cell-specific biogenesis, cargo incorporation, and EV-recipient cell affinity may offer the insight necessary for more targeted and disease-specific
approaches. Further research into the identity of vesicle surface molecules that govern target cell specificity and route of cellular uptake will be critical in mapping the role that EVs play in regulating hematopoiesis (Figure 4A,D). Classifying these surface molecules may also prove useful for harnessing the potential of vesicles to deliver targeted therapeutics within the BM, or blocking the action of can- cer-derived EVs, in order to advance the treatment of hematologic disease. Additionally, the intracellular events that follow uptake are particularly poorly understood. Answering questions about miRNA copy number per EV, or intracellular EV processing, cargo unloading and vesicle degradation will be crucial to realize the therapeutic potential for modified EVs. Finally, understanding how different components of a given vesicle cooperatively alter the behavior of a cell, and whether vesicles with an iden- tical cell origin can differentially regulate multiple cell types in the niche, will be key to utilizing this complex biological process in order to create realistic therapeutics.
In sum, EVs offer fundamental new insight into the biol- ogy of HSC regulation, as well as translational opportuni- ties for mitigating injury, and opposing malignancy. Due to their constitutive role in regulating specific cell popula- tions within the marrow niche, and unique signatures, EVs could prove to be a powerful tool for advancing hematology, and be exploited to improve diagnosis, dis- ease monitoring and therapy.
Acknowledgments
We apologize to those investigators whose work we were unable to cite for space limitations. We recognize funding through the Hyundai Hope on Wheels Program (PK), Max Blue Butterfly Campaign (PK), the Medical Research Foundation of Oregon (SA) and we gratefully acknowledge contributions from Ben Doron.
References
1. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505(7483):327–334.
2. Pietras EM, Warr MR, Passegué E. Cell cycle regulation in hematopoietic stem cells. J Cell Biol. 2011;195(5):709–720.
S, Jablonski E, Sipkins DA. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progeni- tor cells. Science. 2008;322(5909):1861– 1865.
9. Johnstone RM. Exosomes biological signifi- cance: a concise review. Blood Cells Mol Dis. 2006;36(2):315–321.
10.Thomou T, Mori MA, Dreyfuss JM, et al. Adipose-derived circulating miRNAs regu- late gene expression in other tissues. Nature. 2017;542(7642):450–455.
11. Mittelbrunn M, Gutiérrez-Vázquez C, Villarroya-Beltri C, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2017;2:282.
12. Yáñez-Mó M, Siljander PR-M, Andreu Z, et al. Biological properties of extracellular vesi- cles and their physiological functions. J Extracell Vesicles. 2015;4(0):27066.
13. Hornick NI, Doron B, Abdelhamed S, et al. AML suppresses hematopoiesis by releasing exosomes that contain microRNAs targeting c-MYB. Sci Signal. 2016;9(444):ra88.
14.Kumar B, Garcia M, Weng L, et al. Acute myeloid leukemia transforms the bone mar- row niche into a leukemia-permissive microenvironment through exosome secre- tion. Leukemia. 2017 Aug 17. [Epub ahead of print]
15. Wolf P. The nature and significance of
platelet products in human plasma. Br J
Haematol. 1967;13(3):269–288.
16. Pan BT, Johnstone RM. Fate of the transfer-
rin receptor during maturation of sheep reticulocytes in vitro: selective externaliza- tion of the receptor. Cell. 1983;33(3):967– 978.
17. Goloviznina NA, Verghese SC, Yoon YM, Taratula O, Marks DL, Kurre P. Mesenchymal stromal cell-derived extracel- lular vesicles promote myeloid-biased multi- potent hematopoietic progenitor expansion via Toll-like receptor engagement. J Biol Chem. 2016;291(47): 24607–24617.
18.Geddings JE, Hisada Y, Boulaftali Y, et al. Tissue factor-positive tumor microvesicles activate platelets and enhance thrombosis in mice. J Thromb Haemost. 2016;14(1):153– 166.
19. Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J. Endothelial expression of autocrine VEGF upon the uptake of tumor- derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci USA. 2009;106 (10):3794–3799.
20.Hoshino A, Costa-Silva B, Shen T-L, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527 (7578):329–335.
21.Roccaro AM, Sacco A, Maiso P, et al. BM mesenchymal stromal cell-derived exo- somes facilitate multiple myeloma progres-
3.Schepers K, Campbell TB, Passegué E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell. 2015;16(3):254–267.
4. Blank U, Karlsson S. TGF-β signaling in the control of hematopoietic stem cells. Blood. 2015;125(23):3542–3550.
5. Yamazaki S, Iwama A, Takayanagi S-I, et al. Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells. EMBO. 2006;25(15):3515–3523.
6. Fleming HE, Janzen V, Celso Lo C, et al. Wnt signaling in the niche enforces hematopoiet- ic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008;2(3):274–283.
7.Yilmaz OH, Morrison SJ. The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic dif- ference between normal and cancer stem cells. Blood Cells Mol Dis. 2008;41(1):73–76.
8. Colmone A, Amorim M, Pontier AL, Wang
haematologica | 2018; 103(3)