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Hematopoiesis
Megakaryocyte volume modulates bone marrow niche properties and cell migration dynamics
Maximilian G. Gorelashvili,1* Oğuzhan Angay,2* Katherina Hemmen,2 Vanessa Klaus,1 David Stegner1,2 and Katrin G. Heinze2
1Institute of Experimental Biomedicine, University Hospital Würzburg and 2Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
*MGG and OA contributed equally to this work
ABSTRACT
All hematopoietic cells that develop in the bone marrow must cross the endothelial barrier to enter the blood circulation. Blood platelets, however, are released by bigger protrusions of huge pro- genitor cells, named megakaryocytes, and enter the blood stream as so- called proplatelets before fragmenting into mature platelets. Recently, a second function of megakaryocytes has been identified, as they modu- late the quiescence of hematopoietic stem cells, mostly via different sol- uble factors. We know from light sheet fluorescence microscopy images that megakaryocytes are distributed throughout the bone marrow facing a dense vascular network. Here, we used such three-dimensional images to provide a realistic simulation template reflecting the in vivo cell-vessel distributions resulting in reliable whole-bone analysis in silico. Combining this approach with an automated image analysis pipeline, we found that megakaryocytes influence migration of neutrophils and hematopoietic stem cells, and thus act as biomechanical restrainers mod- ulating cell mobility and extravasation. Indeed, as a consequence of increased megakaryocyte volumes in platelet-depleted mice neutrophil mobility was reduced in these animals.
Introduction
Hematopoiesis is the process of forming blood cells, which occurs predominant- ly in the bone marrow (BM). During this process, hematopoietic stem cells (HSC) undergo lineage restriction and differentiate into restricted hematopoietic progeni- tors, which then give rise to blood cells by proliferation and further differentiation.
During the last decade, the identification of new HSC markers, development of genetically modified mouse strains and microscopy techniques enabled the identi- fication and intensive investigation of the perivascular niche as the major site of HSC localization and activity, where 80% of HSC were found to be associated with sinusoids, 10% with arterioles and a further 10% with transition zone ves- sels.1-4 The perivascular niche has been determined to be a microenvironment con- taining different cell types and signaling molecules, together regulating HSC main- tenance, quiescence, proliferation, differentiation and migration.5-8
Blood cells differentiated from HSC leave the BM by migrating towards the sinu- soids to enter the circulation.9 In general, many of these migratory processes are chemotactic, i.e. driven by chemoattractants.9 One of the most prominent cell types of the BM are neutrophils, which are the most abundant subpopulation of leuko- cytes; neutrophils have a short lifespan (6-12 h) in the circulation, after which they quickly migrate to tissues where they perform their functions.10 Neutrophil home- ostasis is orchestrated through a balance of neutrophil production and release from BM into the blood and migration back into the BM for elimination.11 The neutrophil reserve within the BM is estimated to be 6×1011 in humans and 12×107 in mice.10,12
Megakaryocytes are derived from multipotent HSC and belong to the myeloid cell lineage.13 Megakaryocytes mainly reside in the BM, mostly in close proximity
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):895-904
Correspondence:
KATRIN HEINZE katrin.heinze@virchow.uni-wuerzburg.de
DAVID STEGNER stegner@virchow.uni-wuerzburg.de
Received: July 15, 2018. Accepted: June 25, 2019. Pre-published: June 27, 2019.
doi:10.3324/haematol.2018.202010
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/895
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