CXCL12-Abundant Reticular (CAR) Cells Direct Megakaryocyte Protrusions across the Bone Marrow Sinusoid Wall.

Nicole Wagner,Kristina Mott,Berin Upcin,Harald Schulze,David Stegner,Süleyman Ergün

doi:10.3390/cells10040722

Nicole Wagner, Kristina Mott + Show 4 more

Open Access

https://doi.org/10.3390/cells10040722

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Journal: Cells	Publication Date: Mar 24, 2021
Citations: 6	License type: CC BY 4.0

Affiliation: University of Würzburg, University Hospital Würzburg

Abstract

Megakaryocytes (MKs) release platelets into the lumen of bone marrow (BM) sinusoids while remaining to reside within the BM. The morphogenetic events of this complex process are still not fully understood. We combined confocal laser scanning microscopy with transmission and serial block-face scanning electron microscopy followed by 3D-reconstruction on mouse BM tissue sections. These analyses revealed that MKs in close vicinity to BM sinusoid (BMS) wall first induce the lateral retraction of CXCL12-abundant reticular (CAR) cells (CAR), followed by basal lamina (BL) degradation enabling direct MK-sinusoidal endothelial cells (SECs) interaction. Subsequently, an endothelial engulfment starts that contains a large MK protrusion. Then, MK protrusions penetrate the SEC, transmigrate into the BMS lumen and form proplatelets that are in direct contact to the SEC surface. Furthermore, such processes are induced on several sites, as observed by 3D reconstructions. Our data demonstrate that MKs in interaction with CAR-cells actively induce BMS wall alterations, including CAR-cell retraction, BL degradation, and SEC engulfment containing a large MK protrusion. This results in SEC penetration enabling the migration of MK protrusion into the BMS lumen where proplatelets that are adherent to the luminal SEC surface are formed and contribute to platelet release into the blood circulation.

Highlights

[1] In vivo, several additional aspects of platelet biogenesis are required: (i) The MK has to be located at the vessel wall and needs to polarize to avoid ectopic platelet release into the bone marrow (BM) cavity; (ii) the MKs are in steady contact to components of the extracellular matrix (ECM), including collagen, which are strong platelet agonists; (iii) proplatelet protrusions need to cross the endothelium that constitutes the blood-BM barrier
The BM compartment is the main reservoir to provide all blood cells, in order to replenish old and exhausted cells, as well as to produce cells on demand to compensate for blood loss, bleedings or infections
The BM provides all blood cell precursors before mature cells are released into the blood stream

Summary

Introduction

The transition of a megakaryocyte (MK) into proplatelets and platelets in vitro has been deciphered and studied extensively during the last two decades since the seminal report by Italiano et al [1] In vivo, several additional aspects of platelet biogenesis are required: (i) The MK has to be located at the vessel wall and needs to polarize to avoid ectopic platelet release into the bone marrow (BM) cavity; (ii) the MKs are in steady contact to components of the extracellular matrix (ECM), including collagen, which are strong platelet agonists; (iii) proplatelet protrusions need to cross the endothelium that constitutes the blood-BM barrier. Brown et al showed that protruding MKs lose their organelle-free or marginal zone (MZ) and have anchoring points at the sinusoid wall during the passage. [7] Eckly et al demonstrated that podosome-like structures contribute to the MK transendothelial passage through newly formed endothelial pores [8]

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