The Marrow Sinus

The sinus is the exclusive site of exchange between the hematopoietic and the circulating blood. It is at this sole location that mature hematopoietic cells (polymorphs, platelets, and red cells) enter the circulation to finalize their life cycle as blood cells and that hematopoietic stem cells (HSCs) enter the marrow parenchyma during engraftment.

BM Sinus ECs: Molecular Aspects

BM sinus ECs express in a specific way a number of molecules. Some cell adhesion molecules (CAMs), such as E-selectin or vascular cell adhesion molecule-1 (VCAM-1), are expressed constitutively while in ECs from non-hematopoietic tissues, their expression is usually induced by proinflammatory cytokines. The heparan sulfate (HS) pro-teoglycans present on the luminal face of BM ECs bind, with an affinity depending on the sulfatation patterns of the composing disaccharides, chemotactic cytokines (chemokines), such as interleukin-8, macrophage inhibitory protein-1a (MIP-1a), growth-related activity-a(GRO-a), and stromal-derived factor 1 (SDF-1), known to be the major chemotactic factor for HSCs. A current model hypothesizes the existence of a SDF-1 gradient within the hematopoietic parenchyma, with increasing concentration from the sinus wall to the depth of the parenchyma, which would explain how HSCs are maintained within the marrow cords.

Release of Mature Cells

As opposed to diapedesis, where leukocytes migrate between two endothelial cells to enter peripheral tissues (interendothelial migration), the egress of mature cells from BM occurs through pores within endothelial cells (transendothelial migration). When cell maturation is achieved, reticulocytes or polymorphs go through a fenestra with a diaphragm creating a pore whose diameter (of approximately 2 mm) is far less than the cell size. Active movements of ECs favor the cell release into the vessel lumen. In the case of platelet release, pseudopods arising from the megakaryocyte membrane flow through pores into the sinus lumen where platelet fragmentation takes place.

The release of hematopoietic cells must occur when cells are fully differentiated and not before. One mechanism is via extracellular matrix (ECM) to integrin receptor recognition. Fibronectin is such an ECM protein widely expressed in the BM cords. Precursors of red cells express fibronectin receptors (integrins VLA-5) up to the stage of reticulocytes. It is generally assumed that the lack of adhesion of reticulocytes to fibronectin is a critical factor for the release of these cells into circulating blood. Similar, but less known, interactions involving other integrins and ECM molecules might be at play for leukocytes, or even for immature cells in pathological conditions. Other mechanisms might also be operative, in particular those involving abluminal cells whose number and endothelial coverage are tightly regulated.

HSC Homing and Mobilization

Homing of circulating HSC to BM requires sequential specific signals for, first, attachment to sinus ECs; second, transendothelial migration; and third, anchoring within the hematopoietic parenchyma. This multistep process, comparable to transendothelial migration of leukocytes in response to inflammatory stimuli, involves interactions of HSCs with CAMs expressed on sinus vascular cells and with ECM adhesive molecules. These interactions are modulated by HGFs and SDF-1. Present data, provided mainly by studies in vitro, suggest the following scenario (Figure 1A). In the first step, HSCs must reduce their speed by tethering to, and rolling along, the endothelial lining. The sinusal blood flow is relatively slow, allowing weak interactions between P-selectin glycoprotein ligand-1 (PSGL-1) expressed on HSCs and E- and P-selectins expressed on BM ECs. Chemokines, such as SDF-1, or HGFs, such as Flt3-ligand or throm-bopoietin, located on the endothelial membrane or bound to proteoglycans, may then activate VLA-4 and LFA-1 integrins on the rolling HSCs. VLA-4 and LFA-1 activation would convert to firm adhesion the interactions of these molecules with CAMs of the Ig superfamily (VCAM-1 and ICAM-1) on the endothelial cells, resulting in HSC arrest. Actin polymerization would then be activated in HSCs, leading to their migration through the endothelium. The transendothelial migration would be mediated by VLA-4

and VLA-5 expressed on HSCs and fibronectin present in the sinusal ECM. The platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) expressed on both ECs and HSCs could also be involved in this process through homo-typic interactions. In the last step, HSCs would polarize and migrate following a SDF-1 gradient to reach the hematopoietic niche. The final anchoring might depend on interactions of HSC VLA-4 with microenvironmental cell VCAM-1 and of HSC VLA-5 with parenchyma ECM fibronectin; the c-Kit ligand produced locally might enhance the anchoring; moreover, the continuous production of SDF-1 by stromal cells would allow HSCs to be confined within the niche.

Mechanisms leading to the mobilization of HSC are less well understood. Among the multiple CAMs involved in HSC adhesion to the microenvironment, HSC VLA-4 interacting with microenvironmental cell VCAM-1 appears critical. It is now well established that HSC mobilization is associated with an increased local production of proteases within the BM, such as leukocyte serine proteases (elastase, cathepsin G) or matrix metalloproteinases (MMP-9), able to degrade the ECM. Elastase is known to disrupt VLA-4/VCAM-1 interactions (by degrading VCAM-1) and CXCR-4/SDF-1 interactions (by degrading both CXCR-4, the SDF-1 receptor, and SDF-1), while MMP-9 can also cleave SDF-1. Collectively, the increase in BM protease activity can explain the decrease, observed after G-CSF-induced HSC mobilization, in BM SDF-1 levels and in CXCR-4 expression on circulating CD34-positive hematopoietic cells. A model showing the main factors involved in HSC trafficking is proposed in Figure 1B.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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