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[26]
by bone marrow arteriolar endothelial cells and mesenchymal stromal cells (CAR cells) . Del-1 regulates
[26]
HSC proliferation and differentiation toward the myeloid lineage .

Endothelial permeability in acute myeloid leukemia
Vascular permeability is a peculiar property of blood vessels wall to be permissive to the flow of small
molecules or even of whole cells in and out of the vessel. This flow occurs at the level of the cell junctions
between endothelial cells that form microscopic gaps. Vascular permeability is a highly controlled process
related to the intrinsic property of each single vessel and to the physiologic conditions of the tissue of
residence of vessels.

[27]
A recent study by Passaro et al. provided strong evidence that leukemic cells exert a disruptive effect on
bone marrow permeability and vascular architecture; these events are essential for the development of the
malignant phenotype.

To better understand these studies, it is important to analyze the studies on vascular permeability of vessels
of normal bone marrow. In a fundamental study, Itkin and coworkers provided evidence that distinct bone
marrow blood vessels, with different permeability properties, play a key role in the control of homeostasis
of hematopoiesis through a control of hematopoietic stem cell/hematopoietic progenitor cell quiescence
and differentiation. Thus, less-permeable arterial blood vessels maintain HSC in a state of metabolic
quiescence, characterized by a low ROS state, whereas the more permeable sinusoids promote a state of
[28]
metabolic activation of stem/progenitor cells, with high ROS production, triggering differentiation .
[28]
Sinusoids represent the site for immature and mature leukocyte trafficking to and from the bone marrow .
It is well known that there is a deterioration of bone and hematopoiesis with aging, and there is evidence
for the progressive degeneration of arterial endothelial cells from endosteal regions of bone. Aging
determines a reduction in HSC survival and an increase in bone marrow permeability .
[29]
The bone endothelial cell permeability is a physiologically very relevant process because it regulates the
microenvironment and the hematopoietic stem and progenitor cell transmigration. Stem/progenitor cell
transmigration is an essential and fundamental event in the process of homing of transfused HSCs in
stem cell transplantation. This process implies first the firm adhesion of HSC/HPC to endothelial cells and
subsequent transmigration across the endothelial lining.

The fundamental importance of vascular bone marrow permeabilization is highlighted by the procedure
of mobilization of HSCs and HPCs from bone marrow into blood, utilized in clinical practice for the
treatment of patients with hematological malignancies who undergo a treatment with HSC transplantation.
In clinical studies, granulocyte-colony stimulating factor (G-CSF) is the preferred mobilizing agent. Several
studies have in part clarified the mechanisms responsible for G-CSF-mediated HSC/HPC mobilization. The
available evidence indicates that G-CSF-induced trafficking is mediated by bone marrow endothelial cells
mainly through a mechanism involving a remodulation of the CXCL12-CXCR4 axis: (1) under steady-state
conditions, the chemokine receptor CXCR4 expressed on bone marrow endothelial cells actively binds and
internalizes CXCL12, its ligand, resulting in the translocation of this chemokine in the bone marrow with
[30]
consequent activation of a homing signal for HSCs and HPCs in this tissue ; (2) G-CSF administration
determines a decrease of both CXCL12 and CXCR4, determined by serine proteases able to cleave these
molecules [31,32] ; (3) among the various proteases, the dipeptidyl peptidase CD26 seems to play an essential
[33]
role in the process of G-CSF-mediated mobilization, mediating CXCL12 cleavage ; and (4) G-CSF
induces an increase of the expression of CD26 on the surface of bone marrow endothelial cells, promoting
the cleavage of the neuropeptide Y (NPY) to its truncated form, which in turn binds with higher affinity
to NPY receptors expressed on sinusoidal endothelial cells, triggering VE-cadherin internalization and
[34]
degradation, an event that consistently enhances bone marrow vascular permeability .