Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 542

9.7.9 Migration through Subendothelial Layer

and Interstitium

Once the perivascular basement membrane is crossed, interstitial migration requires
extracellular, soluble guidance molecules. Although leukocytes require integrins
when they extravasate from the blood stream, their locomotion in the interstitium
does not depend on these adhesion receptors.
In lymph node and splenic white pulp, lymphocytes migrate along the scaffold
of fibroblastic reticular cell network [ 980 ]. In the dermis, lymphocytes move
preferentially along thick collagen bundles. Guidance structures can then be used
for haptotaxis along adhesive structures and/or chemotaxis according chemokine
gradients that exist in these structures.
Among guidance cues, chemokines and lipid mediators support positioning of
leukocytes. Activators of Rac GTPase, such as PIP 3 -and F actin-binding RacGEF
70-kDa switching B-cell complex-associated protein SwAP70, Vav, and DOCKs are
involved in migration through tissue interstitium [ 980 ]. Polymerizing actin causes
the leading edge to protrude. The prototypic cellular protrusion is the lamellipodium
(Vol. 2 - Chap. 6. Cell Motility). Filopodia also contain a growing mesh of actin
filaments that help pull the leading edge forward [ 993 ].
In addition, modulators of the ARP2-ARP3 complex at the leading edge, such as
cortactin homolog hematopoietic lineage cell-specific Lyn substrate protein HCLS1
(or HS1) and actin- and microtubule-binding coronins are required for efficient cell
protrusion and migration in interstitium [ 980 ]. 115
Cell deformability supports squeezing locomotion in a porous medium,
especially through narrow pores. Contractile and protrusive forces generated by
the actin cytoskeleton and transmitted at the leading edge are transformed into
traction forces. The leading edge pulls the cell forward.
Combined actin polymerization and myosin-2-induced contractility pull
matrix-ligated integrins backward and the cell body forward. Actin filaments grow
at the leading plasma membrane and existing filaments are pushed backward
into the cell body, where the actin network is disassembled (treadmilling) [ 993 ].
Rearward actin flux generates friction between the cell and its environment that can
be sensed by transmembrane force sensors. In addition, behind the leading edge,
myosin-2 pulls the cortex backward (polymerization-driven retrograde movement).
Transmembrane force receptors that couple the retracting actin cortex to the matrix
create traction force to move the cell body.

115 Hematopoietic lineage cell-specific protein HS1, a substrate of intracellular protein Tyr kinases
such as SRC family kinases in hematopoietic cells, colocalizes with and connects to actin-related
protein ARP2-ARP3 complex that causes actin assembly. It increases the rate of the actin assembly
mediated by the ARP2-ARP3 complex [ 994 ]. Actin-associated coronins and coronin-like proteins
participate in the remodeling of the cortical actin cytoskeleton, especially during phagocytosis and
macropinocytosis [ 995 ].