Biomedical Engineering Reference
In-Depth Information
drive cell motility [
76
]. While early experiments implicated roles for ligand
density, integrin expression level, and ligand binding affinity as mediators of cell
migration [
77
], substrate stiffness [
78
,
79
], and strains created in compliant sub-
strates [
80
,
81
] also guide motility. Cell migration in response to a stiffness gra-
dient has been termed durotaxis and has been demonstrated in ECs as well as
vascular smooth muscle cells, fibroblasts, and stem cells [
80
,
82
-
84
]. ECs are
sensitive to strains created in compliant matrices by the traction stresses of
neighboring cells, and this response is dependent on matrix stiffness [
81
]. On
sufficiently compliant matrices, pairs of ECs exhibit hindered migration compared
to single cells indicating that compliant matrices promote cell-cell interactions. On
compliant substrates, the traction forces exerted by one cell may create a perceived
stiffening in the substrate that allows cells to sense each other at a distance [
81
],
and organize into multicellular networks [
85
]. Such network formation on com-
pliant polyacrylamide substrates may be disrupted by growth factor (bFGF,
VEGF)-induced motility [
86
]. These observations suggest that matrix stiffness-
mediated EC network assembly results from tightly-regulated migratory behavior.
While more research is needed to fully understand the role of substrate
mechanics in mediating EC migration during angiogenesis, the study of collective
cell migration in epithelial cell sheets has uncovered some relationships that guide
the interplay between cell contractility and global motility. Collective cell
migration and traction force generation in Madin-Darby canine kidney cell
(MDCK) epithelial sheets indicates that cell scatter correlates with adhesion
strength and actomyosin-dependent contractility that transmits tension to the cell
periphery [
87
]. Traction forces generated by MDCK monolayers are greatest at
the edge of the monolayer and greater than forces measured in isolated cells [
88
],
and may be generated in the bulk of the cell sheet away from the leading edge
[
89
]. Furthermore, MDCK assembly is anisotropic along the stiffest substrate
direction of anisotropic substrates and correlates with traction force and actin
cytoskeletal orientation [
90
]. These data indicate that collective cell migration in
epithelial cells is sensitive to matrix stiffness that alters cell contractility. Future
work should identify the role of matrix stiffness in mediating collective cell
migration in ECs.
5 Matrix Remodeling
During angiogenesis, new vessel formation is facilitated by the disruption of the
basement membrane and the development of a provisional matrix containing
proteins such as collagen and fibronectin [
1
]. While disruption of the basement
membrane is usually attributed to the action of MMPs [
91
] (as discussed by
Grainger and Putnam in this topic), the contractile machinery of ECs is implicated
in ECM remodeling [
92
].
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