Biomedical Engineering Reference
In-Depth Information
Actin cytoskeletal control of cell proliferation originally clarifi ed by studies of
the effect of cell morphology in growth control (Folkman and Moscona
1978
; Chen
et al.
1997
). These studies have suggested that the mechanical tension-dependent
changes in the cell shape govern cell proliferation. Cell shape affects whether indi-
vidual cells grow or die, regardless of the type of the protein of ECM in contact with
the cell (Chen et al.
1997
). It has been shown in non-transformed endothelial cells
and fi broblasts that increased DNA synthesis and cell growth are tightly coupled to
increased cell spreading (Folkman and Moscona
1978
). The best-characterized
pathway is the one that involves stimulation by actin cytoskeletal tension of the
Rho-ROCK (Rho-associated protein kinase) pathway and the resulting integrin
clustering, which increases ERK activity, leading to enhanced cell growth through
ERK-dependent induction of cyclin D1 (Assoian and Klein
2008
; Folkman and
Moscona
1978
; Mammoto and Ingber
2009
). Based on these results, it is generally
accepted that cell spreading, with well-bundled actin stress fi bers and mature focal
adhesions, enhances cell proliferation.
Consistent with the basic fi ndings concerning the Rho-ROCK pathway, self-
assembled vertically oriented TiO
2
nanotubes with a 15 nm diameter effectively
accelerate integrin clustering and the formation of focal adhesion linked to actin
stress fi bers; the cell proliferation rate is high (Park et al.
2007
). In contrast, tubes
100 nm in diameter disrupt integrin clustering and formation of focal adhesion.
Compared to MSCs on tubes of 15 nm diameter, proliferation rates are over fi vefold
lower in those on the nanotubes of 100 nm diameter (Park et al.
2007
). In vascular
smooth muscle cells, TiO
2
nanotubes with an average pore diameter of 30 nm dis-
rupt actin stress fi bers and decrease cell proliferation compared to a fl at surface
(Peng et al.
2009
).
Actin and focal adhesion signaling with a Rho-ROCK-myosin effector for cell
proliferation might not be the case for a synthetic ECM with non-biomimetic topog-
raphy and stiffness. Densely packed and sharp peaks of a silicon nanostructured
substrate promote proliferation of NIH3T3 fi broblasts, whereas more regular ridges
favor adhesion but decrease the rate of proliferation (Gentile et al.
2013
). It has been
reported for various types of cells, such as NIH3T3 fi broblasts, primary low passage
fi broblasts from human lungs, and human MSCs, that proliferation of cells on a soft
(<6 kPa) substrate is tightly coupled with cell spreading, but is decoupled from
myosin light chain phosphorylation, cellular traction, and focal adhesion formation
(Mih et al.
2012
). These fi ndings suggest that non-biomimetic cues possibly give
excellent control of cell proliferation beyond the effect of the topography naturally
provided by living organisms.
11.2.2.3
Stem Cell Differentiation
The conventional approach to understand the regulation of stem cell differentiation
is driven by the discovery of soluble biochemical cues and related signaling path-
ways. In parallel, a growing number of researchers have recognized the signifi cant
role of the mechanical factors provided from ECM niche in a tissue where stem cells
reside (Discher et al.
2009
; Kshitiz et al.
2012
; Spradling et al.
2001
).
