Biomedical Engineering Reference
In-Depth Information
the cell. An increase in the mechanical tension facilitates the recruitment and stable
association of focal adhesion proteins required for the compositional maturation of
integrin clustering (Grashoff et al.
2010
), which enhances the formation of well-
bundled actin stress fi bers and actomyosin contractility (Gardel et al.
2010
). In con-
trast, a decrease in the tension leads to disorganization of the integrin cluster and of
the actin cytoskeleton (Balaban et al.
2001
).
In the cytoplasm, the actin cytoskeleton is connected to the nucleus through inner
nuclear membrane proteins, such as nesprin (nuclear envelope spectrin repeat)
(Zhang et al.
2001
; Martins et al.
2012
). Nesprins interact across the luminal space
with other nuclear envelope proteins such as lamins, which form stable nuclear
structures and can bind to chromosomal DNA (Jaalouk and Lammerding
2009
; Iyer
et al.
2012
). This link directly transmits the mechanical force between ECM and the
nuclear interior (Poh et al.
2012
). The transmitted force changes nuclear morphol-
ogy (Iyer et al.
2012
; Mih et al.
2012
) and intranuclear architecture. In particular,
this force transmission can cause chromatin recombination, nuclear matrix distor-
tion, and DNA melting (Wang et al.
2009
). These nuclear changes alter the nuclear
transportation of soluble signaling intermediates, which affects transcription events
(Thomas et al.
2002
; Booth-Gauthier et al.
2012
). The changes in transcription
events probably affect cell proliferation and stem cell differentiation (Jain et al.
2013
; Brosig et al.
2010
).
Indirect Mechanochemical Signal Transduction
As shown in the left part of Fig.
11.2
, the cell adhesion complex, in addition to serv-
ing as the actin-ECM molecular clutch, works as a node to transduce mechanical
forces acting on the cell-ECM adhesion complex into biochemically relevant sig-
nals. A major pathway in the nuclear relay of mechanical signals is YAP/TAZ sig-
naling (Halder et al.
2012
) for differentiation of human mesenchymal stem cells
(MSCs) and for survival of human lung microvascular endothelial cells (Dupont
et al.
2011
). In addition, Ras/MAPK (Ras-Raf-MEK-ERK) signaling (Schlaepfer
et al.
1994
; Assoian and Klein
2008
) is a well-known pathway that controls prolif-
eration of human MSCs (Muller et al.
2013
; Nanba et al.
2013
) and cancer cells
(Provenzano and Keely
2011
) and participates in keratinocyte stem cell mainte-
nance (Nanba et al.
2013
). Another downstream pathway of Ras is PI3K/Akt signal-
ing, which is involved in self-renewal of mouse embryonic stem (ES) cells (Horiuchi
et al.
2012
; Lee et al.
2012
).
11.2.2.2
Cell Proliferation
As explained in Sect.
11.2.2
, actin cytoskeleton is a key player in regulating intra-
nuclear events by transmitting mechanical and mechanochemical signals to the
nucleus. Predictably, actin cytoskeleton can guide cell proliferation affecting DNA
synthesis.
