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stretching (102 % of original, 10 cycles per minute) during adipogenic induction
of C3H10T1/2 mesenchymal stem cells prevented decreases in both active and
total b-catenin levels and induced nuclear translocation of b-catenin, leading to
stimulate a durable b-catenin signal and inhibition of adipogenesis [
32
].
Taken together, the cyclic stretching has a significant influence on both
canonical and non-canonical Wnt signaling in the inhibition of adipogenesis of
cells having a mesodermal lineage.
3.8 Tension-Induced/Inhibited Proteins Pathway
Tension-induced/inhibited proteins (TIPs) were originally identified as novel
transcription regulatory proteins with a role in myogenic versus adipogenic dif-
ferentiation [
133
]. The TIP family is composed of eight isoforms (TIP-1 to TIP-8)
produced by alternative splicing from a single gene in both humans and mice. TIPs
have several characteristic and/or functional motifs which are found in chromatin
remodeling/interacting proteins, including nuclear localization signals (NLS),
SANT domain (by which chromatin remodeling proteins interact with histone),
and some have a S-adenosyl-
L
-methionine (SAM) binding domain and nuclear
receptor binding box (NRB) motifs [
133
].
Schuger's group has thoroughly investigated the biochemical and physiological
aspects of TIPs, especially concerning the mechanical control of mesenchymal
stem cell fates, as well as preadipocyte differentiation [
133
,
134
]. Both cyclic and
static stretching induces TIP-1 in embryonic undifferentiated mesenchymal stem
cells and differentiating smooth muscle myoblasts, leading to myogenesis [
133
]. In
contrast, TIP-3 is expressed in both progenitor cells and smooth muscle myoblasts
without stretching, but interestingly, it is downregulated by stretching in the
myoblast but not progenitor cells [
133
]. It has been also demonstrated that
expression of TIP-3 is strongly implicated in adipogenesis via its recruitment of
PPARc
2
promoter. TIP-6 is also involved in adipogenesis by a similar mechanism.
The authors clearly indicated that a myogenic-adipogenic switch concerning
mesenchymal stem cell fate is determined at a chromatin remodeling level by
mechanically regulated TIP-1, -3 and -6 expressions, i.e., stretching induces TIP-1
which stimulates myogenesis, whereas TIP-3 and/or TIP-6 are expressed in adi-
pose tissues, stimulate the adipogenesis, and are suppressed by stretching (Fig.
3
).
Although the fundamental role of the TIPs on the stem cell fates regarding
myogenic or adipogenic directions is clear, only TIP-6 transcript, but not other TIP
isoforms, was detected in the differentiating (but not undifferentiated) 3T3-L1 cells
[
134
]. These findings provide important evidence concerning the molecular link-
age between mechanical input and specific gene expression; adipogenic PPARc
promoter is regulated by TIP-6 as well as TIP-3 via mechanically sensitive
chromatin remodeling, though it is yet to be clarified how the expression of TIPs
itself is regulated in response to stretching (Fig.
3
). In this respect, how the cell
senses and transmits the mechanical signal into TIPs is yet to be elucidated.
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