Biomedical Engineering Reference
In-Depth Information
downregulation also can induce the enhancement of the osteogenic or myogenic
potential of MSCs and this finding has important implications for regenerative
medicine.
Stretching, especially with a reciprocally cyclic motion, is inhibitory on the
adipocyte determination program, i.e., downregulation of PPARc expression via
either ERK/MAPK [ 14 , 27 , 30 , 34 ] or Wnt [ 26 , 32 ] signaling, during the terminal
differentiation stage of preadipocytes as well as the earlier commitment stage of
multipotent MSCs. Crosstalk between ERK/MAPK and Wnt pathways has been
suggested [ 151 ]; however, it is necessary to clarify whether or not an interaction
between these pathways actually exists in the mechanotransduction of differenti-
ating preadipocytes and MSCs. Stretching, however, may also possess dual (either
inhibitory or stimulatory) effects on adipogenesis of committed preadipocytes. In
contrast to the inhibitory effect, sustained static stretching accelerates lipid droplet
formations in differentiating adipocytes by ERK-dependent but PPARc-indepen-
dent mechanism(s). Collectively, the ERK/MAPK pathway is indeed activated as a
common signal of mechanotransduction in mesodermal/mesenchymal lineages,
including multipotent MSCs and committed preadipocytes. The ERK/MAPK
pathway is well known as a cell proliferation signal in response to mitogens and
various growth factors; however, the mechanically activated ERK/MAPK pathway
itself may not determine the commitment and terminal differentiation to specific
cell fate. A mechanically activated ERK/MAPK pathway would interact with
many other cellular signals that are chronologically changing during the pro-
gression of adipogenic programs [ 5 ]. Therefore, it is very likely that coexisting
signaling pathways adjust the outcome of the ERK/MAPK-driven mechanotrans-
duction pathway for each timing and each kind of differentiation cue as well as
each type of cells.
Furthermore, since adipose tissue also contains a variety of accessary cells such
as vascular, nerve, and immune-inflammatory cells as well as fundamental adi-
pogenic cells, it is necessary to consider the intercellular communication among
these cells. Therefore, the mechanoresponsiveness of adipose tissue may be more
complicated than those expected by adipocyte biology in vitro. In this regard, Hara
and colleagues have demonstrated that an obesity-associated mechanotransduction
signal, in this case Rho-Rho-kinase activation and chemokine/adipokine produc-
tion in mature hypertrophied adipocytes, further exacerbates inflammation in
adipose tissues [ 35 ]. Therefore, this differential mechanoresponsiveness of pre-
adipocytes/adipocytes should be carefully taken into account when considering a
physiological or pathophysiological impact of mechanical stimuli on the adipo-
cyte-related clinical issues such as obesity and the metabolic syndrome.
Nonetheless, it is highly expected that mechanotransduction in differentiating
adipocytes would provide the molecular and cellular basis and physiological rel-
evance of physical exercise and/or local massage, which may directly affect adi-
pocyte renewal. Furthermore, it may be possible that stretching exerts a fine-tuning
action of drugs that affects both differentiation and post-maturation functions of
adipocytes.
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