Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation - The Mechanobiology of Obesity and Related Diseases - page 108

5 Mechanical Influences
Adipose tissue experiences multiple types of mechanical influences in vivo. Lipid
droplet formation and growth inside a cell promotes ''rounding'' and imposes
tensile forces on the cell membrane, likely affecting adipocyte maturation and
function, though this is currently less well understood. Furthermore, it is difficult to
resolve intracellular mechanical stress effects from morphological effects. Studies
have also focused on the effects of substrate-mediated (e.g. stiffness) or applied
mechanical (e.g. dynamic or static loading) influences on adipogenic differentiation
of stem cells and preadipocytes, where the latter are fibroblast-like progenitor cells
already committed to the adipogenic lineage. Locally resident stem cells and pre-
adipocytes play a critical role in adipose tissue remodeling. It has been shown that
preadipocytes respond to factors secreted by macrophages to increase production of
collagens [ 39 ]. As the profile of ECM proteins synthesized by preadipocytes
changes dramatically upon terminal differentiation [ 40 - 42 ], mechanical influences
on adipogenesis could have profound implications for tissue remodeling.
5.1 Substrate-Mediated Influences
As discussed earlier, the seminal study reported by Chen and coworkers first
demonstrated the significance of cell shape and related cytoskeletal mechanics in
adipogenesis of mesenchymal stem cells with fibronectin-coated, poly-
dimethylsiloxane (PDMS) substrates [ 33 ]. Micropatterns of various sized islands
on the substrates controlled the size and shape of the cells, as well as cytoskeletal
tension. To further explore the effects of morphology and cytoskeletal mechanics
on adipogenesis, Kilian et al. utilized the same technology to examine differen-
tiation of mesenchymal stem cells when cultured in various geometric shapes with
different subcellular curvatures, such as star-shaped and flower-shaped patterns,
and in the presence of competing soluble differentiation factors [ 43 ]. Geometries
that promoted and enhanced actomyosin contractility resulted in osteogenesis,
while geometric features that resulted in low contractility induced adipogenesis.
Additionally, cytoskeletal-disrupting agents and integrin-blocking antibodies each
inhibited actomyosin contractility and promoted adipogenesis, consistent with the
previous report by the Chen group [ 33 ]. Furthermore, pathway inhibition studies
suggested that geometrically driven adipogenesis occurs through negative regu-
lation of Wnt signaling. Taken together, these studies support a critical role for cell
morphology and cytoskeletal tension, influenced by the substrate, in adipogenic
lineage commitment and differentiation of mesenchymal stem cells.
To investigate the effects of cytoskeletal organization on differentiation of
adipose-derived stem cells, we cultured the cells in the presence of cytoskeletal
inhibitors, cytochalasin D or blebbistatin [ 44 ]. Consistent with mesenchymal
stem cell studies, reduced cytoskeletal tension with both inhibitors promoted