Role of Mechanical Stimulations in Directing Mesenchymal Stem Cell Adipogenesis - The Mechanobiology of Obesity and Related Diseases - page 75

controlling adipogenesis by fluid flow, very little data have been accumulated so
far and it may be too early to determine optimal flow conditions and responsible
molecular mechanisms.

3 Control by Substrate Cues

It is apparent that when MSCs are subjected to a certain mechanical stimulation
under the right condition, it significantly affects the differentiation of the cells,
particularly lineages involving osteogenesis and adipogenesis. Another important
factor to consider when analyzing MSC differentiation is the substrate that cells are
grown upon. Studies have reported that substrate characteristics and functionali-
zation are very influential in directing MSC fate. This section will introduce
findings from biomaterial surface modifications relevant to the topic of this
chapter, mechanical control of MSC fate into adipogenesis. Indeed, some bio-
material fabrication methods have targeted to alter mechanical milieus of the
substrates. For example, protein-micropatterned surfaces, nanoscale biomaterials,
and substrates with varying rigidity have been designed to produce differences in
'static' mechanical culture environments. Such modifications have resulted in
significant changes in cell shape, cytoskeletal tension, and cell fate decision. In this
section, the data of substrate control of MSC fate involving adipogenesis will be
reviewed. Note that some contents of this section are reminiscent of our recent
review [ 36 ].
The control of cell behavior by cellular micropatterning dated back to the
pioneering study by Chen et al. [ 8 ]. They patterned capillary endothelial cells on
ECM protein patterns and demonstrated that cell patterning size critically affects
cell growth/apoptosis. Cells patterned on small fibronectin (FN) circular islands
(10-20 lm diameter) showed apoptosis relative to cells patterned on larger islands
(50 lm diameter). This was mediated by cell-substrate interaction through integrin
b1 but not avb3 for this specific case.
Relevant to MSC adipogenesis, a monumental study by McBeath et al. [ 33 ]
reported that cell patterning size and resultant cytoskeletal tension signaling may
critically direct MSC adipogenesis or osteogenesis. Interestingly, MSCs patterned
onto larger area (10000 lm 2 sized FN island) to have well spread cell morphology
showed upregulated RhoA-RhoA kinase (ROCK) signaling and enhanced osteo-
genic differentiation (Fig. 6 ). On the contrary, MSCs patterned within small area
(1024 lm 2 islands) showed downregulated RhoA-ROCK and preferred adipo-
genesis. These were observed with osteogenic/adipogenic mixed (50/50 v/v) dif-
ferentiation media, suggesting that MSCs chose their fate between osteogenesis
and adipogenesis depending on the cell size. The role of cell tension signaling and
its interplay with cell size was further demonstrated. MSCs could not differentiate
to osteogenesis if confined within small island even when RhoA was molecularly
upregulated (Fig. 6 b). On the other hand, molecular activation of ROCK, the
downstream effector of RhoA, rescued the osteogenesis even for MSCs