Role of Mechanical Stimulations in Directing Mesenchymal Stem Cell Adipogenesis - The Mechanobiology of Obesity and Related Diseases - page 74

Several cellular mechanistic elements and signaling mechanisms have been
proposed as mechanistic pathways of fluid flow induction of either osteoblastic cell
mechanotransduction or mesenchymal stem cell osteogenesis. Cellular mecha-
nistic components responsible for fluid flow induction of osteogenesis include
focal adhesion, cytoskeleton, cell-cell interaction, etc. Also, it has been proposed
that fluid flow signaling for inducing osteogenic fate is mediated by cytosolic
calcium (Ca 2+ ), COX-2, prostaglandin E2 (PGE2), nitric oxide (NO), ERK, etc.
These cascades responsible for flow-induced osteogenesis are not the scope of this
chapter. For more information, see our recent review [ 37 ].
One recent study proposed that changes in cell morphology under fluid flow
may be an important regulator of MSC behavior. Zheng et al. [ 56 ] showed that rat
MSCs underwent a contraction and re-spread (CRS) process when they were
subjected to fluid shear stress in a microfluidic device. Further, this morphological
change by fluid flow was shown to be mediated by cytosolic calcium, F-actin, and
Rho-kinases. The initial morphological response to fluid shear stress may be
crucial in determining the behavior of MSCs in the blood stream and MSC-derived
tissue repair where needed. These data may suggest a similar context as with cell
morphological changes due to cell stretch. It is relatively well established that
mechanical stretch induces cell morphological changes, e.g., cell orientation
perpendicular to the stretch direction, and this is responsible for later stage cell
behavior under stretch. See details of cell morphological changes under stretch in
our other review article [ 38 ].
Additionally, when subjecting MSCs to fluid flow, there are several other
factors that affect MSC differentiation besides the level of shear stress. These
include morphogens, flow rate, and medium viscosity [ 12 ]. These factors have
been considered in studies involving a tissue-engineered bone, which is usually
constructed using a perfusion bioreactor in vitro. A b-tricalcium phosphate scaf-
fold was seeded with human bone marrow-derived MSCs [ 28 ]. They added dex-
tran to the media (to alter the viscosity of the media) and changed the flow rate.
Different fluid shear stresses and mass transport rates were thus studied. It was
shown that increasing fluid shear stress accelerated MSC osteogenesis while
increasing mass transport inhibited the formation of bone-like mineralization.
Thus, maximizing fluid shear stress while minimizing mass transport may be the
optimal condition for maximizing fluid flow effects, in this case, inducing osteo-
genesis. This may further suggest that fluid flow conditions may be optimized to
maximally inhibit the adipogenesis of MSCs.
Although fluid flow is generally a powerful stimulator of various cell functions,
including osteogenesis induction and possibly adipogenesis inhibition, several side
effects from turbulence, bubbles, or eddies within the in vitro bioreactor may
occur. This may even lead to forces enough to result in cell death [ 53 ]. The flow
conditions inside the body may be even more complex in comparison with in vitro
flows which are usually modeled as steady, uniform, laminar flows [ 39 ]. There-
fore, it is important to remember that although reported data suggest that fluid
flow-induced shear generally induces osteogenesis and possibly interferes with
adipogenesis, such conditions may have to be more clarified. Specifically for