Biomedical Engineering Reference
In-Depth Information
"basin of attraction," from which they will reach the attractor state, is best reca-
pitulated by the observation that many nonspecific pharmacological stimuli that
activate multiple proteins across several signaling pathways often trigger ex-
pression of the same set of cellular phenotypes. For instance, differentiation of
many cell types can be turned on by a large variety of nonspecific agents, in-
cluding DMSO or ethanol (3,44,47,57,74). Specifically, the differentiation of a
promyelocyte cell line into mature neutrophils (the major white blood cells in-
volved in innate immune response) can be elicited not only by DMSO, but also
by treatment with retinoic acid, hypoxanthin, actinomycine D, flavone, etc. (13).
In these cases, it appears that simultaneous perturbation of multiple targets in
different pathways results in channeling of the biochemical effects into common
end-programs, and hence the same "default" cell fate.
Perhaps the most striking cellular manifestation of the idea that cell fates
represent attractor states comes from experiments in which cell shape was varied
as an independent control parameter using microfabricated geometric islands of
extracellular matrix proteins to which mammalian cells normally adhere (10,32).
The traditional mechanistic, pathway-centered explanation of cell fate switching
assumes that a specific, "instructive signal," i.e., a messenger molecule that in-
teracts with its cognate cell surface receptor, tells the cell which particular genes
to activate in order to establish a new cell phenotype. However, when these in-
structive signals (e.g., soluble growth factors and insoluble extracellular matrix
molecules) were held constant, cell shape distortion alone was able to switch
endothelial cells between proliferation, apoptosis, and differentiation (31). Thus,
variation in one continuous control parameter (cell shape) that is devoid of the
molecular specificity normally assumed to carry "instructive" information led to
switching between multiple, mutually exclusive cell fates, and produced effects
reminiscent of a biological "phase transition." Essentially, cell distortion trig-
gered the cell to "select" between different preexisting attractor states.
Integration of structural and information networks
. Importantly, because
cell shape is governed by changes in cytoskeletal shape and mechanics, pheno-
typic control by cell distortion is a clear example of how structural networks can
impact information-processing networks in living cells. From a mechanistic
point of view one can then ask, how can a "nonspecific" parameter, such as cell
shape, elicit the detailed molecular changes associated with cell growth, differ-
entiation, and apoptosis? If cell fates are attractors, then a large variety of mo-
lecular signals will push the cells into the few available behavioral modes that
the cell can adopt: again, regulation corresponds to selection among a limited
number of preexisting fates, rather than instruction of how to behave.
Changes in cell shape imposed by the microfabricated constraints lead to
massive rearrangements of the cytoskeleton that maintains shape stability in
response to external influences according to the tensegrity rules that govern
these structural networks. Visualization of the actin cytoskeleton in cells grown
on micropatterns, for example, revealed that the actin bundles of the cell reorient
