Our choice of careers as adults isn't determined by whether we slept
on a cot or a feather mattress as a child. But then, we're not stem
cells (at least, not any more). A pair of recent reports shows that
when scientists grow stem cells in the laboratory, the physical
properties of the cells' culture-dish homes influence when they will
adopt a distinct path in life and what that path will be.
At the 2006 annual meeting of the American Society for Cell Biology
in San Diego last December, Christopher J. Murphy of the University
of Wisconsin-Madison presented data showing that embryonic stem
cells are more likely to keep their
pluripotency—their ability to become any type of
cell—when they are grown on a surface stamped with a pattern
of tiny ridges. The effect was independent of the scale of the
ridges, which ranged from nanometers to micrometers in width.
Traditionally, cultured cells are grown on smooth glass or plastic surfaces.
This finding challenges the ingrained culture of cell culture, which
has long assumed that the molecules dissolved in the liquid medium
that bathes cells, including growth factors and other chemical
signals, had the last word in determining cell physiology. Murphy
disagrees, citing work in his laboratory that shows physical
properties of the surface to be "as fundamental an element [in
determining cell behavior] as having growth factors in the media."
So what exactly does the physical topography do to the cell?
"What doesn't it do?" asks Murphy. "It changes
everything—adhesion, migration, proliferation,
differentiation." From his systems-engineering perspective, the
research offers potential benefits for the large-scale production of
embryonic stem cells, which have the theoretical ability to divide
indefinitely but often lose pluripotency for reasons that are poorly understood.
The Wisconsin team's findings echo previous work by scientists at
the University of Pennsylvania. In the August 25, 2006, issue of the
journal Cell, the Penn group showed that the fate of
mesenchymal stem cells could be directed by the stiffness of the
substrate on which they were grown. Mesenchymal stem cells come from
adult bone marrow.
A research team led by Dennis E. Discher found that stem cells grown
on the stiffest matrix became bone precursors. Those grown on the
softest surface became nerve cells, and those grown on a
medium-stiff substrate assumed the characteristics of muscle cells.
The shapes of the cells and the suite of active genes contained
within confirmed their new identities. Previous studies had shown
that chemical cues could effect this kind of differentiation, but
Discher's paper was the first to demonstrate that cell lineage could
be controlled in the absence of soluble stimuli.
This property makes sense, Discher says, given the role of such
cells in tissue regeneration and repair. "These [mesenchymal
stem] cells leave the bone marrow and end up in different
places—muscle, bone, fat." But to repair muscle, or
become a neuron in the brain or cartilage at the end of a bone, the
stem cell must become anchored and "physically engage the
microenvironment" before becoming one of the gang.
Such differences in the relative stiffness of animal tissues are
easy to appreciate, according to Discher. "You can feel it. You
know brains, calf's brains, how soft they are? I take you to
the supermarket, you can feel the difference between steak and bone,
or between fat and calf's brains."
But groceries aside, how exactly does a cell "feel" the
surface it grows on? "It starts with attachment and
contraction," explains Discher. Cells create what are called
focal adhesions—points of attachment on the
substrate—that provide a foundation for the cytoskeleton. A
type of motor protein known as nonmuscle myosin II applies tension
to the actin filaments of the cytoskeleton. At the end of the line,
a complex of proteins near the focal adhesion appears to act as a
"mechano-transducer," translating physical forces into
intracellular signals. In the Cell paper, Discher and his
colleagues showed that inhibiting myosin prevented the
The strong effect of physical properties on cell behavior in these
experiments doesn't mean that scientists were wrong before about
soluble signals. On the contrary, the two types of stimuli seem to
work together. But Discher states—using language similar to
Murphy's—that "physical cues are just as influential [on
cell fate] as chemical cues. It's a balance." In his
mesenchymal stem cells, differentiation was more complete when
chemical and physical cues pointed in the same direction.
The potential implications of this work for cell biologists are
profound, given that everything scientists know about the way cells
behave in culture comes from experiments on hard, smooth surfaces.
For this reason, Discher cautions that biologists need to "take
those data [from rigid substrates] with a grain of salt." Given
the tens of thousands of research papers that include such methods,
that's a lot of salt.
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