Thermodynamic and metabolic rates
Critics have postulated that straw cell structures are the artifacts
from dead cells, the polymerization of membrane systems, or growth of
protein crystals. Assuming that is the case, then the conversion from a
spherical to straw cell is a simple physical deformation process.
Therefore, the free energy needed to maintain spherical and tubular
structures, built from the same amount of biological material, can be
estimated. Following the Helfrich theory ,
the equilibrium shape of a thin membrane covering the vesicle or
emulsion droplet is determined by the minimization of the Helmholtz
free energy EH (or, namely, the "shape energy") of the system
The first term in Eq. (1) is given by the pressure difference across the membrane Δp and the volume of the droplet V, while the second term is determined by the interfacial tension σ and surface area A. The integral term in Eq. (1) is often known as the free bending energy, where R0 is the spontaneous radius of curvature, κ and
is the mean and Gaussian curvature elastic constants, respectively. For
a spherical structure, the two primary radii of curvature R1 = R2 = R, and the first two terms in Eq. (1) are cancelled, so we have
For a tubular structure with the inner radius a, outer radius b and length L, R2 = 8, we have
From literature, the κ and of the lipid bilayers are in the range of (0.1–1.0) × 10-19 J (Derek, 2006), as a result, Eq. (2) yields EH~10-18-10-17 J
per spherical cell. These values for carbohydrates, which are the major
components of the straw cell wall, are not available. From the TEM
measurements, the spherical cell has a typical radius R = 10 μm while the straw cell filaments, has a length of 3 cm, or 3.0 × 104 μm, an inner radius a = 0.3 μm and an outer radius b = 0.5 μm (Figure 7). It is immediately noted that the exceptionally large aspect ratio (104) of the straw cell causes the second term in Eq. (3) to dominate any other term in Eq. (2) and (3) containing κ and .
In addition, the first term in Eq. (3) always contributes
accumulatively to the shape energy. Considerable free energy, mainly in
the form of the elastic energy, is needed to account for the remarkable
spherical-to-tubular shape transformation, with the cell volume
increased from 4.2 × 103 to 2.6 × 104 (μm3) and the cell surface area increased from 1.3 × 103 to 1.8 × 105 (μm2).
We conclude that the tubular structure, as compared to the spherical
cell, is heavily disfavored in free energy; which leads us to believe
that the spontaneous polymerization of dead cell matrix to tubular
structure is an unlikely event.
Figure 7 Spherical cell and straw cell dimensions. Two-dimensional view. Measurements were taken from both light and TEM microscopes.
In reality, the straw cells cannot be simplified to a
rod-shaped structure with an overall uniform composition. Not only do
they have microscopic hair-like structures covering the surface (Fig.2I),
but they also have differences in composition from the tubular center
to the filamentous extensions (anisotropic and inhomogeneous) that
makes a uniformity assumption untenable. During the spherical to
tubular shape transformation, we observed changes in cell volume,
surface area, and cell surface composition. The biological
transformation we describe differs from a physical event where energy
and material exchanges occur throughout the process.
During the reversion of a straw cell to a normal round cell, the tubular center (1 to 2 μm in diameter), houses organelles and grows by enlargement perpendicular to the elongated cell wall (Fig 3A) into a regular round shaped cell. Cellular metabolic rates are determined by the diffusion of ions and biomolecules [17,18]
and are expected to be much slower in straw cells than spherical cells
because of the narrow cylindrical geometry restricting the
intracellular diffusion of solutes compared to a round shaped geometry . The diffusion coefficient of K+ in the t-tubules of skeletal muscle fibers is anomalous and 27% less than its value in free solution .
We also observed a much slower growth rate in straw cells
(approximately 10 to 15 days) during reversion to regular sized cells,
while normal unstressed spherical cells take 2 days to duplicate. It is
unclear how straw cells resume a normal round cellular morphology. It
is also uncertain as to how ion channels operate during straw cell
Straw cell filaments have an outer diameter from 50 to 100 μm (Fig. 1C) and appear to have little cytoplasm (Fig 1D).
This is in contrast to fungal apical growth where the elongation of
hyphae is typically characterized with a much greater amount of
cytoplasm and a distinct endoplasmic reticulum that consists of a
network of tubules connected to the nuclear envelope [21,22].
Cell shape in bacteria is often defined by the distinct presence of
peptidoglycan, a complex polymer built with glycan chains that are
interconnected via peptide crossbridges . Cells with a more complex shape, such as rod-shaped cells, exhibit an additional growth mode responsible for cell elongation .
It is unknown if straw cell assembly in regard to the cell wall is
similar to bacteria, but glycoproteins and sulphated glucose polymers
are primary constituents of the straw cell wall.
Indeed, straw cells can be independently observed in a 5 min
experiment. This simply involves collecting any mammalian tissue fluid,
placing 1 μL on a glass slide, and
observing the droplet under a light microscope. As the droplet dries,
the existence of straw cells and their connected filament networks are
readily seen [see Additional file 1].
Additional file 1. The pre-existence of straw cells from a tissue. Description: A procedure to observe the tubular structure: (1) collect 1 μl
of extracellular fluid from the surface of any frozen bovine liver
tissues from a grocery store, (2) place directly on a glass slide and
observe the straw cells under a light microscope. As the droplet dries,
the existence of tubular structures and their connected networks are
revealed. The time-lapse images can be viewed using the Microsoft
PowerPoint Presentation slideshow function with a click of mouse for
each time point.
This file can be viewed with: Microsoft PowerPoint Viewer
Proposed model of transformation
We propose that water activity sensors, present on the surface of
mammalian cells, survey the hydration status of the environment and may
be a type of membrane bound protein kinase(s). In plants,
mitogen-activated protein (MAP) kinases [25-27] and phospohlipase D 
have been upstream responders to the drought stress signaling pathway
in Arabidopsis. A study of osmotic-stress-related proteins in rice has
identified 12 specific proteins including kinases .
Water sensing may be a conserved mechanism throughout eukaryotes and
mammalian cells may use similar MAP kinases for intracellular
signaling. These sensors, when triggered, invoke a signaling cascade
resulting in stress related transcriptional activity in the nucleus. As
a result, we postulate that in mammalian cells, one of the potential
protective responses involves a dramatic change in cell morphology
resulting in the formation of straw cells.
Fragmentation of the CACO-2 nucleus (Figure 8,
arrow), along with a synthesis of tubular wall was observed during the
straw cell transformation process. The time-lapse images were obtained
over the entire dehydration process using light microscopy and TEM.
These images reveal the presence of polymers assembled along the
nuclear membrane (arrows). These subunits are hypothesized to be the
building material for the tubular cell wall, presumably, after they
have cross-linked to each other.
Figure 8 Proposed mechanism of tubular transformation. Water activity sensors on
the cell surface survey the hydration status of the environment. Once
triggered, they send signals to the nucleus, triggering drastic changes
in the entire cell that result in a fragmented nucleus (arrow) and a
synthesis of cell wall materials (arrow). The fragmented nucleus, with
filamentous branches, resides in the center of fortified tubular
structure. Scale bar is 0.2 μm.
Figure 5c Carbohydrate compositions by Mass spectrometry. Structures of identified polysaccharides.
In an attempt to identify the presence of the surface
water activity sensors and subsequent proteins involved in the signal
cascade, we used small molecules to inhibit straw cell transformation.
Initial results indicated that this process could be manipulated and
inhibited with naturally occurring compounds as well as synthetic
compounds. For example, changes in membrane fluidity by salts and
sugars (1%) disrupt the tubulFigure 8ar transformation; antibiotics
(azithromysin) that inhibit protein synthesis interfered with the
tubular transformation by producing filaments that were somewhat
Implication in human diseases
The large quantities of straw cells and their ubiquitous nature make
them a potential unifying factor across a diversity of age related
diseases. The conversion of cells into straw cells may be involved in
the initial onset and progression of these diseases, the causes of
which are still unknown. Moreover, straw cell formation may be a common
physiological response in various types of human degenerative disease.
Another area of human health where this phenomenon may play a role is
tumor development and proliferation. The hydrophilic, mobile,
detachment of straw cells may be a key component of metastasis. As
such, hydrophilic straw cells from cancer cells may possibly move
around in extracellular fluid and find new locations to grow.
There are many unanswered questions regarding the composition of
these tubular cell structures found in a variety of mammalian tissues.
For example, what suite of genes encodes the instructions governing the
assembly of these tubular structures? What are the necessary molecules
for making "unions" and "tees" in the filaments so as to form straw
cell networks? Is straw cell transformation a conserved mechanism that
mammalian cells use in response to the stress of dehydration and
perhaps other stress inducing environmental factors? What is the
physiological role of straw cell formation in vivo? How much dehydration occurs inside the body either locally or systemically?
Because the cellular transformation is reproducible in vitro in
a 96-well plate, screening chemical libraries for inhibitory compounds
to filamentous transformation is feasible and may result in the ability
to control straw cell development in vivo. This may have implications in mediating degenerative diseases and tumor proliferation. For example, an In vitro assay
using azithromysin at 10 ppm resulted in mammalian straw cells with
both smaller straw cells and shortened filaments (Wu et al.,
unpublished data). One type of strategy could include selectively
inhibiting protein kinases on the cell surface desensitizing the stress