Nociceptive neurons typically lie in an
electrically inactive state under resting
conditions ( 8 ). Upon activation by noxious
stimuli, nociceptive signals are transduced
and sent to the brain through neurons in
the form of an electrical impulse ( 1 ). To
investigate a potential role for the newly
described nociceptive Schwann cells in
the detection of pain-inducing stimuli, the
authors used a technique called optogenet-
ics to modulate the activity of these cells
with light. Taking advantage of the super-
ficial location of the nociceptive Schwann
cell–nociceptor network on the foot pads of
mice, Abdo et al. found that light stimula-
tion of nociceptive Schwann cells produced
a light intensity–dependent limb with-
drawal coupled with an increase in noci-
ceptor firing rates.
Although limb withdrawal under condi-
tions of nociceptive Schwann cell–specific
stimulation supports the idea that these
cells are sensing pain, the behavioral re-
sponse could also be in reaction to a touch
or pressure sensation. Certain behaviors,
such as licking or shaking coupled with
paw withdrawal or guarding upon or
shortly after stimulation, are considered
pain-specific responses ( 9 ). Stimulation of
the nociceptive Schwann cells in mice us-
ing optogenetics led to significant increases
in all of these pain behaviors.
Pain can be caused by a variety of in-
sults, ranging from pressure and touch to
extreme heat or cold. To elucidate specific
stimuli to which nociceptive Schwann cells
are sensitive, subthreshold light stimula-
tion was used to sensitize physiological
stimuli: cold, heat, and mechanical stimuli.
This resulted in responsiveness to all three
stimuli. Moreover, although inhibition of
nociceptive Schwann cell signaling did not
reduce cold or heat sensitivity, mechani-
cal thresholds were significantly increased
when mouse foot pads were poked with fil-
aments. Complementary electrophysiologi-
cal investigations indicated that cultured
nociceptive Schwann cells responded to
changes in force very quickly and adapted
to sustained force over time. These results
indicate that nociceptive Schwann cells
physiologically contribute to the sensation
of mechanical pain.
Nociception plays a crucial role in how
animals interact with the environment,
providing an enhanced awareness of sur-
roundings as well as ensuring safety and
well-being. When this essential system
does not function as expected, however,
unpleasant and debilitating side effects
such as pain can occur. Chronic pain has
become a focus of attention as opioid ad-
diction continues to debilitate lives and
cause mortality. From diseases such as os-
teoarthritis to diabetes, the development
of chronic pain resulting from injury to
the nociceptive network is a challenge for
which therapeutics remain problematic.
The long-standing belief has been that
nociception is an axonally driven process,
with perception occurring in the most dis-
tal nerve endings, which were previously
thought to be free of any glial ensheath-
ment. The discovery by Abdo et al. of no-
ciceptive Schwann cells that cross the
basement membrane into the epidermis,
where they form a mesh-like nociceptive
network with the axonal field, changes this
view and provides a new potential target
cell for pain medication.
The nociceptive Schwann cells function
in conjunction with sensory nerve fibers
to transduce and signal tactile sensations.
Further studies to tease apart how these
nociceptive Schwann cells signal to sensory
nerves will improve understanding of these
glial cells and their role in nociception.
Previous RNA-sequencing studies suggest
that Schwann cells along peripheral nerves
express mechanosensitive Piezo ion chan-
nels ( 10 ); understanding how mechanical
stimuli influence Schwann cell biology is an
area of growing interest ( 11 ). In the future,
it will be interesting to determine whether
and how Piezo channels function in noci-
ceptive Schwann cells to initiate pain sen-
sation. Given that nonglial skin cells can
clear debris after axon damage ( 12 ), it will
be important to investigate how these no-
ciceptive Schwann cells respond to axon in-
jury and function in disease states. Further
investigation of this new sensory network
cell discovered by Abdo et al. will provide a
clearer understanding of how the body per-
ceives pain and may lay the foundation for
more targeted and effective therapeutics. jREFERENCES AND NOTES- A. E. Dubin, A. Patapoutian, J. Clin. Invest. 120 , 3760
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ACKNOWLEDGMENTS
We thank K. Wright for helpful discussions. R.A.D. acknowledges
funding from National Institute of Neurological Disorders and
Stroke training grant T32NS007446.10.1126/science.aay6144sciencemag.org SCIENCEINSIGHTS | PERSPECTIVES
By Marnix JansenT
he surface of the intestines com-
prises epithelial cells arranged in
villi, at the base of which are the
crypts where intestinal stem cells
that produce the epithelial cells are
located. These crypts have become
the cell biologist’s favorite model system
for understanding epithelial stem cell bi-
ology and lineage differentiation. In stark
contrast, the biophysical underpinnings of
crypt-villus biology have received consider-
ably less attention. The simple model that
has been accepted for many years is one
of epithelial cells passively moving along
a conveyor from the crypt to the top of the
villus, pushed forward by stem cells con-
tinuously producing daughter cells at the
base of the crypt. On page 705 of this issue,
Krndija et al. ( 1 ) reveal that this model is
incorrect and that instead, mouse intes-
tinal epithelial cells actively crawl up the
villus after they exit the crypt.
Studies using either induced labeling or
naturally occurring markers of stem cell
lineage in mice and humans, respectively,
have shown that intestinal epithelial cells
leave the crypt and move up the villus in
an orderly manner ( 2 , 3 ). These migratory
streams of cells can be observed as tightly
arranged ribbons along the villus, indicat-
ing that epithelial cells move in cohorts
and rarely break formation ( 4 , 5 ). Once
epithelial cells reach the villus tip, they are
actively extruded from the epithelial sheet,
and the rate of elimination is dependent
on the degree of crowding ( 6 ). This dy-
namic behavior is largely invisible without
external manipulation and must be tightly
regulated to facilitate nutrient absorption
and avoid defects in the epithelial barrier.
Krndija et al. arrive at their conclusion
through a set of fascinating experiments
combined with mathematical modeling.
They first injected mice with hydroxyurea, anCELL BIOLOGYMarching out
of the crypt
Intestinal epithelial cells
actively migrate up
the villus, challenging
a long-held view
UCL Cancer Institute, University College London, UK.
Email: [email protected]642 16 AUGUST 2019 • VOL 365 ISSUE 6454