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Sodium plays key role in tissue regeneration
October, 2010--Sodium gets a bad rap for
contributing to hypertension and
cardiovascular disease. Now biologists at
Tufts University's School of Arts and
Sciences have discovered that sodium also
plays a key role in initiating a
regenerative response after severe injury.
The Tufts scientists have found a way to
regenerate injured spinal cord and muscle by
using small molecule drugs to trigger an
influx of sodium ions into injured cells.
The approach breaks new ground in the field of
biomedicine because it requires no gene
therapy; can be administered after an injury
has occurred and even after the wound has
healed over; and is bioelectric, rather than
chemically based.
In a paper appearing as the cover story of the
September 29, 2010, issue of theJournal of
Neuroscience, the Tufts team reported that a
localized increase in sodium ions was
necessary for young Xenopus laevis tadpoles
to regenerate their tails – complex
appendages containing spinal cord, muscle
and other tissue.
Like human beings, who regenerate fingertips
only as children, these tadpoles lose the
ability to regenerate their tail with age.
Most remarkably, it was shown that such
"refractory" tadpoles whose tails had been
removed could be induced to make a perfect
new tail by only an hour of treatment with a
specific drug cocktail.
The findings have tremendous implications for
treating wounds sustained in war as well as
accidental injuries. The treatment method
used is most directly applicable to spinal
cord repair and limb loss, which are highly
significant medical problems world-wide. It
also demonstrates a proof-of-principle that
may be applicable to many complex organs and
tissues.
"We have significantly extended the effective
treatment window, demonstrating that even
after scar-like wound covering begins to
form, control of physiological signals can
still induce regeneration. Artificially
causing an influx of sodium for just one
hour can overcome a variety of problems,
such as the decline in regenerative ability
that comes with age and the effect of
regeneration-blocking drugs," said Tufts
Professor of Biology Michael Levin, Ph.D.,
corresponding author on the paper and
director of the Center for Regenerative and
Developmental Biology at Tufts. Co-authors
were Research Associate Ai-Sun Tseng,
Postdoctoral Associate Wendy S. Beane,
Research Associate Joan M. Lemire, and
Alessio Masi, a former post-doctoral
associate in Levin's laboratory.
The transport of ions in and out of cells is
regulated by electronic security doors, or
gates, that let in specific ions under
certain circumstances. A role for sodium
current in tissue regeneration had been
proposed in the past, but this is the first
time the molecular-genetic basis of the ion
flow has been identified, and a specific
drug-based treatment demonstrated. Until
now, advances in this model system had
involved administering therapies before the
injury was sustained.
"This is a novel, biomedically-relevant
approach to inducing regeneration of a
complex appendage," noted Levin.
The Tufts research established a novel role in
regeneration for the sodium channel Nav1.2,
a crucial component of nerve and cardiac
function. It showed that local, early
increase in intracellular sodium is required
for initiating regeneration following
Xenopus tail amputation, while molecular and
pharmacological inhibition of sodium
transport causes regenerative failure. The
new treatment induced regeneration only of
correctly-sized and patterned tail
structures and did not generate ectopic or
other abnormal growth.
"The ability to restore regeneration using a
temporally-controllable pharmacological
approach not requiring gene therapy is
extremely exciting," said the researchers.
Of critical importance, they said, was the
discovery that the tail could be induced to
regenerate as late as 18 hours after
amputation, revealing that tissues normally
fated for regenerative failure still
maintain their intrinsic characteristics and
can be programmed to reactivate
regeneration.
Amphibians such as frogs can restore organs
lost during development, including the lens
and tail. The frog tail is a good model for
human regeneration because it repairs injury
in the same way that people do: each tissue
makes more of itself. (In contrast,
regeneration in some other animals occurs
through transdifferentiation (one cell type
turns into another cell type) or adult stem
cell differentiation. Furthermore, though
small, the Xenopus larval tail is complex,
with muscle, spinal cord, peripheral nerves
and vasculature cells.
