Johns Hopkins researchers have identified a novel
way in mice through which mammals — presumably
including people — can regenerate hair follicles and
skin while healing from wounds.
The discovery, summarized in an article published
last week in the journal Cell Stem Cell, could, they
say, eventually help spur the growth of new hair,
skin or other organ tissue in scarred victims of
burns and other injuries.
Untreated skin cells (left) show little activity of
the regeneration protein Wnt7b, shown in green,
compared to skin cells treated with an agent which
activates TLR3 (right). Image: Johns Hopkins
Medicine
"The study uncovers a novel role for a protein that
works as a master regulator of regeneration in the
skin," says senior study author Luis A. Garza,
associate professor of dermatology at the Johns
Hopkins University School of Medicine. "Medications
that turn on this protein have the powerful
potential to decrease scarring as healing of wounds
takes place, thereby promoting skin and hair
follicle regeneration."
Garza says his team's work is based on the knowledge
that damaged skin releases double-stranded RNA, or
dsRNA — genetic information normally carried by some
viruses — that is sensed by a specific protein known
as toll-like receptor 3, or TLR3.
TLR3 plays a fundamental role in recognizing some
disease-causing organisms and activating the immune
system. During wounding, it also activates genes
(IL6 and STAT3) and molecules to promote hair
follicle regeneration and development and a gene
that plays an important role in skin development.
Developing embryos have all of the instructions they
need to make organs and skin in genetic material
within the cells, says Garza. Advanced knowledge
about this cell signaling pathway may lead to
therapies that reactivate these early developmental
signals to promote healing.
"A lot of human disability is from scarring," Garza
says. "After a heart attack, we're really good at
replacing the blood flow, but it's the scar on the
heart afterward that's the real problem. We and
others in the field of regenerative medicine are
interested in how to enhance or trigger regeneration
in such situations."
For the study, Garza and colleagues compared the
protein expression of certain genes in healed wounds
in two groups of mice. One group was genetically
proficient in wound-induced hair neogenesis, a
process in mice and rabbits in which skin and hair
follicles regenerate after wounds. The other inbred
group of mice was noted to lack this ability.
Expression of TLR3 was three times higher in the
mice that were better able to regenerate hair.
In other experiments, the team found that the
expression of TLR3 was five times higher in
scratched human skin cell samples compared to
healthy skin cell samples, that adding synthetic
dsRNA to mouse skin wounds led to a greater number
of regenerated follicles, that adding a substance
that breaks up dsRNA decreased the number of
regenerated follicles, and that regeneration was
nearly nonexistent in mice deficient in TLR3.
Garza notes that it has long been known that skin
damage can trigger regeneration. Several cosmetic
dermatological procedures, including chemical peels,
dermabrasion, and laser treatments, have been used
to do that for decades. But Garza cautions that
clinical applications of the team's discoveries must
await many more experiments and the development and
testing of drugs that target the pathway they
uncovered.
"One implication from our work is that all of those
different rejuvenation techniques are likely working
through dsRNA pathways," he says. "It may also be
that dsRNA could be directly used to stimulate
rejuvenation in aging or hair follicle growth in
burn patients to regain structures that have been
lost."
Study coauthors were Amanda M. Nelson, Ph.D.;
Sashank K. Reddy, M.D., Ph.D.; Tabetha S. Ratliff;
M. Zulfiquer Hossain, Ph.D.; Adiya S. Katseff;
Amadeus S. Zhu; Emily Chang; Sydney R. Resnik; Carly
Page, Ph.D.; Dongwon Kim, Ph.D.; Alexander J.
Whittam; and Lloyd S. Miller, M.D., Ph.D.
For more information
Cell Stem Cell
dsRNA Released by Tissue Damage Activates TLR3 to
Drive Skin Regeneration
DOI:
http://dx.doi.org/10.1016/j.stem.2015.07.008
Garza Laboratory
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