YSM Issue 90.2

cell biology
FOCUS
to be affected by changes in PDFGA levels.
Fat stem cells that did not express CD24 were
unaffected by the deletion of the PDGFA-encoding
gene, and no changes were observed
in adipose depots that were not in the dermis.
Understanding the Mechanism
Once the researchers identified PDGFA as
a key player in the maintenance and growth
of CD24-expressing fat stem cells, the next
step was to understand exactly what role it
played in these processes. Using a program
called Ingenuity Pathway Analysis (IPA),
which analyzes gene expression data to
highlight key interaction networks, the researchers
sequenced the RNA of fat cell precursors
that had been treated with PDGFA
to identify pathways correlated with the protein.
The data highlighted significant changes
in pathways involved in proliferation, differentiation,
and survival—indicating that
PDGFA is significant in these processes; in
particular, their results implicated two pathways
called PI3K/AKT and MAPK.
The PI3K/AKT pathway is a signaling pathway
involved in cell proliferation, growth,
and metabolism. The research team’s data indicated
that the pathway could be activated
by PDGFA in mesenchymal cells, stem cells
that eventually differentiate into connective
tissue cells., They found that an increase of
PDGFA in treated cells correlated with an
increase in phosphorylated AKT—the major
signaling molecule involved in this pathway.
Further indicating a connection, the researchers
found that inhibition of the PI3K/
AKT pathway negated the effects of PDGFA
treatment, and deleting genes that encoded
AKT2, a protein in the pathway, reduced the
area of the dermal white adipose tissue in later
stages of hair growth. As with the previous
experiments, these effects were restricted to
CD24-expressing fat stem cells.
Although PDGFA seemed to only affect the
activity of this pathway in dermal white adipose
tissue, the PI3K/AKT pathway has been
shown to aid growth and maintenance in other
adipose tissue depots. The team speculated
that in dermal white adipose tissue, signals
from atrophied fat cells in the dermis may
have stimulated the activation of CD24-expressing
fat stem cells during the hair cycle.
They also predicted that aging reduces the
possibility of this activation. Similar mechanisms
are thought to activate other depots
for adipose tissue during obesity. For example,
one recent study showed that during a
high-fat diet, CD24 adipocyte stem cells are
activated to induce the expansion of abdominal
fat depots while subcutaneous fat depots
remain unchanged. This activation was
shown to occur when the bodily signals present
during obesity activate PI3K/AKT signaling,
similar to way PDGFA activated this
pathway and caused the expansion of dermal
white adipose tissue. In essence, the researchers
hypothesized that white adipose tissue depot-specific
mechanisms that activate PI3K/
AKT signaling could actually be used to regulate
many other types of adipose tissue. In
future, the team plans to identify the targets of
AKT2 to further elucidate the pathway connecting
PDGFA with dermal white adipose
tissue expansion and fat cell maturation.
Fun Fa(c)ts
So why is this one little molecular mechanism
important beyond its role in hair
growth? First of all, dermal white adipose tissue
has been shown to play a role in several
important bodily functions, including wound
healing, responses to infection, and thermal
regulation. As such, understanding the mechanisms
by which adipogenesis occurs may
help us identify how defects in the molecular
pathways contribute to diseases such as skin
disorders or immune response malfunctions.
According to Guillermo Rivera Gonzalez,
lead author on the paper, one future direction
for the team is to investigate how mature fat
cells communicate with the immune system
to affect the immune response. In particular,
he would like to examine the interaction between
the immune system and adipose tissue
in wound healing. Research on this interaction
could have important implications for
improving the body’s capacity to heal.
Another of the important functions of dermal
white adipose tissue is to maintain skin
integrity over time. As PDGFA levels decrease
with age, the pool of CD24-expressing
fat stem cells is also depleted, slowing the
rate at which new fat cells are generated. As a
result, aged skin is extremely thin and fragile
and loses elasticity, one of the reasons why
human skin wrinkles and becomes easily broken
with age. Thus, a better understanding of
the mechanisms involved in maintaining skin
integrity could potentially improve skincare
later in life. “If we can improve maintenance
of adipose tissue in aging, we could increase
the strength of the skin and it would be more
resistant to mechanical stretch that could
break the skin,” says Rivera Gonzalez.
Furthermore, as PDGFA has been shown to
be involved in regulating stem cells of other
tissues, its role in other types of adipose stem
cells outside of dermal white adipose tissue
can be further explored. “We may be able to
maintain fat in aged skin using PDGFA, or
PDGFA may regulate adipose stem cells in
other tissues,” said Horsley, the principal investigator
on the paper. As the full processes
of fat cell maturation have only recently begun
to be understood, there is a lot of potential
for future exploration into the many
applications of adipose tissue maintenance,
from cosmetics to old age.
Given the role of adipose tissue in countless
bodily processes, understanding the signaling
pathways involved in its functioning is critically
important. This study has provided one
of the first insights into how adipocyte stem
cells are maintained in the skin, or in any other
depot of adipose tissue. The future seems
bright in this area of study, and hopefully future
studies will further clarify this relatively
unknown but promising biological pathway.
ABOUT THE AUTHOR
JESSICA SCHMERLER
JESSICA SCHMERLER is a senior in Jonathan Edwards College majoring
in molecular, cellular & developmental biology, neuroscience track. She is
a member of the Yale Journalism Initiative, a freelance writer for Scientific
American MIND magazine, and Editor-in-Chief of the Yale Global Health
Review. She also works in William Cafferty’s lab studying spinal cord injury.
THE AUTHOR WOULD LIKE TO THANK Drs. Rivera Gonzalez and Horsley
for their time and enthusiasm about their research.
FURTHER READING
Rivera Gonzalez, G.C. et al. (2016). Skin Adipocyte Stem Cell Self-Renewal
Is Regulated by a PDGFA/AKT-Signaling Axis. Cell Stem Cell, 19, 738-751.
Inveroracit.
www.yalescientific.org
March 2017
Yale Scientific Magazine
21