A magnification of
the four distinct strata of human skin. At the top is the stratum corneum
consisting of several layers of flat, dead, waterproof keratinocytes -- the
outer layer of skin cells. Beneath the stratum corneum are the strata
granulosum, spinosum and basale. It is in the stratum basale that resident stem
cells differentiate to provide new cells and renew the skin. Below the stratum
basale is the dermis, a collagen rich tissue that cushions the body. Credit: UC
San Diego School of Medicine
In the July 6 issue
of Cell Stem Cell, researchers at the University of California, San Diego
School of Medicine describe how human epidermal progenitor cells and stem cells
control transcription factors to avoid premature differentiation, preserving
their ability to produce new skin cells throughout life.
The findings provide new insights into the role and
importance of exosomes and their targeted gene transcripts, and may help point
the way to new drugs
or therapies for not just skin diseases, but
other disorders in which stem and progenitor cell populations are
affected.
Stem cells, of course, are specialized cells capable of
endlessly replicating to become any type of cell needed, a process known as
differentiation. Progenitor cells are more limited, typically differentiating
into a specific type of cell and able to divide only a fixed number of times.
Throughout life, human skin self-renews.
Progenitor and stem
cells deep in the epidermis constantly produce new skin cells called
keratinocytes that gradually rise to the surface where they will be sloughed
off. One of the ways that stem and progenitor cells maintain internal health
during their lives is through the exosome – a collection of approximately 11
proteins responsible for degrading and recycling different RNA elements, such
as messenger RNA that wear out or that contain errors resulting in the
translation of dysfunctional proteins which could potentially be deleterious to
the cell.
"In short," said George L. Sen, PhD, assistant
professor of medicine and cellular and molecular medicine, "the exosome
functions as a surveillance system in cells to regulate the normal turnover of
RNAs as well as to destroy RNAs with errors in them."
Sen and colleagues Devendra S. Mistry, PhD, a
postdoctoral research fellow, and staff scientist Yifang Chen, MD, PhD,
discovered that in the epidermis the exosome functions to target and destroy
mRNAs that encode for transcription
factors that induce differentiation. Specifically, they found that the
exosome degrades a transcription factor called GRHL3 in epidermal progenitor
cells, keeping the latter undifferentiated. Upon receiving differentiation
inducing signals, the progenitor cells lose expression of certain subunits of
the exosome which leads to higher levels of GRHL3 protein. This increase in
GRHL3 levels promotes the differentiation of
the progenitor cells.
"Without a functioning exosome in progenitor
cells," said Sen, "the progenitor cells prematurely differentiate due
to increased levels of GRHL3 resulting in loss of epidermal tissue over
time."
Sen said the findings could have particular relevance if
future research determines that mutations in exosome genes are linked to skin
disorders or other diseases. "Recently there was a study showing that
recessive mutations in a subunit of the exosome complex can lead to
pontocerebellar hypoplasia, a rare neurological disorder characterized by
impaired development or atrophy of parts of the brain," said Sen.
"This may potentially be due to loss of progenitor cells.
Once mutations in exosome complex genes are identified in either skin diseases
or other diseases like pontocerebellar hypoplasia, it may be possible to design
drugs targeting these defects."
Provided by University
of California - San Diego
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