Despite the
promise associated with the therapeutic use of human stem cells, a complete
understanding of the mechanisms that control the fundamental question of
whether a stem cell becomes a specific cell type within the body or remains a
stem cell has—until now—eluded scientists.
A University of
Georgia study published in Cell Stem Cell,
however, creates the first ever blueprint of how stem cells are wired to
respond to the external signaling molecules to which they are constantly
exposed. The finding, which reconciles years of conflicting results from labs
across the world, gives scientists the ability to precisely control the
development, or differentiation, of stem cells into specific cell types.
“We can use
the information from this study as an instruction book to control the behavior
of stem cells,” said lead author Stephen Dalton, Georgia Research Alliance
Eminent Scholar of Molecular Biology and professor of cellular biology in the
UGA Franklin College of Arts and Sciences. “We’ll be able to allow them to
differentiate into therapeutic cell types much more efficiently and in a far
more controlled manner.”
The previous
paradigm held that individual signaling molecules acted alone to set off a
linear chain of events that control the fate of cells. Dalton’s study, on the
other hand, reveals that a complex interplay of several molecules controls the
“switch” that determines whether a stem cell stays in its
undifferentiated state or goes on to become a specific cell type, such as a
heart, brain, or pancreatic cell.
“This work
addresses one of the biggest challenges in stem cell research-figuring out how
to direct a stem cell toward becoming a specific cell type,” said Marion
Zatz, who oversees stem cell biology grants at the National Institutes of
Health’s National Institute of General Medical Sciences, which partially
supported the work.
“In this
paper, Dr. Dalton puts together several pieces of the puzzle and offers a model
for understanding how multiple signaling pathways coordinate to steer a stem
cell toward differentiating into a particular type of cell. This framework
ultimately should not only advance a fundamental understanding of embryonic
development, but facilitate the use of stem cells in regenerative medicine.”
To get a sense of
how murky the understanding of stem cell differentiation was, consider that
previous studies reached opposite conclusions about the role of a common
signaling molecule known as Wnt. About half the published studies found that
Wnt kept a molecular switch in an “off” position, which kept the stem
cell in its undifferentiated, or pluripotent, state. The other half reached the
opposite conclusion.
Could the same
Wnt molecule be responsible for both outcomes? As it turns out, the answer is
yes. Dalton’s
team found that in small amounts, Wnt signaling keeps the stem cell in its
pluripotent state. In larger quantities, it does the opposite and encourages
the cell to differentiate.
But Wnt doesn’t
work alone. Other molecules, such as insulin-like growth factor (Igf),
fibroblast growth factor (Fgf2), and Activin A also play a role. To complicate
things further, these signaling molecules amplify each other so that a two-fold
increase in one can result in a 10-fold increase in another. The timing with which
the signals are introduced matters, too.
“One of the
things that surprised us was how all of the pathways ‘talk’ to each
other,” Dalton
said. “You can’t do anything to the Igf pathway without affecting the Fgf2
pathway, and you can’t do anything to Fgf2 without affecting Wnt. It’s like a
house of cards; everything is totally interconnected.”
Dalton and his
team spent a painstaking five years creating hypotheses about the how the
signaling molecules function, testing those hypotheses, and-when faced with an
unexpected result-rebuilding their hypotheses and re-testing. This process
continued until the entire system was resolved.
Their finding
gives scientists a more complete understanding of the first step that stem
cells take as they differentiate, and Dalton
is confident that the same approach can be used to understand subsequent
developmental steps that occur as the cells in an embryo divide into ever-more
specific cell types.
“Hopefully this type of
approach will give us a greater understanding of cells and how they can be
manipulated so that we can progress much more rapidly toward the routine use of
stem cells in therapeutic settings,” Dalton
said.
