Adult stem cells lack key pluripotency regulator
CAMBRIDGE, Mass. (October 10, 2007) - The protein Oct4 plays a major role
in embryonic stem cells, acting as a master regulator of the genes that
keep the cells in an undifferentiated state. Unsurprisingly, researchers
studying adult stem cells have long suspected that Oct4 also is critical
in allowing these cells to remain undifferentiated. Indeed, more than 50
studies have reported finding Oct4 activity in adult stem cells.
But those findings are misleading, according to research in the lab of Whitehead Member Rudolf Jaenisch.
In a paper published online in Cell Stem Cells on October 10, postdoctoral
fellow Christopher Lengner has shown that Oct4 is not required to maintain
mouse adult stem cells in their undifferentiated state, and that adult tissues
function normally in the absence of Oct4. Furthermore, using three independent
detection methods in several tissue types in which Oct4-positive adult stem cells
had been reported, Lengner found either no trace of Oct4, or so little Oct4 as
to be indistinguishable from background readings.
"This is the definitive survey of Oct4," says Rudolf Jaenisch. "It puts all those claims of pluripotent adult stem cells into perspective." |
This means that pluripotency, the ability of stem cells to change into
any kind of cell, is regulated differently in adult and embryonic stem cells.
"This is the definitive survey of Oct4," says Jaenisch, who is also an MIT
professor of biology. "It puts all those claims of pluripotent adult stem cells into perspective."
Oct4 is essential in maintaining the pluripotency of embryonic stem cells,
but only for a short time before the embryo implants in the uterine wall.
After implantation Oct4 is turned off, and the cells differentiate into
all of the 200-plus cell types in the body.
"We have convincingly shown that Oct4 has no role in adult stem cells," says Lengner.
He initially set out to determine how tissues previously shown to express
Oct4 (the intestinal lining, brain, bone marrow, and hair follicle)
functioned without the protein. To do so, he bred mice in which the Oct4
gene had been deleted from a given tissue type.
Next, Lengner stressed the tissue in several ways, forcing the adult
stem cells within to regenerate the tissue. All regenerated normally.
Lengner and his fellow researchers then tested to confirm that Oct4
had indeed been deleted from these cells. Finally, the researchers set
out to validate the previously published reports claiming Oct4 was
expressed in these adult stem cell types. Using highly sensitive assays
that could detect Oct4 at the single cell level, they were unable to confirm the earlier reports.
"This is a cautionary tale of believing what you read in the
literature," says Lengner, who suggests that earlier studies may have misapplied
tricky analytical techniques or worked with cell cultures
that had spent too much time in an incubator.
"We now know that adult stem cells regulate their pluripotency,
or 'stemness', using different mechanisms from embryonic stem cells,
and we're studying these mechanisms," he says. "Is there a common pathway
that governs stemness in different adult stem cells, or does each
stem cell have its own pathway? We don't yet know."
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