New findings may increase longevity of stem cells

By B.D. Colen
Harvard News Office

Identifying the mechanisms that control cell life span is one of the
more important questions facing stem cell researchers, indeed, all
researchers attempting to understand normal and abnormal cell and organ
development. So the recent discovery by a Harvard Stem Cell Institute
team that a family of well-known transcription factors plays a major
role in regulating the life span and longevity of hematopoietic, or
blood, stem cells is of particular note. Transcription factors are
proteins that participate in the synthesis of RNA using a DNA template.

Gary Gilliland, director of Harvard Stem Cell Institute's (HSCI) Cancer
Stem Cell Program, and colleagues at Brigham and Women's Hospital and
the Dana-Farber Cancer Institute believe that their findings may have
broad implications for stem cells in other tissue types as well, and
may eventually lead to strategies to increase cell longevity.

It is possible, the researchers say, that their findings could
eventually lead to ways to enhance the blood stem cells that are at the
heart of the bone marrow transplants used to treat leukemia.

Gilliland, a professor of medicine at Harvard Medical School (HMS) and
a Howard Hughes Medical Institute investigator, said that the recent
findings from his lab and Ronald A. DePinho's lab at Dana-Farber "have
important implications for normal stem cell biology, and for cancer
stem cells.

"In brief, we have shown that a highly redundant family of
transcription factors, FoxO, is required for regulation of longevity
and life span of normal adult hematopoietic stem cells. Furthermore,"
said Gilliland, "the critical effectors of FoxO function are genes that
regulate response to reactive oxygen species - these findings thus have
important implications for strategies that might seek to modulate
longevity of adult tissue stem cells."

Zuzana Tothova, an HMS graduate student in Gilliland's lab and the lead
author of the report on the work in the journal Cell, said that when
three types of Fox0 genes were switched off, the life span of the
hematopoietic stem cells was sharply reduced. In an accompanying Cell
paper, a group lead by DePinho, an HMS professor of medicine, reported
that the FoxO genes also have tumor suppressor functions.

Tothova said that the findings of both groups of researchers add to the
understanding of the molecular mechanisms limiting the life span of
blood stem cells. And understanding the mechanisms limiting the life
span is essential to finding ways to increase it.

Gilliland explained that the findings indicate that the FoxO proteins
"play essential roles in the response to physiologic stress related to
oxidation," which has implications in other types of tissues. It might
conceivably be possible, he said, to increase cellular longevity by
findings ways to protect the cells against the effect of reactive
oxygen.

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