Adapted from “A Molecular Model of Blood Cell Renewal.” ©2004 by the Public Library of Science.
A developing organism captured on time-lapse video is a
wonder to behold. If you’re watching a chick embryo, by day 3,
you’ll see millions of cells engaged in a frenzy of activity, as
rapidly dividing cells migrate to new positions, acquire the
characteristics of specialized cells, and craft well-defined
tissues, organs, and limbs in just under two weeks. In addition
to the cells destined for specialization is another important
group, stem cells, whose progeny have two very different fates.
They can either “self renew”—that is, make identical copies of
themselves—or generate intermediate progenitor cells that give
rise to mature, differentiated cells.
Both differentiation and self renewal are guided by an
elaborately regulated genetic program, which transforms
embryonic stem cells into the many different cell types that
make up the body. Adult stem cells share the hallmark trait of
self renewal, but are relatively rare: in bone marrow, the source
of hematopoiesis, or blood [formation], only an estimated one
in 10,000–15,000 cells is an adult hematopoietic stem cell
(HSC).
Studies that have compared the gene expression profiles of
different types of stem cells to identify genetic signatures of
“stemness” have found only a limited number of signature
genes. And the molecular mechanisms that regulate this so-
called potency and the self renewal process have remained
obscure. Now, focusing on HSCs, Margaret Goodell and
colleagues have undertaken a systematic evaluation of HSC
renewal. The study identifies molecular signatures associated
with discrete stages of the HSC self renewal cycle and
proposes a molecular model of the process.
HSC renewal passes through three stages: quiescence,
activation and proliferation, and a return to the dormant state.
HSCs give rise to both red blood cells, which carry oxygen and
carbon dioxide, and white blood cells, which fight infection.
Once activated by a trigger, dormant HSCs engage a regulatory
program that rapidly churns out billions of cells, then puts the
brakes on cell division, prompting the return to a nondividing,
quiescent state.
To understand the genetic programs underlying this process,
Goodell and colleagues induced proliferation in HSCs (with the
chemotherapeutic drug, 5-fluorouracil, or 5FU), then allowed
the cells to return to quiescence, so they could characterize the
changes in gene expression that occurred during each stage.
They compared these time-specific patterns to the gene
expression profiles of naturally proliferating fetal mouse HSCs
(which undergo massive proliferation) and quiescent adult
mouse HSCs (which hardly divide at all) to find genes
associated with the two different states.
Genes were grouped into proliferating or quiescent groups
based on when they were expressed after 5FU treatment, and
these groupings were refined based on comparisons to
previously published HSC gene expression data. Functional
analysis of these genes found a bias toward genes involved in
cell division processes in the proliferation stage and toward cell
division inhibitors in the quiescent stage, supporting the logic
of the groupings.
With these results, Goodell and colleagues constructed a
model of the HSC self renewal cycle: quiescent HSCs maintain
a “state of readiness,” molecularly speaking, that allows a
quick response to environmental triggers. A stressor (like the
chemotherapy mentioned above) triggers a “prepare to
proliferate” state—a kind of pregnant pause—and then the
proliferation machinery kicks in, going through an early and
late phase before quiescence returns. By shedding light on the
molecular mechanisms of stem cell renewal, this study will aid
efforts to develop stem-cell-based clinical therapies, which
depend on replicating the HSC self renewal cycle to replenish
diseased or damaged tissue, and will ultimately guide efforts to
grow stem cell colonies outside the body, a long-standing goal
that would have many clinical applications.
A developing organism captured on time-lapse video is a
wonder to behold. If you’re watching a chick embryo, by day 3,
you’ll see millions of cells engaged in a frenzy of activity, as
rapidly dividing cells migrate to new positions, acquire the
characteristics of specialized cells, and craft well-defined
tissues, organs, and limbs in just under two weeks. In addition
to the cells destined for specialization is another important
group, stem cells, whose progeny have two very different fates.
They can either “self renew”—that is, make identical copies of
themselves—or generate intermediate progenitor cells that give
rise to mature, differentiated cells.
Both differentiation and self renewal are guided by an
elaborately regulated genetic program, which transforms
embryonic stem cells into the many different cell types that
make up the body. Adult stem cells share the hallmark trait of
self renewal, but are relatively rare: in bone marrow, the source
of hematopoiesis, or blood [formation], only an estimated one
in 10,000–15,000 cells is an adult hematopoietic stem cell
(HSC).
Studies that have compared the gene expression profiles of
different types of stem cells to identify genetic signatures of
“stemness” have found only a limited number of signature
genes. And the molecular mechanisms that regulate this so-
called potency and the self renewal process have remained
obscure. Now, focusing on HSCs, Margaret Goodell and
colleagues have undertaken a systematic evaluation of HSC
renewal. The study identifies molecular signatures associated
with discrete stages of the HSC self renewal cycle and
proposes a molecular model of the process.
HSC renewal passes through three stages: quiescence,
activation and proliferation, and a return to the dormant state.
HSCs give rise to both red blood cells, which carry oxygen and
carbon dioxide, and white blood cells, which fight infection.
Once activated by a trigger, dormant HSCs engage a regulatory
program that rapidly churns out billions of cells, then puts the
brakes on cell division, prompting the return to a nondividing,
quiescent state.
To understand the genetic programs underlying this process,
Goodell and colleagues induced proliferation in HSCs (with the
chemotherapeutic drug, 5-fluorouracil, or 5FU), then allowed
the cells to return to quiescence, so they could characterize the
changes in gene expression that occurred during each stage.
They compared these time-specific patterns to the gene
expression profiles of naturally proliferating fetal mouse HSCs
(which undergo massive proliferation) and quiescent adult
mouse HSCs (which hardly divide at all) to find genes
associated with the two different states.
Genes were grouped into proliferating or quiescent groups
based on when they were expressed after 5FU treatment, and
these groupings were refined based on comparisons to
previously published HSC gene expression data. Functional
analysis of these genes found a bias toward genes involved in
cell division processes in the proliferation stage and toward cell
division inhibitors in the quiescent stage, supporting the logic
of the groupings.
With these results, Goodell and colleagues constructed a
model of the HSC self renewal cycle: quiescent HSCs maintain
a “state of readiness,” molecularly speaking, that allows a
quick response to environmental triggers. A stressor (like the
chemotherapy mentioned above) triggers a “prepare to
proliferate” state—a kind of pregnant pause—and then the
proliferation machinery kicks in, going through an early and
late phase before quiescence returns. By shedding light on the
molecular mechanisms of stem cell renewal, this study will aid
efforts to develop stem-cell-based clinical therapies, which
depend on replicating the HSC self renewal cycle to replenish
diseased or damaged tissue, and will ultimately guide efforts to
grow stem cell colonies outside the body, a long-standing goal
that would have many clinical applications.