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0:06
Now I'd like to just
take each pathway
and discuss what goes on as
you mature from the progenitor.
And we're showing here
the CFU-GM and its ability
to give rise under the influence
of G-CSF to granulocytes,
and under the influence
of M-CSF to monocytes.
0:34
Granulopoiesis takes about five
to seven days from the progenitor
stage to the production
of the mature polymorph
with its characteristic
segmented nucleus.
0:53
This is now to describe one of
the cytokines that's become very
important because
of its clinical use
as the granulocyte-colony
stimulating factor.
It selectively promotes the
generation of neutrophils
and it induces proliferation
and differentiation
of the myeloid progenitor cell.
It is required at every step throughout the differentiation lineage.
It's not just an initiator
of differentiation.
Differentiation requires it even at
the terminal stage of maturation.
And if the terminal
maturation does not occur,
cells can be generated that
are partially differentiated,
and they have completely
different properties.
They become myeloid derived
suppressor cells, which actually
behave as suppressors
of the immune system.
They inhibit T lymphocytes,
and they actually
favor the production of tumors.
They're the Darth Vaders, if you
will, of the hematopoietic system.
But if they're allowed to
differentiate completely
to neutrophils, the neutrophil
is a major protector of the body
against bacterial
infection, and it also
has very potent activities
in killing tumor cells.
It uses the same mechanism to
kill bacteria by throwing out
a net, comprised of its nuclear
DNA, to surround the bacterium
or the tumor cell and releasing its
granule content of toxic substances
and kill quite effectively.
When it does so, it dies and has
to be replaced by a new population
of neutrophils that
migrate to the site
of inflammation or the tumor site.
It has no effect on the
more primitive cells
outside the G-CSF
progenitor pathway.
But interestingly, if you give
G-CSF for a number of days,
it actually mobilizes,
from the bone marrow
into the peripheral blood,
hematopoietic stem cells.
The way it does this is it
actually crowds the bone marrow out
with differentiating
granulocyte cells.
And this crowding actually
results in pushing
out the stem cells from their niche.
So it's almost a
mechanical crowding out
process that results
in this mobilization,
together with some enzymes
that cleave certain tethering
molecules such as the integrins
and some of the bound cytokines.
So clinically, G-CSF has a major use
in stem cell harvesting, stem cell
mobilization to
transplantation purposes.
But its major use is to
prevent the decline,
or at least reduce the decline, in
neutrophils following chemotherapy
or radiation therapy in patients.
It is the decline and the
loss of neutrophils that
make patients very
susceptible to infection.
And there was a lot of morbidity
and mortality associated
with high-dose chemotherapy until
G-CSF came along and could be used
to greatly reduce the period of
neutropenia when a patient was very
susceptible to these
infectious events.
