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This is David Scadden.
I'm hematologist-oncologist at
Mass General Hospital, co-direct
the Harvard Stem Cell Institute, and
co-chair of the Department of Stem
Cell and Regenerative Biology
at Harvard University.
I'll be talking today
about niche oncogenesis,
the role of the hematopoietic
stem cell niche in particular,
and the development of malignancy.
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The stem cell niche is a concept
first proposed by Ray Schofield
back in 1978 when he was
looking at blood stem cells.
At the time, the method by
which cells were analyzed
was called a colony-forming unit
of the spleen-- a so-called CFU-S.
And he recognized that stem cells
that he had been able to isolate
from the spleen in these colonies
seemed to behave less robustly
than stem cells derived
from the bone marrow.
And he proposed what now seems to
be an entirely obvious concept,
that where a stem cell resides
was in some ways playing
a critical role for its
function-- that the niche was
the basis for stem cells
having regulated self-renewal
and differentiation.
It was a competing hypothesis at the
time, which was that stem cells had
their own intrinsic engineering
and were capable of going
in the direction
that they knew best.
And it was Ray Schofield
who proposed that there was
this imposition of
information from the tissue
in which the stem cell resided.
It was a concept initially, and
one that really did not have much
in the way of experimental
definition until some years later
and mostly in invertebrates.
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So the ability to then use
this information as a way
to try to understand
and experimentally
define how stem cells behaved
in vivo in mammalian systems
was first tested in the
hematopoietic system.
And their, my lab and other labs
were interested in just what
the relationship was between bone
marrow and the bone in which bone
marrow resides, and hypothesized
that there might be something
regulatory about bone that
governed stem cell function.
And so we set out to initially
just look at models where there was
genetic modification
of molecules that
could regulate cell
numbers in the bone.
And so in particular we used a
system that had been worked out
by Hank Kronenberg, where
he had a constitutively
active parathyroid hormone
receptor that was expressed
under the control of an
osteoblastic cell specific promoter.
Colleagues were, at the same
time, conducting a series
of conditional deletions of
the BMP receptor 1a, which
ended up having a very
similar phenotype.
And that phenotype was
basically to increase the number
of osteolineage cells and with that,
a concurrent increase in the number
of hematopoietic
stem and progenitors.
That led to the hypothesis that
these cells were central players
in being able to
regulate stem cells.
But it was subsequent work
that further defined that.
And there was the genetic
depletion of cells conducted
by two laboratories-- one of which
used a thymidine kinase being
expressed under control of
a bone specific promoter
and treating the cells
with a ganciclovir.
The other was to use conditional
deletion of osterix, which
prevented the development
of any osteoblastic cells.
And in both those cases,
there was a decrease
in the number of osteoblastic
cells and a decrease
in the number of stem cells.
