Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 352-352
Rebuttal to Metcalf
THE REVIEW OF lineage commitment and
maturation presented by Donald Metcalf complements and agrees with many
of the points that were raised in own article. Indeed, it seems in the
end that it was easier for us three limeys to accomodate the views of
our esteemed antipodean colleague than those of each other! Thus, we
all agree that, although hematopoietic cell regulatory molecules can
play an active role in expansion and maturation of committed cells, a
role in lineage commitment has not yet been really identified. Nonetheless, Metcalf has raised some issues that need addressing.
First, we agree that extrinsic influences and, in particular, gradients
of inducing molecules influence embryonic development. And, it is
reasonable to propose that generation of hematopoietic stem cells in
the embryo arises via similar mechanisms. Indeed, candidate inducing
agents have been tabled and are currently under intense investigation
(see Neave et al1 and refs therein). However, it is also
possible that known hematopoietic regulatory molecules may have a role
to play in the decision making processes, because, contrary to the
suggestion made by Metcalf, very primitive and nonhematopoietic cells
do indeed have receptors for, and can respond to, known regulators of
hematopoiesis, eg, primordial germ cells to stem cell
factor2 and embryonic stem cells to leukemia inhibitory
factor.3 Furthermore, because low levels of receptor
expression are very difficult to detect, it could be that such
primitive cells express receptors for some of the other, more
classical, regulators of hematopoiesis. Still, the question remains as to whether or not these act in an inductive capacity.
As we and Metcalf point out, many of the experiments purporting to
demonstrate an inductive role of hematopoietic regulatory molecules,
may simply be showing selective survival and expansion of previously
committed cells. Of course, absence of evidence is not evidence of
absence and so we cannot dismiss Metcalf's assertion that as yet
undiscovered molecules play instructive roles in the process of early
lineage commitment. That said, and until we have more robust data (such
as following the fate of individual cells in a homogenous
multipotential stem cell population), we believe that the current
balance of evidence presented both by us and by Metcalf favors the
hypothesis, put forward in our review and elsewhere, that
differentiation of stem cells involves mainly stochastic processes but
that instructive events probably play a greater role in more
lineage-restricted cells.
 |
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Article
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