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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1302-1309
HEMATOPOIESIS
Deterministic regulation of hematopoietic stem cell
self-renewal and differentiation
Christa E. Müller-Sieburg,
Rebecca H. Cho,
Marilyn Thoman,
Becky Adkins, and
Hans B. Sieburg
From the Sidney Kimmel Cancer Center and Department of
Mathematics, University of California at San Diego, CA; and the
Department of Microbiology and Immunology, University of Miami Medical
School, FL.
Most current theories assume that self-renewal and differentiation
of hematolymphoid stem cells (HSCs) is randomly regulated by intrinsic
and environmental influences. A direct corollary of these tenets is
that self-renewal will continuously generate functionally heterogeneous
daughter HSCs. Decisions about self-renewal versus commitment are made
by individual, single HSCs and, thus, require examination on the clonal
level. We followed the behavior of individual, clonally derived HSCs
through long-term, serial repopulation experiments. These studies
showed that daughter HSCs derived from individual clones were
remarkably similar to each other in the extent and kinetics of
repopulation. Moreover, daughter HSCs within a clone showed equivalent
contributions to the myeloid or lymphoid lineages. Lineage contribution
could be followed because of the discovery of a new subset of HSCs that
gave rise stably to skewed ratios of myeloid and lymphoid cells.
Overall, the data argue that self-renewal does not contribute to the
heterogeneity of the adult HSC compartment. Rather, all HSCs in a clone
follow a predetermined fate, consistent with the generation-age
hypothesis. By extension, this suggests that the self-renewal and
differentiation behavior of HSCs in adult bone marrow is more
predetermined than previously thought.
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