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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1215-1222
PERSPECTIVE
A ligand-receptor signaling threshold model of stem cell
differentiation control: a biologically conserved mechanism
applicable to hematopoiesis
Peter W. Zandstra,
Douglas
A. Lauffenburger, and
Connie J. Eaves
From the Institute of Biomaterials and Biomedical
Engineering and Department of Chemical Engineering and Applied
Chemistry, University of Toronto, Toronto, Ontario,
Canada; Biotechnology Process Engineering Center,
Massachusetts Institute of Technology, Cambridge, MA; Terry Fox
Laboratory, British Columbia Cancer Agency and Department of Medical
Genetics, University of British Columbia, Vancouver, British Columbia,
Canada.
A major limitation to the widespread use of hematopoietic stem
cells (HSC) is the relatively crude level of our knowledge of how to
maintain these cells in vitro without loss of the long-term multilineage growth and differentiation properties required for their
clinical utility. An experimental and theoretical framework for
predicting and controlling the outcome of HSC stimulation by exogenous
cytokines would thus be useful. An emerging theme from recent HSC
expansion studies is that a net gain in HSC numbers requires the
maintenance of critical signaling ligand(s) above a threshold level.
These ligand-receptor complex thresholds can be maintained, for
example, by high concentrations of soluble cytokines or by
extracellular matrix- or cell-bound cytokine presentation. According to
such a model, when the relevant ligand-receptor interaction falls below
a critical level, the probability of a differentiation response is
increased; otherwise, self-renewal is favored. Thus, in addition to the
identity of a particular receptor-ligand interaction being important to
the regulation of stem cell responses, the quantitative nature of this
interaction, as well as the dynamics of receptor expression,
internalization, and signaling, may have a significant influence on
stem cell fate decisions. This review uses examples from hematopoiesis
and other tissue systems to examine existing evidence for a role of
receptor activation thresholds in regulating hematopoietic stem cell
self-renewal versus differentiation events.
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