A ligand-receptor signaling threshold model of stem cell differentiation control: a biologically conserved mechanism applicable to hematopoiesis

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 cel ls in vitro without loss of the long-term multilineage growth and different iation properties required for their clinical utility. An experimental and theoretical framework for predicting and controlling the outcome of HSC sti mulation by exogenous cytokines would thus be useful, An emerging theme fro m recent HSC expansion studies is that a net gain in HSC numbers requires t he maintenance of critical signaling ligand(s) above a threshold level. The se ligand-receptor complex thresholds can be maintained, for example, by hi gh concentrations of soluble cytokines or by extracellular matrix- or cell- bound cytokine presentation. According to such a model, when the relevant l igand-receptor interaction falls below a critical level, the probability of a differentiation response is increased; otherwise, self-renewal is favore d. Thus, in addition to the identity of a particular receptor-ligand intera ction being important to the regulation of stem cell responses, the quantit ative nature of this interaction, as well as the dynamics of receptor expre ssion, 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 ac tivation thresholds in regulating hematopoietic stem cell self-renewal vers us differentiation events. (Blood, 2000; 96:1215-1222) (C) 2000 by The Amer ican Society of Hematology.