The continuum model of marrow stem cell regulation

Abstract

We review the continuum model of stem cell regulation. A series of studies on purified lineage negative rhodamine low Hoechst low murine stem cells driven through cell cycle by cytokine exposure have shown that many phenotypic features show reversible changes with cycle progression. We and others have shown that purified murine marrow stem cells are a cycling population. Features that are labile with cycle progression are in-vivo engraftment, progenitor numbers, expression of adhesion proteins and cytokine receptors, global gene expression and differentiation into granulocytes and megakaryocytes. These observations have led to a theory that regulation of hematopoietic stem cells is on a continuum and not in a hierarchy. Out-of-tissue plasticity in which marrow cells show a capacity to produce nonhematopoietic cells in non-marrow tissues also exists. We have shown 'robust' production of lung and skeletal muscle cells by marrow cells in the presence of appropriate tissue injury and demonstrated that the capacity of marrow cells to produce nonhematopoietic cells in the lung also varies reversibly with cell cycle status. Thus, stem cells show a plastic plasticity and the continuum appears to hold for both nonhematopoietic and hematopoietic lineages.