The stem cell continuum: cell cycle, injury, and phenotype lability.

The phenotype of the hematopoietic stem cell is intrinsically labile and impacted by cell cycle and the effects of tissue injury. In published studies we have shown that there are changes in short- and long-term engraftment, progenitor numbers, gene expression, and differentiation potential with cytokine-induced cell cycle transit. Critical points here are that these changes are reversible and not unidirectional weighing, heavily against a hierarchical model of stem cell regulation. Furthermore, a number of studies have now established that stem cells separated by lineage depletion and selection for Sca-1 or c-kit or low rhodamine and Hoechst staining are in fact a cycling population. Last, studies on Hoechst separated "cycling" stem cells indicates that the observed phenotype shifts relate to phase of cell cycle and are not due to in vitro exposure to cytokines. These data suggest a continuum model of stem cell regulation and further indicate that this model holds for in vivo situations. Observations that marrow cells can convert to various tissue cells under different injury conditions continue to be published despite a small, but influential, number of negative studies. Our studies and those of others indicate that conversions of marrow-derived cells to different tissue cells, such as skeletal muscle and lung, is critically dependent upon multiple variables, the most important of which is the presence of tissue injury. Variables which affect conversion of marrow cells to nonhematopoietic cells after in vivo transplantation include the nature and timing of the injury; marrow mobilization; the marrow cell type infused; the timing of cell infusion and the number of cells infused; the cell cycle state of the marrow cells, and other functional alterations in the marrow cells the treatment of the host mouse separate from specific injury; the mode of cell delivery; and possibly the presence of microvesicles from injured tissue. At least some of the highlighted negative reports on stem cell plasticity appear to be due to a failure to address these variables. Recently, we have observed that irradiated lung releases microvesicles which can enter marrow cells and lead to the marrow cells expressing lung-specific mRNA and protein. This could provide an underlying mechanism for many of the plasticity phenomena. Altogether, marrow appears to represent a highly flexible ever-changing cell system with the capacity to respond to products of injured cells and top repair a broad range of tissues.