Stem cell plasticity revisited: the continuum marrow model and phenotypic changes mediated by microvesicles

The phenotype of marrow hematopoietic stem cells is determined by cell-cycle state and microvesicle entry into the stem cells. The stem cell population is continually changing based on cell-cycle transit and can only be defined on a population basis. Purification of marrow stem cells only addresses the heterogeneity of these populations. When whole marrow is studied, the long-term repopulating stem cells are in active cell cycle. However, with some variability, when highly purified stem cells are studied, the cells appear to be dormant. Thus, the study of purified stem cells is intrinsically misleading. Tissue-derived microvesicles enhanced by injury effect the phenotype of different cell classes. We propose that previously described stem cell plasticity is due to microvesicle modulation. We further propose a stem cell population model in which the individual cell phenotypes continually change, but the population phenotype is relatively stable. This, in turn, is modulated by microvesicle and microenvironmental influences.