Problems in the promised land: status of adult marrow stem cell biology.

Long-term engrafting marrow hematopoietic stem cells have been considered to be a quiescent stem cell in G(0). However, there are contradictory reports on this point in the literature, showing marked variability of results over time and between mice. Furthermore, there are circadian rhythms for stem cells and progenitors. In general, most studies have not taken stochastic variability or circadian rhythms into account. In addition, stem cell purification has represented the present gold standard in stem cell research. However, evidence exists that the stem cell separations leave behind most stem cells and are not random. Thus, purified stem cells may not be representative of the stem cells in the unseparated marrow cell population. The epitope-based purification of stem cells may have misled the stem cell field. Lastly, there are interesting published studies indicating that the irradiated marrow microenvironment might be toxic to marrow stem cells, limiting self-renewal capacity, and that quantitative engraftment occurs in nonablated mice. These considerations suggest that in carrying out stem cell studies, attention needs to be directed to the appropriate number of repeat experiments, to circadian rhythms, to possible purification skewing of results, and to the most appropriate transplant assay model.