In vivo kinetics of murine hemopoietic stem cells

We used stochastic modeling and computer simulation to study the replicatio n, apoptosis, and differentiation of murine hemopoietic stem cells (HSCs) i n vivo, This approach allows description of the behavior of an unobserved p opulation tie, HSCs) on the basis of the behavior of observed progeny cells tie, granulocytes and lymphocytes). The results of previous limiting-dilut ion, competitive-repopulation studies in 44 mice were compared with the res ults of simulated transplantation studies to identify parameters that led t o comparable outcomes. Using this approach, we estimated that murine HSCs r eplicate ton average) once every 2.5 weeks and that the frequency of murine HSCs is 8 per 10(5) nucleated marrow cells. If it is assumed that short-te rm repopulating cells are distinct from HSCs, that they contribute to hemop oiesis early after transplantation, and that they are independently regulat ed, a frequency of 4 HSCs per 105 nucleated marrow cells also allows simula tions that best approximate the observed data. When stochastic modeling and computer simulation were applied to limiting-dilution, autologous-transpla ntation studies in cats heterozygous for glucose-6-phosphate-dehydrogenase, different estimates of HSC replication rate (1 per 8.3-10 weeks) and frequ ency (6 per 10(7) cells) were derived. Therefore, it appears that these par ameters vary inversely with increased longevity, size, or both. An implicat ion of these data is that human HSCs may be less frequent and replicate mor e slowly. These findings on cell kinetics have several implications. (C) 20 00 by The American Society of Hematology.