Hemopoietic stem cells (HSC), the earliest hematologic parent cells, can differentiate into all mature blood cell lineages. HSC maintain hemopoiesis throughout an animal's lifetime and can reconstitute hemopoiesis after transplantation into an irradiated recipient. The in vivo behavior of HSC cannot be observed directly, but rather must be inferred from observations of the behavior of derivative cell populations. The goal of this competitive renewal application is to use multiple independent, yet complementary biological and mathematical approaches, to define the kinetics of HSC in cats and mice. Specifically, we will analyze the contributions of feline HSC (labeled by viral gene transfer) to granulopoiesis, erythropoiesis, and lymphopoiesis after limiting dilution transplantations. These results will be compared to the outcomes predicted from computer simulations based on the analysis of data from G6PD heterozygous (female Safari) cats. As a second approach, we will estimate the rate of feline HSC replication by observing the pace (with age) of telomere shortening in granulocytes, lymphocytes, and marrow cells. In additional studies, the importance of apoptosis in maintaining HSC homeostasis will be investigated in cats and in mice, by analyzing the consequences of the overexpression in HSC of Bcl-2 (or Bcl-XL). The physiologic fate of circulating HSC will be explored in studies of parabiotic mice. Bayesian inference tools will be applied to statistical problem of estimating the frequencies of HSC and the average rates of HSC replication, apoptosis, and differentiation. By analyzing HSC kinetics in cats and mice, experimental systems with vastly different hemopoietic demands, we hope to gain insights that will allow an extrapolation to human hemopoiesis.
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