Hematopoietic stem cells (HSC), the earliest hematologic parent cells, can differentiate into mature cells of all blood lineages. HSC also maintain hematopoiesis throughout an animal's lifetime and can reconstitute blood cell production after transplantation into an irradiated recipient. HSC are infrequent (1 to 10 per 105 nucleated marrow cells in mouse, likely < 1 per 107 nucleated marrow cells in man), reside in geographically separate regions of the marrow space, and are dependent on extrinsic (microenvironmental), as well as intrinsic, cues for fate decisions. Thus, the in vivo behavior of HSC cannot be observed directly, but rather must be inferred from observations of the behavior of derivative cell populations. Previously, we have estimated the replication, differentiation, and apoptosis rates of murine and feline HSC in vivo by stochastic analyses of limiting dilution competitive repopulation studies. The goal of this competitive renewal application is to use multiple independent and complementary biological and mathematical approaches to extend this data to non-human primates and man. This would allow us to simulate human hematopoiesis, optimize strategies for gene therapy, and study the clonal evolution of the myeloproliferative diseases, such as chronic myelogenous leukemia (CML).
A second aim of these studies is to determine the physiologic relevance of mobilization and homing using parabiotic mice. Specifically, we will use this experimental system to confirm that niche availability determines the number of HSC. Lastly, we will refine the statistical methods we use to simulate murine and feline hematopoiesis and will test the hypothesis that the HSC fate is determined at the time of stem cell division. Broadly, this application uses parabiosis, evolutionary analyses and stochastic simulation, 3 systems biology approaches, to gain insights into the in vivo behavior of HSC.
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