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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL046598-13A1
Application #
6976960
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
1991-05-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
13
Fiscal Year
2005
Total Cost
$379,000
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Xu, Jason; Wang, Yiwen; Guttorp, Peter et al. (2018) Visualizing hematopoiesis as a stochastic process. Blood Adv 2:2637-2645
Catlin, Sandra N; Busque, Lambert; Gale, Rosemary E et al. (2011) The replication rate of human hematopoietic stem cells in vivo. Blood 117:4460-6
Roeder, Ingo; d'Inverno, Mark; other participants (2009) New experimental and theoretical investigations of hematopoietic stem cells and chronic myeloid leukemia. Blood Cells Mol Dis 43:88-97
Fong, Youyi; Guttorp, Peter; Abkowitz, Janis (2009) BAYESIAN INFERENCE AND MODEL CHOICE IN A HIDDEN STOCHASTIC TWO-COMPARTMENT MODEL OF HEMATOPOIETIC STEM CELL FATE DECISIONS. Ann Appl Stat 3:1696-1709
Shepherd, Bryan E; Kiem, Hans-Peter; Lansdorp, Peter M et al. (2007) Hematopoietic stem-cell behavior in nonhuman primates. Blood 110:1806-13
Abkowitz, Janis L; Chen, Jing (2007) Studies of c-Mpl function distinguish the replication of hematopoietic stem cells from the expansion of differentiating clones. Blood 109:5186-90
Chen, Jing; Larochelle, Andre; Fricker, Simon et al. (2006) Mobilization as a preparative regimen for hematopoietic stem cell transplantation. Blood 107:3764-71
Catlin, Sandra N; Guttorp, Peter; Abkowitz, Janis L (2005) The kinetics of clonal dominance in myeloproliferative disorders. Blood 106:2688-92
Lucas, M Lee; Seidel, Nancy E; Porada, Christopher D et al. (2005) Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes. Blood 106:51-8
Shepherd, Bryan E; Guttorp, Peter; Lansdorp, Peter M et al. (2004) Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths. Exp Hematol 32:1040-50

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