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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1635-1643
HEMATOPOIESIS
Xenotransplantation of immunodeficient mice with
mobilized human blood CD34+ cells provides an in vivo
model for human megakaryocytopoiesis and platelet
production
Lia E. Perez,
Henry M. Rinder,
Chao Wang,
Jayne B. Tracey,
Noel Maun, and
Diane S. Krause
From the Department of Internal Medicine, Section of
Hematology, and Department of Laboratory Medicine, Yale University
School of Medicine, New Haven, CT.
The study of megakaryocytopoiesis has been based largely on in
vitro assays. We characterize an in vivo model of megakaryocyte and platelet development in which human peripheral blood stem cells
(PBSCs) differentiate along megakaryocytic as well as
myeloid/lymphoid lineages in sublethally irradiated nonobese
diabetic/severe combined immunodeficient (NOD-SCID) mice. Human
hematopoiesis preferentially occurs in the bone marrow of the murine
recipients, and engraftment is independent of exogenous cytokines.
Human colony-forming units-megakaryocyte (CFU-MK) develop
predominantly in the bone marrow, and their presence correlates with
the overall degree of human cell engraftment. Using a sensitive and
specific flow cytometric assay, human platelets are detected in the
peripheral blood from weeks 1 to 8 after transplantation. The number of
circulating human platelets peaks at week 3 with a mean of
20 × 109/L. These human platelets are functional as
assessed by CD62P expression in response to thrombin stimulation in
vitro. Exogenous cytokines have a detrimental effect on CFU-MK
production after 2 weeks, and animals treated with these cytokines have
no circulating platelets 8 weeks after transplantation. Although
cytokine stimulation of human PBSCs ex vivo led to a significant
increase in CFU-MK, CD34+/41+, and
CD41+ cells, these ex vivo expanded cells provided only
delayed and transient platelet production in vivo, and no CFU-MK
developed in vivo after transplantation. In conclusion, xenogeneic
transplantation of human PBSCs into NOD/SCID mice provides an excellent
in vivo model to study human megakaryocytopoiesis and platelet production.
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