The discovery of the severe combined immunodeficiency (scid) mouse mut
ation has provided a tool for establishment of small animal models as
hosts for the in vivo analysis of normal and malignant human pluripote
nt hemopoietic stem cells. Intravenous injection of irradiated scid mi
ce with human bone marrow, cord blood, or G-CSF cytokine-mobilized per
ipheral blood mononuclear cells, all rich in human hemopoietic stem ce
ll activity, results in the engraftment of a human hemopoietic system
in the murine recipient. This model has been used to identify a plurip
otent stem cell, termed ''scid-repopulating cell'' (SRC) that is more
primitive than any of the hemopoietic stem cell populations identified
using the currently available in vitro methodology, In this review, w
e describe the development and use of this model system, termed Hu-SRC
-SCID, and summarize the discoveries that have resulted from the inves
tigation of human stem cells in this model. Finally, we detail the rec
ent extension of the original Hu-SRC-SCID model system based on the C.
B-17-scid mouse as the murine host to the Hu-SRC-NOD-SCID model based
on the NOD-scid mouse as the host. The engraftment of human stem cells
in the Hu-SRC-NOD-SCID model is enhanced over that observed in the Hu
-SRC-SCID model and results in exceptionally high levels of human hemo
poietic cells in the murine recipient, Future directions to further im
prove the Hu-SRC-NOD-SCID model system and the potential utility of th
is model in the preclinical and diagnostic arenas of hematology and on
cology are discussed.