Retention and multilineage expression of human hematopoietic stem cells in human-sheep chimeras

We have taken advantage of the permissive environment of the early gestational age fetus to engraft human hematopoietic stem cells (HSC) into preimmune fetal lambs. The resulting chimeras exhibit long-term multilineage engraftment of human cells in the bone marrow (BM) and peripheral blood (PB). Long-term multilineage reconstitution of second generation recipients by human cells isolated from chimeric sheep BM indicates that the engraftment in this model involved long-term repopulating human HSC. The model appears to be sensitive enough to detect relatively small numbers of transplanted HSC from pre- and postnatal human sources. Finally, transplantation of mature T lymphocyte-containing cells from a variety of sources results in lethal graft-versus-host disease (GVHD), analogous to clinical BM transplantation, suggesting that, at least in some respects, the model is biologically relevant. The human-sheep model is promising and may have important advantages over murine models for the in vivo study of normal and abnormal hematopoiesis and as a potential assay system for human HSC.