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

We have taken advantage of the permissive environment of the preimmune fetus to achieve engraftment of hematopoietic stem cells (HSC) from fetal and postnatal human sources in sheep. The resulting chimeric lambs exhibited long-term multilineage (erythroid, myeloid, lymphoid) expression of donor cells that remained responsive to human-specific cytokines. The small size of the fetus allowed the assessment of the engraftment potential of relatively small numbers of highly characterized human HSC populations, while the large size of the chimeric sheep permitted the long-term evaluation of the HSC activity and response in vivo. The human/sheep xenograft may offer a useful large animal model for the assay and long-term study of the human HSC subsets.