Human-ovine xenogenic transplantation of stem cells in utero.

The preimmune status of the early gestational age fetus provides a permissive environment that bypasses the immunological barrier and permits the engraftment and expression of hemopoietic stem cells (HSC). We used in utero approach to establish long term (greater than 2 years) engraftment and expression of human fetal liver HSC in sheep. Engraftment occurred in 40% (13 of 33) of the recipients. Of 5 live born sheep, all were chimeric. Engraftment was multilineage, involving lymphoid, myeloid and erythroid donor (human) cells. Interestingly, these progenitors have continued to exhibit responsiveness to human specific growth factors both in vitro and in vivo. Therefore, the integration of human HSC into the hemopoietic framework of the host appeared to be incomplete, with donor progenitors retaining certain phenotypic characteristics that may be exploited to preferentially manipulate the donor (human) cell population in these animals. Donor HSC primarily seeded the host bone marrow. Since the donor cells were of liver origin and the host liver at the time of transplantation was the major hemopoietic organ, this near exclusive seeding to the marrow indicates the greater affinity of marrow for the homing HSC. Nonetheless, no cells of donor origin appeared in the host circulation until the perinatal period, suggesting that donor HSC expand with the developing marrow spaces, but do not undergo terminal differentiation. The absence of a significant immunological barrier and the availability of expanding marrow homing sites render the fetus an excellent host (and donor) for HSC transplantation.