Engraftment and long-term expression of human fetal hemopoietic stem cells in sheep following transplantation in utero

Hemopoietic stem cells from human fetal liver were transplanted in utero into preimmune fetal sheep (48-54 days of gestation). The fate of donor cells was followed using karyotype analysis, by immunofluorescence labeling with anti-CD antibodies, and by fluorescent in situ hybridization using human-s...

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Bibliographic Details
Published in:The Journal of clinical investigation 1992-04, Vol.89 (4), p.1178-1188
Main Authors: Zanjani, E D, Pallavicini, M G, Ascensao, J L, Flake, A W, Langlois, R G, Reitsma, M, MacKintosh, F R, Stutes, D, Harrison, M R, Tavassoli, M
Format: Article
Language:English
Subjects:
Animals
Antigens, CD - analysis
Culture Media
Female
Fetus - immunology
Glycophorin - analysis
Graft Survival
Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells - physiology
Humans
Interleukin-3 - pharmacology
Pregnancy
Recombinant Proteins - pharmacology
Sheep
Transplantation, Heterologous
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Summary:Hemopoietic stem cells from human fetal liver were transplanted in utero into preimmune fetal sheep (48-54 days of gestation). The fate of donor cells was followed using karyotype analysis, by immunofluorescence labeling with anti-CD antibodies, and by fluorescent in situ hybridization using human-specific DNA probes. Engraftment occurred in 13 of 33 recipients. Of five live born sheep that exhibited chimerism, all expressed human cells in the marrow, whereas three expressed them in blood as well. Engraftment was multilineage (erythroid, myeloid, and lymphoid) and human hemopoietic progenitors (multipotent colony-forming units, colony-forming units-granulocyte, macrophage, and erythroid burst-forming units) capable of forming colonies in vitro were detected in all five lambs for greater than 2 yr. These progenitors responded to human-specific growth factors both in vitro and in vivo. Thus the administration of recombinant human IL-3 and granulocyte macrophage-colony-stimulating factor to chimeric sheep resulted in a 2.1-3.4-fold increase in the relative expression of donor (human) cells. These results demonstrate that the permissive environment of the preimmune fetal sheep provides suitable conditions for the engraftment and long-term multilineage expression of human hemopoietic stem cells in a large animal model. In this model, donor human cells appear to retain certain phenotypic and functional characteristics that can be used to manipulate the size of donor cell pool.
ISSN:0021-9738
DOI:10.1172/jci115701