Adoptive transfer of genetically modified human hematopoietic stem cells into preimmune canine fetuses

To develop a surrogate model system for assaying gene transfer into human hematopoietic stem cells (HSCs) with in vivo repopulating potential, we injected human marrow cells transduced with a reporter retroviral vector in long-term marrow cultures (LTMCs), into the yolk sacs of preimmune canine fetu...

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Bibliographic Details
Published in:Experimental hematology 1999-02, Vol.27 (2), p.242-249
Main Authors: Omori, Fusayuki, Lutzko, Carolyn, Abrams-Ogg, Anthony, Lau, Kathy, Gartley, Cathy, Dobson, Howard, Nanji, Shaherose, Ruedy, Christine, Singaraja, Roshni, Li, Liheng, Stewart, A.Keith, Kruth, Stephen, Dubé, Ian D
Format: Article
Language:English
Subjects:
Adoptive Transfer
Animals
Dogs
Female
Fetus - physiology
Genes, Reporter
Genetic Vectors
Hematopoiesis
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells - physiology
Hematopoietic stem cells—Preimmune fetus—In utero transfer—Long-term marrow culture (LTMC)
Humans
Pregnancy
Retroviridae
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Summary:To develop a surrogate model system for assaying gene transfer into human hematopoietic stem cells (HSCs) with in vivo repopulating potential, we injected human marrow cells transduced with a reporter retroviral vector in long-term marrow cultures (LTMCs), into the yolk sacs of preimmune canine fetuses. Of eight mid-gestation fetuses injected through the exteriorized uterine wall and under ultrasound guidance, seven were born alive. One puppy died in the neonatal period accidentally. The remaining six puppies are all healthy at 31 months of age. There was no evidence for graft-versus-host disease or any untoward effects of in utero adoptive transfer of transduced human LTMC cells. All puppies were chimeras. Human cells, detected by fluorescence in situ hybridization, were present in blood, declining from 38% to 0.05% between 10 and 44 weeks after birth. Corresponding numbers for marrow were from 20% to 0.05%. Human cells were also detected in assays of hematopoietic cell progenitors and in stimulated blood cultures. All six puppies were positive for the presence of proviral DNA at various time-points after birth. In three dogs, provirus was detected up to 41 weeks after birth in blood or marrow, and in one dog up to 49 weeks in blood. These data support the further development of this large-animal model system for studies of human hematopoie-sis.
ISSN:0301-472X
1873-2399
DOI:10.1016/S0301-472X(98)00043-5