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Long-Term Cytokine Production from Engineered Primary Human Stromal Cells Influences Human Hematopoiesis in an In Vivo Xenograft Model

Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital Los Angeles and University of Southern California, School of Medicine, Department of Pediatrics and School of Dentistry, Department of Craniofacial Molecular Biology, Los Angeles, California, USA

Key Words. Differentiation • Retroviral-mediated transduction • Marrow stroma immune deficient mice • Stem cells • Xenotransplantation

Dr. Jan A. Nolta, Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital Los Angeles and University of Southern California, School of Medicine, Department of Pediatrics and School of Dentistry, Department of Craniofacial Molecular Biology, 4650 Sunset Boulevard, Mailstop No. 62, Los Angeles, CA 90027, USA.

Human hematopoiesis can be supported in beige/nude/ XID (bnx) mice by coinjection of human bone marrow stromal cells engineered to secrete human interleukin 3 (HuIL-3). The major limitation is a total absence of human B cell development in the mice, which could be due to supraphysiological levels of HuIL-3 in the circulation. In an effort to obtain human B lymphoid, as well as T lymphoid and myeloid cell development in the mice, CD34⁺ cells were coinjected with human marrow stromal cells engineered to secrete human IL-2, IL-7, stem cell factor or FLT3 ligand, ± IL-3. No single factor other than IL-3 supported sustained human hematopoiesis in the mice, although cytokines were expressed for four to six months post-transplantation. Production of both HuIL-3 and IL-7 in the mice supported extrathymic development of human T lymphocytes, but no B cells, myeloid cells, or clonogenic progenitors were detected. Human B cells were not produced from CD34⁺ cells in the bnx mice under any condition tested. Another limitation to the bnx/Hu system is a lack of maturation of human red blood cells, although BFU-E are maintained. Stromal cells secreting human erythropoietin and IL-3 were cotransplanted into mice with HuCD34⁺ cells and an increase in hematocrit from 40%-45% to 80%-85% resulted, with production of human and murine red blood cells. Unfortunately, all mice (n = 9) suffered strokes, displayed paralysis and died within three weeks. The bnx/Hu cotransplantation model provides an interesting system in which to study human hematopoietic cell differentiation under the influence of various cytokines.

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