Long-term cytokine production from engineered primary human stromal cells influences human hematopoiesis in an in vivo xenograft model.
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.
Dao
M A
MA
Division of Research Immunology/Bone Marrow Transplantation, Children's Hospital Los Angeles, California, USA.
Pepper
K A
KA
Nolta
J A
JA
D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D011994:Recombinant Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000378:metabolism / Q000637:transplantation; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous
D018952:Antigens, CD34; D016207:Cytokines; D011994:Recombinant Proteins