Treatment of non-obese diabetic (NOD)/Severe-combined immunodeficient mice (SCID) with flt3 ligand and interleukin-7 impairs the B-lineage commitment of repopulating cells after transplantation of human hematopoietic cells.
Until recently, the identification of cellular factors that govern the developmental program of human stem cells has been difficult due to the absence of repopulation assays that detect human stem cells. The transplantation of human bone marrow (BM) or cord blood (CB) into non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) mice has enabled identification of primitive human cells capable of multilineage repopulation of NOD/SCID mice (termed the SCID-repopulating cell [SRC]). Here, we examined the effect of long-term in vivo treatment with various combinations of human cytokines on the developmental program of SRC. Detailed flow cytometric analysis of engrafted mice indicated that the vast majority of the human graft of untreated mice was comprised of B lymphocytes at various stages of development as well as myeloid and primitive cells; T cells were not reproducibly detected. Many studies, including murine in vitro and in vivo data and human in vitro experiments, have suggested that flt3 ligand (FL) and/or Interleukin-7 (IL-7) promotes T- and B-cell development. Unexpectedly, we found that treatment of engrafted mice with the FL/IL-7 combination did not induce human T- or B-cell development, but instead markedly reduced B-cell development with a concomitant shift in the lineage distribution towards the myeloid lineage. Effects on lineage distribution were similar in engrafted mice transplanted with highly purified cells indicating that the action of the cytokines was not via cotransplanted mature cells from CB or BM cells. These data show that the lineage development of the human graft in NOD/SCID mice can be modulated by administration of human cytokines providing a valuable tool to evaluate the in vivo action of human cytokines on human repopulating cells.
Kapp
U
U
Department of Genetics, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; and Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada.
Bhatia
M
M
Bonnet
D
D
Murdoch
B
B
Dick
J E
JE
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D019070:Cell Lineage / Q000187:drug effects; D004359:Drug Therapy, Combination; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007274:Injections, Intraperitoneal; D015851:Interleukin-7 / Q000008:administration & dosage* / Q000009:adverse effects; D008024:Ligands; D018655:Lymphocyte Count / Q000187:drug effects; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID
D015851:Interleukin-7; D008024:Ligands; D008565:Membrane Proteins; C084881:flt3 ligand protein