title: Analysis of parameters that affect human hematopoietic cell outputs in mutant c-kit-immunodeficient mice.
abstract: Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34+cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1-/--IL2Rγc-/-(NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdcscid/scid-IL2Rγc-/-(NSG) hosts. Comparison of sublethally irradiated and non-irradiated NRG mice and W41/W41derivatives showed superior chimerism in the W41-deficient recipients, with some differential effects on different lineage outputs. Consistently superior outputs were observed in female recipients regardless of their genotype, age, or pretransplantation conditioning, with greater differences apparent later after transplantation. These results define key parameters for optimizing the sensitivity and minimizing the intraexperimental variability of human hematopoietic xenografts generated in increasingly supportive immunodeficient host mice.
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Miller
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Rabu
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Margarita
authors.initials: M
authors.lastname: MacAldaz
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: David J H F
authors.initials: DJ
authors.lastname: Knapp
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Alice M S
authors.initials: AM
authors.lastname: Cheung
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Kiran
authors.initials: K
authors.lastname: Dhillon
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Naoto
authors.initials: N
authors.lastname: Nakamichi
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beer
authors.affiliation: Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Humphries
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address: ceaves@bccrc.ca.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
mesh_terms: D000367:Age Factors; D000818:Animals; D015415:Biomarkers; D002452:Cell Count; D005260:Female; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012737:Sex Factors; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous
chemical_list: D015415:Biomarkers; D019009:Proto-Oncogene Proteins c-kit