Analysis of parameters that affect human hematopoietic cell outputs in mutant c-kit-immunodeficient mice

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-Prkdc^scid/scid-IL2Rγc^-/- (NSG) hosts. Comparison of sublethally irradiated and non-irradiated NRG mice and W⁴¹/W⁴¹ derivatives 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.