Nonirradiated NOD,B6.SCID Il2rγ ^−/− Kit ^W41/W41 (NBSGW) Mice Support Multilineage Engraftment of Human Hematopoietic Cells

Summary

In this study, we demonstrate a newly derived mouse model that supports engraftment of human hematopoietic stem cells (HSCs) in the absence of irradiation. We cross the NOD.Cg- Prkdc ^scid Il2rg ^tm1Wjl /SzJ (NSG) strain with the C57BL/6J- Kit ^W-41J /J (C57BL/6. Kit ^W41 ) strain and engraft, without irradiation, the resulting NBSGW strain with human cord blood CD34+ cells. At 12-weeks postengraftment in NBSGW mice, we observe human cell chimerism in marrow (97% ± 0.4%), peripheral blood (61% ± 2%), and spleen (94% ± 2%) at levels observed with irradiation in NSG mice. We also detected a significant number of glycophorin-A-positive expressing cells in the developing NBSGW marrow. Further, the observed levels of human hematopoietic chimerism mimic those reported for both irradiated NSG and NSG-transgenic strains. This mouse model permits HSC engraftment while avoiding the complicating hematopoietic, gastrointestinal, and neurological side effects associated with irradiation and allows investigators without access to radiation to pursue engraftment studies with human HSCs.

Highlights

• •

  In engraftment experiments, nonirradiated NBSGW mice show enhanced humanization

• •

  Similar levels of human chimerism are observed between both irNSG and NBSGW mice

• •

  NBSGW mice are conducive to serial transplantation without irradiation

• •

  NBSGW mice harbor a mutant Kit ^W41 allele, aiding Gly-A+ development in the marrow

Abstract

In a newly generated murine strain, Thomson et al. demonstrate enhanced engraftment of human hematopoietic stem cells in the absence of irradiation. Maintained as a homozygous line, a mutant Kit (W ⁴¹) allele, combined with Prkdc ^scid , Il2rγ ⁻ , and NOD.Sirpa, yields humanized grafts comparable to those observed in irradiated strains. This advancement allows researchers to humanize hosts without ionizing radiation.