Journal
BLOOD
Volume 119, Issue 12, Pages 2778-2788Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-05-353243
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Funding
- National Institutes of Health [AI46629, AI050864, AI083911, AI073871, HL077642, CA34196, DK089572]
- Diabetes Endocrinology Research Center [DK32520]
- University of Massachusetts Center for AIDS Research [P30 AI042845]
- Juvenile Diabetes Research Foundation, International
- Helmsley Foundation
- US Army Medical Research Institute for Infectious Diseases
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Immunodeficient mice engrafted with human HSCs support multidisciplinary translational experimentation, including the study of human hematopoiesis. Heightened levels of human HSC engraftment are observed in immunodeficient mice expressing mutations in the IL2-receptor common gamma chain (IL2rg) gene, including NOD-scid IL2r gamma(null) (NSG) mice. Engraftment of human HSC requires preconditioning of immunodeficient recipients, usually with irradiation. Such preconditioning increases the expression of stem cell factor (SCF), which is critical for HSC engraftment, proliferation, and survival. We hypothesized that transgenic expression of human membrane-bound stem cell factor Tg(hu-mSCF)] would increase levels of human HSC engraftment in nonirradiated NSG mice and eliminate complications associated with irradiation. Surprisingly, detectable levels of human CD45(+) cell chimerism were observed after transplantation of cord blood-derived human HSCs into nonirradiated adult as well as newborn NSG mice. However, transgenic expression of human mSCF enabled heightened levels of human hematopoietic cell chimerism in the absence of irradiation. Moreover, nonirradiated NSG-Tg(hu-mSCF) mice engrafted as newborns with human HSCs rejected human skin grafts from a histoincompatible donor, indicating the development of a functional human immune system. These data provide a new immunodeficient mouse model that does not require irradiation preconditioning for human HSC engraftment and immune system development. (Blood. 2012; 119(12): 2778-2788)
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