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Summary: Due to its lack of both innate and acquired immune responses to human cells, the NODSCIDIl2rγ−/− (NSG) mouse model has become an important tool for human stem cell research. When compared with the mouse, the rat is physiologically more similar to humans and offers advantages in preclinical efficacy studies on human stem cells, particularly in evaluating neural, hepatic, and cardiac functions. Therefore, we generated a human SIRPα +Prdkc−/−Il2rγ−/− rat model, denoted NSG-like (NSGL) rat, which expresses human SIRPα and is abolished in the development of B, T, and natural killer cells. When compared with Prdkc−/−Il2rγ−/− (SG) rats, NSGL rats allow more efficient engraftment of human cancer cells and human pluripotent stem cells. In addition, only NSGL rats, but not SG rats, can be engrafted with human hematopoietic stem cells to reconstitute the human immune system. Therefore, NSGL rats represent an improved xenotransplantation model for efficacy studies of human stem cells. : Due to the significant difference in physiology between mouse and human, mouse models are not appropriate for preclinical efficacy studies of some human stem cell-based therapies, especially in the context of neural and cardiac functions. To mitigate this challenge, Xu and colleagues established NSG-like rat model that can be efficiently engrafted with human stem cells. Keywords: immunodeficient rat models, innate immunity, acquired immunity, human stem cells, hematopoietic stem cells