Long-term engraftment of human stem and progenitor cells for large-scale production of functional immune cells in engineered pigs

Abstract

Existing immunodeficient pig models have demonstrated limited success in supporting robust human haematopoietic engraftment and multilineage differentiation. Here we hypothesize that the targeted deletion of integrin-associated protein (Cd47) in severe combined immunodeficient pigs, with deletions in the X-linked interleukin-2 receptor gamma chain and recombination activating gene 1, would enable long-term haematopoietic engraftment following transplantation with human haematopoietic stem/progenitor cells. In Cd47-deficient pigs, we observed high levels of human haematopoietic chimerism in the blood and spleen, with functional T and B lymphocytes, natural killer and myeloid cells, as well as robust thymopoiesis. Our findings suggest that severe combined immunodeficient pigs with Cd47 deletion represent an improved preclinical model for studying human haematopoiesis, disease mechanisms and therapies, and offer potential as a bioreactor for large-scale production of human immune cells.