Human Hematopoietic Stem Cell Engraftment and Differentiation in Immunodeficient Pigs

ABSTRACT Immunodeficient large animals that allow engraftment of human tissues and cells are highly valuable for translational studies. Recently, a strain of immunodeficient pigs (termed RGD pigs) was developed through the genetic inactivation of RAG1 , IL2RG , and CD47 . These RGD pigs lack functional T, B, and NK cells and do not exhibit CD47‐SIRPα incompatibility‐triggered macrophage xenoresponses. Transplantation of human hematopoietic stem/progenitor cells (HSPCs) into RGD pigs results in high levels of durable human hematopoietic engraftment and systemic repopulation with multilineage human lymphohematopoietic cells, including T, B, NK, and myeloid cells. The transplanted pigs maintain robust human hematopoiesis in the bone marrow (BM) and ongoing thymopoiesis in the thymus. Human T and B cells developing in these pigs express broad antigen receptor repertoires and exhibit tolerance to the recipient pig. The RGD pig is considered a valuable preclinical model for investigating normal or diseased human hematopoiesis and related therapies, and offers a potential bioreactor for large‐scale production of human immune cells. These pigs are also highly valuable for in vivo studies on other types of human tissues and cells.