Efficient generation of human immune system rats using human CD34+ cells

• Published in: Stem cell reports 2024-09, Vol.19 (9), p.1255-1263
• Main Authors: Ménoret, Séverine, Renart-Depontieu, Florence, Martin, Gaelle, Thiam, Kader, Anegon, Ignacio
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD34 - metabolism; Antigens, Differentiation; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; cancer models; Cytokines - metabolism; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; human immune system mice; Humans; Immune System - metabolism; immunodeficient rodents; immunotherapy; Life Sciences; Mice; Rats; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; Receptors, Immunologic - metabolism; regenerative medicine; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; transplantation
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2024.07.005

Human immune system (HIS) mice generated using human CD34+ hematopoietic stem cells serve as a pivotal model for the in vivo evaluation of immunotherapies for humans. Yet, HIS mice possess certain limitations. Rats, due to their size and comprehensive immune system, hold promise for translational experiments. Here, we describe an efficacious method for long-term immune humanization, through intrahepatic injection of hCD34+ cells in newborn immunodeficient rats expressing human SIRPα. In contrast to HIS mice and similar to humans, HIS rats showed in blood a predominance of T cells, followed by B cells. Immune humanization was also high in central and secondary lymphoid organs. HIS rats treated with the anti-human CD3 antibody were depleted of human T cells, and human cytokines were detected in sera. We describe for the first time a method to efficiently generate HIS rats. HIS rats have the potential to be a useful model for translational immunology. •Immunodeficient/hSIRPα+ rats were efficiently immune humanized by hCD34+ cells•hCD45+ cells in the blood of rats were equivalent to immune humanized mice•Contrary to mice, the proportion of T and B cells in rats was as in human blood•Thymus, bone marrow, spleen, and lymph nodes of rats were also immune humanized In this article, Anegon et al. show an efficient method to generate human immune system (HIS) rats using hCD34+ cells. Numbers of hCD45+ cells in HIS rats’ blood were equivalent to HIS mice, but contrary to mice, the proportion of T and B cells was as in human blood. HIS rats showed high percentages of hCD45+ cells in lymphoid organs.