The evidence of a macrophage barrier in the xenotransplantation of human hematopoietic stem cells to severely immunodeficient rats

• Published in: Xenotransplantation (Københaven) 2021-07, Vol.28 (4), p.e12702-n/a
• Main Authors: Furuya, Kinji, Zheng, Yun‐Wen, Ge, Jian‐Yun, Zhang, Ludi, Furuta, Tomoaki, Liang, Chen, Abe, Haruna, Yagi, Hiroya, Hamada, Hiromi, Isoda, Hiroko, Hui, Lijian, Ohkohchi, Nobuhiro, Oda, Tatsuya
• Format: Article
• Language: English
• Subjects: Animal models; Bisphosphonates; Cesarean section; chimerism; Clodronic acid; Cord blood; Flow cytometry; hematopoietic stem cell transplantation; Hematopoietic stem cells; human‐to‐rat; Immunodeficiency; Immunological tolerance; Leukocytes (mononuclear); Lymphocytes; macrophage; Macrophages; Phagocytosis; RAG2 protein; Spleen; Stem cell transplantation; Umbilical cord; Xenografts
• ISSN: 0908-665X; 1399-3089
• DOI: 10.1111/xen.12702

Background The human‐to‐rat hematopoietic stem cell transplantation (HSCT) model is rare, unlike its human‐to‐mouse counterpart. The rat models are desired, especially in areas of physiology, toxicology, and pharmacology. In addition to lymphocytes, macrophages are also considered to be important for xenotransplantation. We generated a rat xenotransplantation model to prove the role of macrophages as a xenotransplantation barrier. Methods Immunodeficiency in SRG rats, which are Sprague–Dawley (SD) rats lacking Rag2 and Il2rg, was confirmed by flow cytometry and spleen immunostaining. Human umbilical cord blood was collected after scheduled cesarean section at the University of Tsukuba Hospital. Cord blood mononuclear cells (CB‐MNCs) were transplanted into the SRG rats administered several injections of clodronate liposome (CL), which cause macrophage depletion. Survival of human cells was observed by flow cytometry. Rat macrophage phagocytosis assay was performed to check the species‐specific effects of rat macrophages on injected human/rat blood cells. Results SRG rats were deficient in T/B/NK cells. Without CL pretreatment, human CB‐MNCs were removed from SRG rats within 7 hours after transplantation. The rats pretreated with CL could survive after transplantation. Prolonged survival for more than 4 weeks was observed only following a one‐time CL injection. Rat macrophages had a species‐specific potential for the phagocytosis of human blood cells in vivo. Conclusion In human‐to‐rat HSCT, the short period of early macrophage control, leading to macrophage immunotolerance, is important for engraftment. The generated model can be useful for the creation of future xenotransplantation models or other clinical research.