A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells

Fumiaki Jinnouchi, Takuji Yamauchi, Ayano Yurino, Takuya Nunomura, Michitaka Nakano, Chika Iwamoto, Teppei Obara, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Eishi Baba, Koichi Akashi, Katsuto Takenaka

Research output: Contribution to journalArticle

Abstract

In human-to-mouse xenogeneic transplantation, polymorphisms of signal-regulatory protein α (SIRPA) that decide their binding affinity for human CD47 are critical for engraftment efficiency of human cells. In this study, we generated a new C57BL/6.Rag2nullIl2rgnull (BRG) mouse line with Sirpahuman/human (BRGShuman) mice, in which mouse Sirpa was replaced by human SIRPA encompassing all 8 exons. Macrophages from C57BL/6 mice harboring Sirpahuman/human had a significantly stronger affinity for human CD47 than those harboring SirpaNOD/NOD and did not show detectable phagocytosis against human hematopoietic stem cells. In turn, Sirpahuman/human macrophages had a moderate affinity for mouse CD47, and BRGShuman mice did not exhibit the blood cytopenia that was seen in Sirpa-/- mice. In human to mouse xenograft experiments, BRGShuman mice showed significantly greater engraftment and maintenance of human hematopoiesis with a high level of myeloid reconstitution, as well as improved reconstitution in peripheral tissues, compared with BRG mice harboring SirpaNOD/NOD (BRGSNOD). BRGShuman mice also showed significantly enhanced engraftment and growth of acute myeloid leukemia and subcutaneously transplanted human colon cancer cells compared with BRGSNOD mice. BRGShuman mice should be a useful basic line for establishing a more authentic xenotransplantation model to study normal and malignant human stem cells.

Original languageEnglish
Pages (from-to)1661-1672
Number of pages12
JournalBlood
Volume135
Issue number19
DOIs
Publication statusPublished - May 7 2020

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