Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation

Author:

Takagi Shinsuke123,Saito Yoriko1,Hijikata Atsushi4,Tanaka Satoshi156,Watanabe Takashi4,Hasegawa Takanori7,Mochizuki Shinobu7,Kunisawa Jun5,Kiyono Hiroshi5,Koseki Haruhiko7,Ohara Osamu48,Saito Takashi39,Taniguchi Shuichi2,Shultz Leonard D.10,Ishikawa Fumihiko1

Affiliation:

1. Research Unit for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan;

2. Department of Hematology, Toranomon Hospital, Tokyo, Japan;

3. Department of Immune Regulation Research, Chiba University of Medical and Pharmaceutical Sciences, Chiba, Japan;

4. Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan;

5. Division of Mucosal Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;

6. Nippon Becton Dickinson Company, Tokyo, Japan;

7. Laboratory for Developmental Genetics, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan;

8. Department of Human Gene Research, Kazusa DNA Research Institute, Kisarazu, Japan;

9. Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan; and

10. The Jackson Laboratory, Bar Harbor, ME

Abstract

AbstractIn recent years, advances in the humanized mouse system have led to significantly increased levels of human hematopoietic stem cell (HSC) engraftment. The remaining limitations in human HSC engraftment and function include lymphoid-skewed differentiation and inefficient myeloid development in the recipients. Limited human HSC function may partially be attributed to the inability of the host mouse microenvironment to provide sufficient support to human hematopoiesis. To address this problem, we created membrane-bound human stem cell factor (SCF)/KIT ligand (KL)–expressing NOD/SCID/IL2rgKO (hSCF Tg NSG) mice. hSCF Tg NSG recipients of human HSCs showed higher levels of both human CD45+ cell engraftment and human CD45+CD33+ myeloid development compared with NSG recipients. Expression of hSCF/hKL accelerated the differentiation of the human granulocyte lineage cells in the recipient bone marrow. Human mast cells were identified in bone marrow, spleen, and gastrointestinal tissues of the hSCF Tg NSG recipients. This novel in vivo humanized mouse model demonstrates the essential role of membrane-bound hSCF in human myeloid development. Moreover, the hSCF Tg NSG humanized recipients may facilitate investigation of in vivo differentiation, migration, function, and pathology of human mast cells.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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