Effective expansion of engrafted human hematopoietic stem cells in bone marrow of mice expressing human Jagged1.

Abstract

The human immune system can be reconstituted in experimental animals by transplanting human hematopoietic stem cells (hHSCs) into immunodeficient mice. To generate such humanized mice, further improvements are required, particularly to ensure that transplanted hHSCs are maintained in mice and proliferate long enough to follow prolonged immune responses to chronic diseases or monitor therapeutic effects. To prepare the relatively human bone marrow environment in mice, we generated nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor gamma chain null (NOG) mice expressing human Jagged1 (hJ1) in an osteoblast-specific manner (hJ1-NOG mice) to examine whether Notch signaling induced by hJ1 mediates hHSC proliferation and/or maintenance in mice. The established hJ1-NOG mice possess relatively larger bone marrow space and thinner cortical bone compared with nontransgenic littermates, but the number of c-kit(+) Sca-1(+) lineage(-) cells was not significantly different between hJ1-NOG and nontransgenic littermates. In the transplantation experiments of CD34(+) cells obtained from human cord blood, CD34(+)CD38(-) cells (hHSCs) were more increased in hJ1-NOG recipient mice than in nontransgenic littermates in mouse bone marrow environment. In contrast, the transplanted mouse c-kit(+) Sca-1(+) lineage(-) cells did not show significant increase in the same hJ1-NOG mice. These results suggest that hJ1-NOG mice could contribute to the growth of transplanted human CD34(+) cells in a human-specific manner and be useful to study the in vivo behavior and/or development of human stem cells, including cancer stem cells and immune cells.

• Authors: Naoko Negishi, Daisuke Suzuki, Ryoji Ito, Naoko Irie, Koichi Matsuo, Takashi Yahata, Kenichi Nagano, Kazuhiro Aoki, Keiichi Ohya, Katsuto Hozumi, Kiyoshi Ando, Norikazu Tamaoki, Mamoru Ito, Sonoko Habu
• Journal: Experimental hematology (Exp Hematol) Vol. 42 Issue 6 Pg. 487-94.e1 (Jun 2014) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 24530466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, CD34
• Calcium-Binding Proteins
• Intercellular Signaling Peptides and Proteins
• JAG1 protein, human
• Jag1 protein, mouse
• Jagged-1 Protein
• Membrane Proteins
• Serrate-Jagged Proteins

Topics

• Animals
• Antigens, CD34 (immunology)
• Bone Marrow
• Calcium-Binding Proteins (genetics, metabolism)
• Cell Proliferation
• Flow Cytometry
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells (cytology)
• Humans
• Immunohistochemistry
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Jagged-1 Protein
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, SCID
• Mice, Transgenic
• Serrate-Jagged Proteins