Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts

Ryoji Ito, Naoko Negishi, Naoko Irie, Koichi Matsuo, Daisuke Suzuki, Ikumi Katano, Eri Hayakawa, Kenji Kawai, Tsutomu Kamisako, Tomoo Eto, Tomoyuki Ogura, Katsuto Hozumi, Kiyoshi Ando, Sadakazu Aiso, Norikazu Tamaoki, Sonoko Habu, Mamoru Ito

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

NOD/Shi-scid IL2rγnull (NOG) mice with severe immunodeficiency are excellent recipients to generate "humanized" mice by the transplantation of human CD34+ hematopoietic stem cells (HSCs). In this study, we developed NOG mice carrying a human Delta-like1 (DLL1) gene, which is a ligand of the Notch receptor and is known to be important in HSC maintenance and self-renewal. We also analyzed the effect of DLL1 signaling on human hematopoiesis and HSC maintenance using humanized DLL1 transgenic NOG mice. To develop DLL1 transgenic NOG (NOG-D1-Tg) mice, a transgenic vector consisting of a human DLL1 complementary DNA fragment placed downstream of the α1(I) collagen (Col1a1) promoter for expression specifically in osteoblasts was constructed. Human CD34+ HSCs were transplanted into NOG-D1-Tg mice, and differentiation of lymphoid or myeloid lineage cells from human HSCs and maintenance of HSCs in bone marrow were analyzed. Severe osteosclerosis accompanied by increased bone mass and a decreased number of bone marrow cells were observed in NOG-D1-Tg mice. After human HSC transplantation, development of human B lymphocytes, but not T lymphocytes, was significantly suppressed in both bone marrow and the periphery of NOG-D1-Tg mice. Contrary to the initial expectation, retention of human CD34+ HSCs was inhibited in the bone marrow of NOG-D1-Tg mice. In conclusion, our data suggest that the development of human B lymphocytes and HSC maintenance in osteosclerotic bone may be suppressed by introducing DLL1. These unique humanized mice with sclerotic bone reconstituted by human HSCs are useful models of hematopoiesis in patients with osteosclerosis, such as osteopetrosis, and for investigation of osteogenesis via Notch signaling.

Original languageEnglish
Pages (from-to)953-963
Number of pages11
JournalExperimental Hematology
Volume40
Issue number11
DOIs
Publication statusPublished - 2012 Nov 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

Cite this

Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts. / Ito, Ryoji; Negishi, Naoko; Irie, Naoko; Matsuo, Koichi; Suzuki, Daisuke; Katano, Ikumi; Hayakawa, Eri; Kawai, Kenji; Kamisako, Tsutomu; Eto, Tomoo; Ogura, Tomoyuki; Hozumi, Katsuto; Ando, Kiyoshi; Aiso, Sadakazu; Tamaoki, Norikazu; Habu, Sonoko; Ito, Mamoru.

In: Experimental Hematology, Vol. 40, No. 11, 01.11.2012, p. 953-963.

Research output: Contribution to journalArticle

Ito, R, Negishi, N, Irie, N, Matsuo, K, Suzuki, D, Katano, I, Hayakawa, E, Kawai, K, Kamisako, T, Eto, T, Ogura, T, Hozumi, K, Ando, K, Aiso, S, Tamaoki, N, Habu, S & Ito, M 2012, 'Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts', Experimental Hematology, vol. 40, no. 11, pp. 953-963. https://doi.org/10.1016/j.exphem.2012.07.002
Ito, Ryoji ; Negishi, Naoko ; Irie, Naoko ; Matsuo, Koichi ; Suzuki, Daisuke ; Katano, Ikumi ; Hayakawa, Eri ; Kawai, Kenji ; Kamisako, Tsutomu ; Eto, Tomoo ; Ogura, Tomoyuki ; Hozumi, Katsuto ; Ando, Kiyoshi ; Aiso, Sadakazu ; Tamaoki, Norikazu ; Habu, Sonoko ; Ito, Mamoru. / Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts. In: Experimental Hematology. 2012 ; Vol. 40, No. 11. pp. 953-963.
@article{d62fd06d4be0483ca75c759bd86b04c8,
title = "Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts",
abstract = "NOD/Shi-scid IL2rγnull (NOG) mice with severe immunodeficiency are excellent recipients to generate {"}humanized{"} mice by the transplantation of human CD34+ hematopoietic stem cells (HSCs). In this study, we developed NOG mice carrying a human Delta-like1 (DLL1) gene, which is a ligand of the Notch receptor and is known to be important in HSC maintenance and self-renewal. We also analyzed the effect of DLL1 signaling on human hematopoiesis and HSC maintenance using humanized DLL1 transgenic NOG mice. To develop DLL1 transgenic NOG (NOG-D1-Tg) mice, a transgenic vector consisting of a human DLL1 complementary DNA fragment placed downstream of the α1(I) collagen (Col1a1) promoter for expression specifically in osteoblasts was constructed. Human CD34+ HSCs were transplanted into NOG-D1-Tg mice, and differentiation of lymphoid or myeloid lineage cells from human HSCs and maintenance of HSCs in bone marrow were analyzed. Severe osteosclerosis accompanied by increased bone mass and a decreased number of bone marrow cells were observed in NOG-D1-Tg mice. After human HSC transplantation, development of human B lymphocytes, but not T lymphocytes, was significantly suppressed in both bone marrow and the periphery of NOG-D1-Tg mice. Contrary to the initial expectation, retention of human CD34+ HSCs was inhibited in the bone marrow of NOG-D1-Tg mice. In conclusion, our data suggest that the development of human B lymphocytes and HSC maintenance in osteosclerotic bone may be suppressed by introducing DLL1. These unique humanized mice with sclerotic bone reconstituted by human HSCs are useful models of hematopoiesis in patients with osteosclerosis, such as osteopetrosis, and for investigation of osteogenesis via Notch signaling.",
author = "Ryoji Ito and Naoko Negishi and Naoko Irie and Koichi Matsuo and Daisuke Suzuki and Ikumi Katano and Eri Hayakawa and Kenji Kawai and Tsutomu Kamisako and Tomoo Eto and Tomoyuki Ogura and Katsuto Hozumi and Kiyoshi Ando and Sadakazu Aiso and Norikazu Tamaoki and Sonoko Habu and Mamoru Ito",
year = "2012",
month = "11",
day = "1",
doi = "10.1016/j.exphem.2012.07.002",
language = "English",
volume = "40",
pages = "953--963",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "11",

}

TY - JOUR

T1 - Osteosclerosis and inhibition of human hematopoiesis in NOG mice expressing human Delta-like 1 in osteoblasts

AU - Ito, Ryoji

AU - Negishi, Naoko

AU - Irie, Naoko

AU - Matsuo, Koichi

AU - Suzuki, Daisuke

AU - Katano, Ikumi

AU - Hayakawa, Eri

AU - Kawai, Kenji

AU - Kamisako, Tsutomu

AU - Eto, Tomoo

AU - Ogura, Tomoyuki

AU - Hozumi, Katsuto

AU - Ando, Kiyoshi

AU - Aiso, Sadakazu

AU - Tamaoki, Norikazu

AU - Habu, Sonoko

AU - Ito, Mamoru

PY - 2012/11/1

Y1 - 2012/11/1

N2 - NOD/Shi-scid IL2rγnull (NOG) mice with severe immunodeficiency are excellent recipients to generate "humanized" mice by the transplantation of human CD34+ hematopoietic stem cells (HSCs). In this study, we developed NOG mice carrying a human Delta-like1 (DLL1) gene, which is a ligand of the Notch receptor and is known to be important in HSC maintenance and self-renewal. We also analyzed the effect of DLL1 signaling on human hematopoiesis and HSC maintenance using humanized DLL1 transgenic NOG mice. To develop DLL1 transgenic NOG (NOG-D1-Tg) mice, a transgenic vector consisting of a human DLL1 complementary DNA fragment placed downstream of the α1(I) collagen (Col1a1) promoter for expression specifically in osteoblasts was constructed. Human CD34+ HSCs were transplanted into NOG-D1-Tg mice, and differentiation of lymphoid or myeloid lineage cells from human HSCs and maintenance of HSCs in bone marrow were analyzed. Severe osteosclerosis accompanied by increased bone mass and a decreased number of bone marrow cells were observed in NOG-D1-Tg mice. After human HSC transplantation, development of human B lymphocytes, but not T lymphocytes, was significantly suppressed in both bone marrow and the periphery of NOG-D1-Tg mice. Contrary to the initial expectation, retention of human CD34+ HSCs was inhibited in the bone marrow of NOG-D1-Tg mice. In conclusion, our data suggest that the development of human B lymphocytes and HSC maintenance in osteosclerotic bone may be suppressed by introducing DLL1. These unique humanized mice with sclerotic bone reconstituted by human HSCs are useful models of hematopoiesis in patients with osteosclerosis, such as osteopetrosis, and for investigation of osteogenesis via Notch signaling.

AB - NOD/Shi-scid IL2rγnull (NOG) mice with severe immunodeficiency are excellent recipients to generate "humanized" mice by the transplantation of human CD34+ hematopoietic stem cells (HSCs). In this study, we developed NOG mice carrying a human Delta-like1 (DLL1) gene, which is a ligand of the Notch receptor and is known to be important in HSC maintenance and self-renewal. We also analyzed the effect of DLL1 signaling on human hematopoiesis and HSC maintenance using humanized DLL1 transgenic NOG mice. To develop DLL1 transgenic NOG (NOG-D1-Tg) mice, a transgenic vector consisting of a human DLL1 complementary DNA fragment placed downstream of the α1(I) collagen (Col1a1) promoter for expression specifically in osteoblasts was constructed. Human CD34+ HSCs were transplanted into NOG-D1-Tg mice, and differentiation of lymphoid or myeloid lineage cells from human HSCs and maintenance of HSCs in bone marrow were analyzed. Severe osteosclerosis accompanied by increased bone mass and a decreased number of bone marrow cells were observed in NOG-D1-Tg mice. After human HSC transplantation, development of human B lymphocytes, but not T lymphocytes, was significantly suppressed in both bone marrow and the periphery of NOG-D1-Tg mice. Contrary to the initial expectation, retention of human CD34+ HSCs was inhibited in the bone marrow of NOG-D1-Tg mice. In conclusion, our data suggest that the development of human B lymphocytes and HSC maintenance in osteosclerotic bone may be suppressed by introducing DLL1. These unique humanized mice with sclerotic bone reconstituted by human HSCs are useful models of hematopoiesis in patients with osteosclerosis, such as osteopetrosis, and for investigation of osteogenesis via Notch signaling.

UR - http://www.scopus.com/inward/record.url?scp=84867397059&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867397059&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2012.07.002

DO - 10.1016/j.exphem.2012.07.002

M3 - Article

VL - 40

SP - 953

EP - 963

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 11

ER -