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.
authors: Central Institute for Experimental Animals, Kawasaki, Japan.
authors: Ryoji
authors: R
authors: Ito
authors: Naoko
authors: N
authors: Negishi
authors: Naoko
authors: N
authors: Irie
authors: Koichi
authors: K
authors: Matsuo
authors: Daisuke
authors: D
authors: Suzuki
authors: Ikumi
authors: I
authors: Katano
authors: Eri
authors: E
authors: Hayakawa
authors: Kenji
authors: K
authors: Kawai
authors: Tsutomu
authors: T
authors: Kamisako
authors: Tomoo
authors: T
authors: Eto
authors: Tomoyuki
authors: T
authors: Ogura
authors: Katsuto
authors: K
authors: Hozumi
authors: Kiyoshi
authors: K
authors: Ando
authors: Sadakazu
authors: S
authors: Aiso
authors: Norikazu
authors: N
authors: Tamaoki
authors: Sonoko
authors: S
authors: Habu
authors: Mamoru
authors: M
authors: Ito
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics*; D006410:Hematopoiesis; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000473:pathology*; D010026:Osteosclerosis / Q000473:pathology*; D000099176:Noggin Protein
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000099176:Noggin Protein; C512925:Dlk1 protein, mouse