Bone Marrow Microenvironments for Hematopoiesis

• Project/Area Number: 15590344
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National University Corporation Tottori University
• Principal Investigator: HAYASHI Shin-ichi Tottori University, Faculty of Medicine, Professor, 医学部, 教授 (50208617)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: Bone marrow / Hematopoiesis / Osteoclast / B cell / Toll-like receptor / Lipopolysaccharide(LPS) / Tyrosine phosphatase / Embryonic stem(ES) cell / 髄外造血 / 幹細胞 / 造血支持細胞 / Notchシグナル / リポポリサッカライド

Research Abstract

1)Analysis of osteoclastogenesis for bone marrow formation :
Osteoclasts are hematopoietic cells, which participate in bone resorption and remodeling. Receptor activator of NF-κB ligand(RANKL) and macrophage colony-stimulating factor(M-CSF) are critical for development of osteoclasts. The Toll-like receptor(TLR) family shares some of the downstream signaling with RANK, however, the signaling via TLRs has never been reported to induce osteoclastogenesis without RANKL. We showed that significant numbers of mature osteoclasts were generated from protein tyrosine phosphatase SHP-1-defective me^v/me^v bone marrow cells in the presence of M-CSF and LPS, a TLR4 ligand without addition of RANKL in culture. The osteoclast precursors were present in the Kit-positive cell enriched fraction of BM cells. Although me^v/me^v bone marrow cells required a comparable concentration of RANKL or TNF-α as wild-type cells for the initiation of osteoclastogenesis, numbers of multinucleated osteoclasts in me^v/ me^v bone marrow cultures were significantly increased by the equivalent dose of RANKL or TNF-α in the presence of M-CSF. These results indicate that a defect of SHP-1 function not only accelerates physiological osteoclast development by RANKL/RANK, but also acquires an aberrant pathway for osteoclastogenesis by LPS.
2)Induction of hematopoiesis from blood-less embryonic stem (ES) cell line :
Transcription factor Tal-1 is essential for the specification of hematopoietic development. Mice lacking Tall fail to generate any hematopoietic precursors. Using our co-culture system with stromal cells, we demonstrate that enforced expression of the transcription factor PU.1 under tetracycline control in Tall-null ES cells rescues the development of osteoclasts and macrophage-like phagocytes expressing a macrophage restricted marker. Other hematopoietic lineage cells were not generated. Their development was dependent on M-CSF and RANKL. These results suggest that the expression of PU.1 is a critical event for osteoclastogenesis and that Tal-1 may lie upstream of PU.1 in a regulatory hierarchy during osteoclastogenesis.

Research Products

• [Journal Article] Enforced expression of PU.1 rescues osteoclastogenesis from embryonic stem cells lacking Tal-1 (2005)
  • Author(s): Tsuneto, M., et al.
  • Journal Title: Stem Cells 23 Pages: 134-143
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Presence and distribution of neural crest-derived cells in the murine developing thymus and their potential for differentiation (2005)
  • Author(s): Yamazaki, H., et al.
  • Journal Title: Int.Immunol. (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Neural crest stem cells and organogenesis. (2005)
  • Author(s): Yamazaki, H., et al.
  • Journal Title: Progress in Stem Cell Research (Nova Science Publishers) (In press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Enforced expression of PU.1 rescues osteoclastogenesis from embryonic stem cells lacking Tal-1. (2005)
  • Author(s): Tsuneto, M., Tominaga, A., Yamazaki, H., Yoshino, M., Orkin, S.H., Hayashi, S.I.
  • Journal Title: Stem Cells 23 Pages: 134-143
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neural crest stem cells and organogenesis. (2005)
  • Author(s): Yamazaki, H., et al.
  • Journal Title: Trends in Stem Cell Research, Nova Science Publishers (In press)
• [Journal Article] Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice. (2004)
  • Author(s): Hayashi, S.I., et al.
  • Journal Title: Endocrinology 145 Pages: 2721-2729
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Migration of dendritic cells determines divergent immune responses (2004)
  • Author(s): Yoshino, M., et al.
  • Journal Title: Recent Research Development in Biophysics and Biochemistry (Research Signpost) 4 Pages: 29-48
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contribution of neural crest cells in the tooth development and the possibility of tooth regeneration (2004)
  • Author(s): Yamazaki, H., Hayashi, S.I.
  • Journal Title: J.Oral.Sci. 46 Pages: 509-518
  • NAID: 110003166651
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lipopolysaccharide-induced osteoclastogenesis in Src homology 2-domain phosphatase-1-deficient viable motheaten mice. (2004)
  • Author(s): Hayashi.S.I., Tsuneto, M., Yamada, T., Nose, M., Yoshino, M., Shultz, L.D., Yamazaki, H.
  • Journal Title: Endocrinology 145 Pages: 2721-2729
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Osteoclast Lineage (Chapter 27). (2004)
  • Author(s): Yamane, T., Okuyama, H., Tsuneto, M., Hemmi, H., Yamazaki, H., Hayashi.S.I.
  • Journal Title: Handbook of Stem Cells (Eds.R.P.Lanza, et al.)(Academic Press, San Diego, CA.)Embryonic Stem Cells Vol.1 Pages: 295-303
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Migration of dendritic cells determines divergent immune responses. (2004)
  • Author(s): Yoshino, M., Yamazaki, H., Hayashi.S.I.
  • Journal Title: Recent Research Development in Biophysics and Biochemistry (Research Signpost) 4 Pages: 29-48
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Contribution of neural crest cells in the tooth development and the possibility of tooth regeneration. (2004)
  • Author(s): Yamazaki, H., Hayashi, S.I.
  • Journal Title: J.Oral.Sci. 46 Pages: 509-518
  • NAID: 110003166651
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells (2003)
  • Author(s): Yamada, T., et al.
  • Journal Title: Blood 101 Pages: 2227-2234
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reduction of osteoclasts in the critical embryonic period is essential for inhibition of mouse tooth eruption (2003)
  • Author(s): Yoshino, M., et al.
  • Journal Title: J.Bone Miner.Res. 18 Pages: 108-116
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Generation of structures formed by lens and retinal cells differentiating from embryonic stem cells (2003)
  • Author(s): Hirano, M., et al.
  • Journal Title: Dev.Dyn. 228 Pages: 664-671
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distinct osteoclast precursors in the bone marrow and extramedullary organs characterized by responsiveness to Toll-like receptor ligands and TNF-α (2003)
  • Author(s): Hayashi, S.I., et al.
  • Journal Title: J.Immunol. 171 Pages: 5130-5139
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Discrete types of osteoclast precursors can be generated from embryonic stem cells (2003)
  • Author(s): Okuyama, H., et al.
  • Journal Title: Stem Cells 21 Pages: 670-680
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distinct antigen trafficking from skin in the steady and active states. (2003)
  • Author(s): Yoshino, M., et al.
  • Journal Title: Int.Immunol. 15 Pages: 773-779
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] In vitro differentiation of mouse ES cells into hematopoietic, endothelial, andosteoblastic cell lineages : A possibility of in vitro organogenesis (2003)
  • Author(s): Tsuneto, M., et al.
  • Journal Title: Methods Enzymol. 365 Pages: 98-114
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tooth development and tooth regeneration using tooth germ, dental pulp cells, neural crest cells and embryonic stem cells (2003)
  • Author(s): Yamazaki, H., et al.
  • Journal Title: Recent Research Development in Biophysics and Biochemistry. (Research Signpost) 3 Pages: 907-925
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through atromal cells. (2003)
  • Author(s): Yamada, T., Yamazaki, H., Yamane, T., Yoshino, M., Okuyama, H., Tsuneto, M., Kurino, T, Hayashi, S.I., Sakano, S.
  • Journal Title: Blood 101 Pages: 2227-2234
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Reduction of osteoclasts in the critical embryonic period is essential for inhibition of mouse tooth eruption. (2003)
  • Author(s): Yoshino, M., Yamazaki, H., Yoshida, H., Niida, S., Nishikawa, S.I., Ryoke, K., Kunisada, T., Hayashi, S.I.
  • Journal Title: J.Bone Miner.Res. 18 Pages: 108-116
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of structures formed by lens and retinal cells differentiating from embryonic stem cells. (2003)
  • Author(s): Hirano, M., Yamamoto, A., Yoshimura, N., Tokunaga, T., Motohashi, T., Ishizaki, K., Yoshida, H., Okazaki, K, Yamazaki, H., Hayashi, S.I., Kunisada, T.
  • Journal Title: Dev.Dyn. 228 Pages: 664-671
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinct osteoclast precursors in the bone marrow and extramedullary organs characterized by responsiveness to Toll-like receptor ligands and TNF-α (2003)
  • Author(s): Hayashi.S.I., Yamada, T., Tsuneto, M., Yamane, T., Takahashi, M., Shultz, L.D., Yamazaki H.
  • Journal Title: J.Immunol. 171 Pages: 5130-5139
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Discrete types of osteoclast precursors can be generated from embryonic stem cells. (2003)
  • Author(s): Okuyama, H., Tsuneto, M., Yamane, T., Yamazaki, H., Hayashi, S.I.
  • Journal Title: Stem Cells 21 Pages: 670-680
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinct antigen trafficking from skin in the steady and active states. (2003)
  • Author(s): Yoshino, M., Yamazaki, H., Nakano, H., Kakiuchi, T., Ryoke, K., Kunisada, T., Hayashi, S.I.
  • Journal Title: Int.Immunol. 15 Pages: 773-779
  • NAID: 10014341739
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] In vitro differentiation of mouse ES cells into hematopoietic, endothelial, and osteoblastic cell lineages : A possibility of in vitro organogenesis. (2003)
  • Author(s): Tsuneto, M., Yamane, T., Okuyama, H., Yamazaki, H., Hayashi, S.I.
  • Journal Title: Differentiation of Embryonic Stem Cells (Eds.P.M.Wassarman, and G.M.Keller)(Academic Press, San Diego, CA) Methods Enzymol. 365 Pages: 98-114
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tooth development and tooth regeneration using tooth germ, dental pulp cells, neural crest cells and embryonic stem cells. (2003)
  • Author(s): Yamazaki, H., Kurino, T., Sakata, E., Yoshino, M., Hayashi.S.I.
  • Journal Title: Recent Research Development in Biophysics and Biochemistry (Research Signpost) 3 Pages: 907-925
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Presence and distribution of neural crest-derived cells in the murine developing thymus and their potential for differentiation.
  • Author(s): Yamazaki, H., Sakata, E., Yamane, T., Yanagisawa, A., Abe, K., Yamamura, K.I., Hayashi, S.I., Kunisada, T.
  • Journal Title: Int.Immunol. (In press)
  • NAID: 10019359234
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Neural crest stem cells and organogenesis.
  • Author(s): Yamazaki, H., Yoshino, M., Hayashi, S.I.
  • Journal Title: Progress in Stem Cell Research (Ed.F.Columbus)(Nova Science Publishers, Inc., Hauppauge, NY.) (In press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] Osteoclast Lineage (Chapter 27) (pp295-303, Handbook of Stem Cells, Vol.1, Embryonic Stem Cells) (2004)
  • Author(s): Yamane, T., et al.
  • Total Pages: 806
  • Publisher: Academic Press
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Osteoclast Lineage (Chapter 27) pp295-303, Handbook of Stem Cells, Vol.1, Embryonic Stem Cells". (2004)
  • Author(s): Yamane, T., et al.
  • Total Pages: 806
  • Publisher: Academic Press
• [Publications] Yamada, T., et al.: "Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells"Blood. 101. 2227-2234 (2003)
• [Publications] Yoshino, M., et al.: "Reduction of osteoclasts in the critical embryonic period is essential for inhibition of mouse tooth eruption"J.Bone Miner.Res.. 18. 108-116 (2003)
• [Publications] Yoshino, M., et al.: "Distinct antigen trafficking from skin in the steady and active states"Int.Immunol.. 15. 773-779 (2003)
• [Publications] Okuyama, H., et al.: "Discrete types of osteoclast precursors can be generated from embryonic stem cells"Stem Cells. 21. 670-680 (2003)
• [Publications] Hayashi, S.I., et al.: "Distinct osteoclast precursors in the bone marrow and extramedullary organs characterized by responsiveness to Toll-like receptor ligands and TNF-α"J.Immunol.. 171. 5130-5139 (2003)
• [Publications] Hirano, M., et al.: "Generation of structures formed by lens and retinal cells differentiating from embryonic stem cells"Dev.Dyn.. 228. 664-671 (2003)
• [Publications] Tsuneto, M., et al.: "In vitro differentiation of mouse ES cells into hematopoietic, endothelial, and osteoblastic cell lineages : A possibility of in vitro organogenesis"Methods Enzymol.. 365. 98-114 (2003)
• [Publications] Yamazaki, H., et al.: "Tooth development and tooth regeneration using tooth germ, dental pulp cells, neural crest cells and embryonic stem cells"Recent Research Development in Biophysics and Biochemistry (Research Signpost). 3. 907-925 (2003)
• [Publications] Hayashi, S.I., et al.: "Lipopolysaccharide-induced osteoclastogenesis in SHP-1-deficient viable motheaten mice"Endocrinology. (in press). (2004)
• [Publications] Yamane, T., et al.: "Osteoclast Lineage. In"Handbook of Embryonic Stem Cells""Academic Press(in press). (2004)