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Discrete Types of Osteoclast Precursors Can Be Generated from Embryonic Stem Cells

^a Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan;
^b Division of Regenerative Medicine and Therapeutics, Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Yonago, Tottori, Japan;
^c The Center for Cell and Gene Therapy, Takara Bio Inc., Otsu, Shiga, Japan;
^d Department of Pathology, Stanford University School of Medicine, Beckman Center, Stanford, California, USA

Key Words. Clonal assays • Development • Embryonic stem cell • Experimental models • Hematopoiesis • In vitro culture • Mice • Progenitor • Osteoclast

Shin-Ichi Hayashi, M.D., Ph.D., Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, 86 Nishi-Machi, Yonago, Tottori, 683-8503, Japan. Telephone: 81-859-34-8269; Fax: 81-859-34-8272; e-mail: shayashi{at}grape.med.tottori-u.ac.jp

Osteoclast precursors (OCPs) share some characteristics with the monocyte/macrophage lineages, but the early events of OCP development are not yet clear. To investigate osteoclastogenesis from the earliest stage, we used step-wise cultures of embryonic stem (ES) cells to induce mature osteoclasts and assessed the effect of vascular endothelial growth factor receptor (VEGFR)-1/Fc chimeric protein on osteoclast development. Addition of VEGFR-1/Fc for the first 5 days of culture (phase I) severely inhibited the development of OCPs. Although OCPs were detected after culturing for a further 5 days (phase II), the reduction of OCPs in phase I was maintained in phase II. The generation of OCPs in phase I was resistant to signal blocking mediated by Kit receptors, but that in phase II was partially inhibited by either an anti-Kit antagonistic antibody or VEGFR-1/Fc and was severely inhibited by the combination of both reagents. Moreover, the OCPs in phase I gave rise to larger numbers of osteoclasts but required a longer period for maturation than the OCPs in phase II. We thus showed that OCPs expanded in phase II, but the majority of OCPs arose from ES cells in a manner dependent on VEGFR-1 binding factor(s) in phase I.

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