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Enforced Expression of PU.1 Rescues Osteoclastogenesis from Embryonic Stem Cells Lacking Tal-1

^a Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan;
^b Department of Molecular and Cellular Biology, Kochi Medical School, and Laboratory of Human Health and Medical Science, Graduate School of Kuroshio Science, Nankoku, Kochi, Japan;
^c 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.;
^d Department of Pediatric Oncology, Children’s Hospital and the Dana Farber Cancer Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts, USA

Key Words. Embryonic stem cells • Hematopoiesis • PU.1 • Transcription factor SCL/Tal-1 • Osteoclast

Correspondence: Motokazu Tsuneto, 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: 81-859-34-8270; Fax: 81-859-34-8272; e-mail: tsune13{at}grape.med.tottori-u.ac.jp

Transcription factor T-cell acute lymphocytic leukemia 1 (Tal-1) is essential for the specification of hematopoietic development. Mice lacking Tal1 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 Tal1-null embryonic stem (ES) cells rescues the development of osteoclasts and macrophage–like phagocytes. It was low efficiency compared with wild–type ES cells; other hematopoietic lineage cells of granulocytes, B cells, mast cells, megakaryocytes, and erythroid cells were not generated. Osteoclasts developed in this culture were multinucleated and competent for bone resorption. Their development depended on macrophage colony-stimulating factor and receptor activator of nuclear factor B ligand. The majority of cells with the potential to differentiate into osteoclasts expressed fetal liver kinase 1 (Flk-1) and could be isolated using anti–Flk-1 antibody. 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.

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