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Translin/TRAX Deficiency Affects Mesenchymal Differentiation Programs and Induces Bone Marrow Failure

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Stem Cells and Human Diseases

Abstract

The decision regarding self-renewal versus differentiation of hematopoietic stem cells (HSCs) is a crucial issue in bone marrow hematopoiesis. We have generated mice homozygous for an inactivating mutation of the whole Translin gene (Translin−/−) and investigated their hematopoietic status during early and later in life. Here we show that Translin deficiency affects mesenchymal differentiation and results in perturbation of self-renewal HSCs. Young Translin−/− mice, especially around 3 weeks of age, displayed markedly reduced lymphocyte counts in the peripheral blood, attributable to developmental arrest of B-lymphocytes in the earliest progenitor stage. With aging, progressive bone marrow failure was displayed, with developmental arrest of myeloid cells and B lymphocytes in a stroma-dependent manner, and eventually ectopic osteogenesis, vasculogenesis and adipogenesis resulted. Despite apparent hematopoietic aplasia, however, the frequency of HSCs in the bone marrow of mutant mice was remarkably increased. Furthermore, knockdown of Translin and its binding partner protein, TRAX, up-regulated genes associated with mesenchymal differentiation in a mesenchymal stem cell line. Taken together, these findings suggest that the Translin and TRAX complex influences both self-renewal and multilineage differentiation of HSCs by targeting mesenchymal stem/progenitor cells.

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Acknowledgements

We are grateful to Drs. N. Kaneki, G.C. Bagby, J.C. Wang and J.L. Strominger for valuable suggestions. This work was supported by grant to M. K. from the Japan Health Sciences Foundation (JHSF) (SHC 4432).

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Authors and Affiliations

  1. Department of Immunology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan

    Reiko Ishida, Katsunori Aoki, Yuko Fukuda & Masataka Kasai

  2. Department of Hematology (Internal Medicine), The University of Tokyo, Tokyo, Japan

    Katsunori Aoki

  3. National Institution for Academic Degrees and University Evaluation, Tokyo, Japan

    Kazuhiko Nakahara

  4. Faculty of Science and Engineering, Waseda University, Tokyo, Japan

    Momoko Ohori, Yumi Saito, Kimihiko Kano & Shigetaka Asano

  5. Laboratory of Animal Models for Human Diseases, National Institute of Biomedical Innovation, Osaka, Japan

    Junichiro Matsuda

  6. Bone Marrow Transplantation Program, Center for Hematological Malignancies, Oregon Health and Science University, Portland, OR, USA

    Richard T. Maziarz

  7. Center for Stem Cell and Regenerative Medicine, Institute of Medical Science,, The University of Tokyo, Tokyo, Japan

    Masataka Kasai

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  1. Reiko Ishida
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  2. Katsunori Aoki
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  11. Masataka Kasai
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Correspondence to Masataka Kasai .

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Editors and Affiliations

  1. , Pharmacology and Toxicology, University of Kansas Medical Center, Rainbow Blvd 3901, Kansas City, 66160, Kansas, USA

    Rakesh Srivastava

  2. , Pathology and Laboratory Medicine, University of Kansas Medical Center, Rainbow Blvd 3901, Kansas City, 66160, Kansas, USA

    Sharmila Shankar

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Ishida, R. et al. (2012). Translin/TRAX Deficiency Affects Mesenchymal Differentiation Programs and Induces Bone Marrow Failure. In: Srivastava, R., Shankar, S. (eds) Stem Cells and Human Diseases. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2801-1_21

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