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

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.

Keywords

  • Translin
  • TRAX
  • MSCs
  • HSCs
  • Bone marrow failure

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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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Correspondence to Masataka Kasai .

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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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