Molecular Functions of the LIM-Homeobox Transcription Factor Lhx2 in Hematopoietic Progenitor Cells Derived from Mouse Embryonic Stem Cells

Authors

  • Kenji Kitajima,

    Corresponding author
    1. Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    • Correspondence: Kenji Kitajima, Ph.D., Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Telephone: 81-3-5316-3130; Fax: 81-3-5316-3226; e-mail: kitajima-kj@igakuken.or.jp Correspondence: Takahiko Hara, Ph.D., Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156–8506, Japan. Telephone: 81-3-5316-3130; Fax: +81-3-5316-3226; e-mail: hara-tk@igakuken.or.jp

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    • Author contributions: K.K.: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; M.Ka.: collection and assembly of data; M.I., M.Ky.: provision of study material; T.H.: conception and design and manuscript writing.

  • Manami Kawaguchi,

    1. Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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  • Michelina Iacovino,

    1. Lillehei Heart Institute, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
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  • Michael Kyba,

    1. Lillehei Heart Institute, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
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  • Takahiko Hara

    Corresponding author
    1. Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
    • Correspondence: Kenji Kitajima, Ph.D., Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan. Telephone: 81-3-5316-3130; Fax: 81-3-5316-3226; e-mail: kitajima-kj@igakuken.or.jp Correspondence: Takahiko Hara, Ph.D., Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156–8506, Japan. Telephone: 81-3-5316-3130; Fax: +81-3-5316-3226; e-mail: hara-tk@igakuken.or.jp

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Abstract

We previously demonstrated that hematopoietic stem cell (HSC)-like cells are robustly expanded from mouse embryonic stem cells (ESCs) by enforced expression of Lhx2, a LIM-homeobox domain (LIM-HD) transcription factor. In this study, we analyzed the functions of Lhx2 in that process using an ESC line harboring an inducible Lhx2 gene cassette. When ESCs are cultured on OP9 stromal cells, hematopoietic progenitor cells (HPCs) are differentiated and these HPCs are prone to undergo rapid differentiation into mature hematopoietic cells. Lhx2 inhibited differentiation of HPCs into mature hematopoietic cells and this effect would lead to accumulation of HSC-like cells. LIM-HD factors interact with LIM domain binding (Ldb) protein and this interaction abrogates binding of LIM-only (Lmo) protein to Ldb. We found that one of Lmo protein, Lmo2, was unstable due to dissociation of Lmo2 from Ldb1 in the presence of Lhx2. This effect of Lhx2 on the amount of Lmo2 contributed into accumulation of HSC-like cells, since enforced expression of Lmo2 into HSC-like cells inhibited their self-renewal. Expression of Gata3 and Tal1/Scl was increased in HSC-like cells and enforced expression of Lmo2 reduced expression of Gata3 but not Tal1/Scl. Enforced expression of Gata3 into HPCs inhibited mature hematopoietic cell differentiation, whereas Gata3-knockdown abrogated the Lhx2-mediated expansion of HPCs. We propose that multiple transcription factors/cofactors are involved in the Lhx2-mediated expansion of HSC-like cells from ESCs. Lhx2 appears to fine-tune the balance between self-renewal and differentiation of HSC-like cells. Stem Cells 2013;31:2680–2689

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