Molecular Integration of HoxB4 and STAT3 for Self-Renewal of Hematopoietic Stem Cells: A Model of Molecular Convergence for Stemness

Authors

  • Sung-Hyun Hong,

    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Seung-Jip Yang,

    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Tae-Min Kim,

    1. Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea
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  • Jae-Seung Shim,

    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Ho-Sun Lee,

    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Ga-Young Lee,

    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Bo-Bae Park,

    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
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  • Suk Woo Nam,

    1. Cancer Evolution Research Center, The Catholic University of Korea, Seoul, Korea
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  • Zae Young Ryoo,

    1. School of Life Science and Biotechnology, Kyungpook National University, Daegu, Korea
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  • Il-Hoan Oh

    Corresponding author
    1. Catholic High-Performance Cell Therapy Center and Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Korea
    • Correspondence: Il-Hoan Oh, MD, Ph.D., Catholic High-Performance Cell Therapy Center, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku, Seoul 137-701, Korea. Telephone: 82-2-2258-8268; Fax: 82-2-591-3994; e-mail: iho@catholic.ac.kr

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Abstract

The upregulation of HoxB4 promotes self-renewal of hematopoietic stem cells (HSCs) without overriding the normal stem cell pool size. A similar enhancement of HSC self-renewal occurs when signal transducer and activator of transcription 3 (STAT3) is activated in HSCs. In this study, to gain insight into the functional organization of individual transcription factors (TFs) that have similar effects on HSCs, we investigated the molecular interplay between HoxB4 and STAT3 in the regulation of HSC self-renewal. We found that while STAT3-C or HoxB4 similarly enhanced the in vitro self-renewal and in vivo repopulating activities of HSCs, simultaneous transduction of both TFs did not have additive effects, indicating their functional redundancy in HSCs. In addition, activation of STAT3 did not cause changes in the expression levels of HoxB4. In contrast, the inhibition of STAT3 activity in HoxB4-overexpressing hematopoietic cells significantly abrogated the enhancing effects of HoxB4, and the upregulation of HoxB4 caused a ligand-independent Tyr-phosphorylation of STAT3. Microarray analysis revealed a significant overlap of the transcriptomes regulated by STAT3 and HoxB4 in undifferentiated hematopoietic cells. Moreover, a gene set enrichment analysis showed significant overlap in the candidate TFs that can recapitulate the transcriptional changes induced by HoxB4 or STAT3. Interestingly, among these common TFs were the pluripotency-related genes Oct-4 and Nanog. These results indicate that tissue-specific TFs regulating HSC self-renewal are functionally organized to play an equivalent role in transcription and provide insights into the functional convergence of multiple entries of TFs toward a conserved transcription program for the stem cell state. Stem Cells 2014;32:1313–1322

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