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Thioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity

Author

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  • Haiyoung Jung

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Dong Oh Kim

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Jae-Eun Byun

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    School of Life Sciences, Chungbuk National University)

  • Won Sam Kim

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Mi Jeong Kim

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Hae Young Song

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB))

  • Young Kwan Kim

    (Scripps Korea Antibody Institute)

  • Du-Kyeong Kang

    (Bioenergy and Biochemical Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Young-Jun Park

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Tae-Don Kim

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Suk Ran Yoon

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Hee Gu Lee

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

  • Eun-Ji Choi

    (Asan Medical Center, University of Ulsan College of Medicine)

  • Sang-Hyun Min

    (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF))

  • Inpyo Choi

    (Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
    University of Science and Technology)

Abstract

Ageing is a natural process in living organisms throughout their lifetime, and most elderly people suffer from ageing-associated diseases. One suggested way to tackle such diseases is to rejuvenate stem cells, which also undergo ageing. Here we report that the thioredoxin-interacting protein (TXNIP)-p38 mitogen-activated protein kinase (p38) axis regulates the ageing of haematopoietic stem cells (HSCs), by causing a higher frequency of long-term HSCs, lineage skewing, a decrease in engraftment, an increase in reactive oxygen species and loss of Cdc42 polarity. TXNIP inhibits p38 activity via direct interaction in HSCs. Furthermore, cell-penetrating peptide (CPP)-conjugated peptide derived from the TXNIP-p38 interaction motif inhibits p38 activity via this docking interaction. This peptide dramatically rejuvenates aged HSCs in vitro and in vivo. Our findings suggest that the TXNIP-p38 axis acts as a regulatory mechanism in HSC ageing and indicate the potent therapeutic potential of using CPP-conjugated peptide to rejuvenate aged HSCs.

Suggested Citation

  • Haiyoung Jung & Dong Oh Kim & Jae-Eun Byun & Won Sam Kim & Mi Jeong Kim & Hae Young Song & Young Kwan Kim & Du-Kyeong Kang & Young-Jun Park & Tae-Don Kim & Suk Ran Yoon & Hee Gu Lee & Eun-Ji Choi & Sa, 2016. "Thioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity," Nature Communications, Nature, vol. 7(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13674
    DOI: 10.1038/ncomms13674
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    Cited by:

    1. Marc Jan Bonder & Stephen J. Clark & Felix Krueger & Siyuan Luo & João Agostinho de Sousa & Aida M. Hashtroud & Thomas M. Stubbs & Anne-Katrien Stark & Steffen Rulands & Oliver Stegle & Wolf Reik & Fe, 2024. "scEpiAge: an age predictor highlighting single-cell ageing heterogeneity in mouse blood," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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