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

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, Sang-Hyun Min and Inpyo Choi ()
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Haiyoung Jung: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Dong Oh Kim: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jae-Eun Byun: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Won Sam Kim: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Mi Jeong Kim: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
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)
Tae-Don Kim: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Suk Ran Yoon: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Hee Gu Lee: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
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)

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13674

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