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Nat Commun. 2016 Dec 8;7:13674. doi: 10.1038/ncomms13674.

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

Jung H1,2, Kim DO1,2, Byun JE1,3, Kim WS1,2, Kim MJ1,2, Song HY1, Kim YK4, Kang DK5, Park YJ1,2, Kim TD1,2, Yoon SR1,2, Lee HG1,6, Choi EJ7, Min SH8, Choi I1,2.

Author information

1
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong-gu, Daejeon 34141, Republic of Korea.
2
Department of Functional Genomics, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
3
Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju 28644, Republic of Korea.
4
Scripps Korea Antibody Institute, 1 Kangwondaehak-gil, Chuncheon 24341, Republic of Korea.
5
Bioenergy and Biochemical Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
6
Department of Biomolecular Science, University of Science and Technology, Yuseong-gu, Daejeon 34113, Republic of Korea.
7
Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
8
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Chumbokro Dong-gu 41061, Daegu, Republic of Korea.

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.

PMID:
27929088
PMCID:
PMC5155146
DOI:
10.1038/ncomms13674
[Indexed for MEDLINE]
Free PMC Article

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