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, Inpyo Choi

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61 Scopus citations

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.

Original languageEnglish
Article number13674
JournalNature Communications
Volume7
DOIs
StatePublished - 8 Dec 2016

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