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* Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea;
Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea;
Department of Biological Science, Dong-A University, Busan, Republic of Korea; and
Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
Hematopoietic stem cells (HSCs) are maintained in a quiescent state in bone marrow (BM) niches by intrinsic and extrinsic signals. The mechanisms regulating the quiescence and mobilization of HSCs, however, remain unclear. In this study, we report that the expression of thioredoxin-interacting protein (TXNIP) is decreased during HSC activation. In Txnip–/– mice, the long-term reconstituting HSC population is decreased and exhausted, and its capacity to repopulate is rapidly lost. These effects are associated with hyperactive Wnt signaling, an active cell cycle, and reduced p21 expression under conditions of stress. TXNIP deficiency reduced the CXCL12- and osteopontin-mediated interaction between HSCs and the bone marrow, and impaired homing and retention in the osteoblastic niche, resulting in mobilized HSCs. Therefore, we propose that TXNIP is essential for maintaining HSC quiescence and the interaction between HSCs and the BM niche.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported, in part, by a Global Research Laboratory (GRL) project grant and a grant of Discovery of New Drug Target Project, the Ministry of Science and Technology, Republic of Korea.
2 Address correspondence and reprint requests to Dr. Inpyo Choi, Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong, Taejon 305-333, Republic of Korea. E-mail address: ipchoi{at}kribb.re.kr
3 Abbreviations used in this paper: HSC, hematopoietic stem cell; pVHL, von Hippel-Lindau protein; LKS, Lineage– ckit+ Sca-1+; 5-FU, 5-fluorouracil; BM, bone marrow; MPP, multipotent progenitor cell; OB, osteoblast; OPN, osteopontin; PB, peripheral blood; TXNIP, thioredoxin-interacting protein; WT, wild type.
4 The online version of this article contains supplemental material.
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