Thioredoxin-Interacting Protein Regulates Hematopoietic Stem Cell Quiescence and Mobilization under Stress Conditions

Abstract

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.

Hematopoietic stem cells lacking Ott1 display aspects associated with aging and are unable to maintain quiescence during proliferative stress

“…Among these are Hypoxia inducible factor-1␣ (HIF1␣), Thioredoxin interacting protein (Txnip), and Retinoblastoma (Rb). [42][43][44] A common feature of these genes is their involvement in the modulation and response to ROS. Levels of ROS in LT-HSCs are relatively low in part because of the low oxygen tension of the osteoblast niche, overall metabolic state, and ROS scavenger systems.…”

Two patterns of thrombopoietin signaling suggest no coupling between platelet production and thrombopoietin reactivity in thrombocytopenia-absent radii syndrome

“…Mice lacking TXNIP have a decreased long-term hematopoietic stem cell pool that becomes exhausted over time. 37 TXNIP-deficiency reduced SDF1α-and osteopontin-mediated interactions between stem cells and the bone marrow niche, causing impaired homing and retention in the osteoblastic niche. Plasma levels of SDF1α and FGF-4, both cytokines mediating TPO-independent thrombopoiesis, 38 were normal in our TAR patients (data not shown).…”

Genetic control of quiescence in hematopoietic stem cells

“…39 The transcriptional repressor thioredoxininteracting protein (Txnip) induces cell cycle arrest and quiescence in HSCs; therefore, Txnip-null HSCs exhibit increased proliferation and exhaustion associated with a lower retention in the HSC niche. 40 Other genes involved in diverse functions, such as kinase (Atm), nucleosome deacetylase (Mi-2β), proliferating cell nuclear antigen (PCNA), and RNA binding protein (Ott1), have shown a reduction of HSC quiescence by somatic deletion ( Table 2).…”