Regulation of hematopoietic stem cell quiescence by TXNIP (36.1)

Abstract

Abstract Hematopoietic stem cells (HSCs) are distinct cells that are predominantly located in the bone marrow microenvironment, which is referred to as the niche. HSC quiescence, activation, and mobilization are coordinately regulated in their niche by intrinsic and extrinsic mechanisms. Several genes, including those that encode transcriptional regulators, cell cycle regulatory proteins, tumor suppressors, and proto-oncogenes, intrinsically regulate the balance between HSC quiescence and activation. The vitamin D3 up-regulated protein 1 (VDUP1) is a 397 amino acid residue, 50-kDa protein that belongs to the arrestin family. We hypothesized that VDUP1 plays a pivotal role in controlling HSC cell cycle, migration, and BM niche interactions. The expression of VDUP1 is decreased during HSC activation. In VDUP1-/- mice, the LT-HSC population is decreased and exhausted, and its capacity to repopulate is rapidly lost. The VDUP1 deficiency reduced the osteopontin/integrin β1-mediated interaction between HSCs and the bone marrow niche and impaired homing and retention in the osteoblastic niche, resulting in mobilized HSCs. Thus, we propose that VDUP1 is essential for maintaining HSC quiescence and interactions with the BM niche.