Maintenance of Hematopoietic Stem Cells through Regulation of Wnt and mTOR Pathways

Hematopoietic stem cell (HSC) self-renewal and lineage commitment depend on complex interactions with the microenvironment, and the ability to maintain or expand HSCs for clinical applications or for basic research has been significantly limited because these interactions are not well defined. Recent evidence suggests that HSCs reside in a low perfusion, reduced nutrient niche and that nutrient sensing pathways contribute to HSC homeostasis. Here we report that suppression of the mammalian target of rapamycin (mTOR) pathway, an established nutrient sensor, combined with activation of canonical Wnt/β-catenin signaling, allows the ex vivo maintenance of human and mouse long-term HSCs under cytokine-free conditions. We also show that combining two clinically approved medications that activate Wnt/β-catenin signaling and inhibit mTOR increases the number (but not the proportion) of long-term HSCs in vivo.