Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways.
Pubmed ID: 23142822
Pubmed Central ID: PMC3518679
Journal: Nature medicine
Publication Date: 12/01/2012
Affiliation: Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
MeSH Terms: Humans, Cell Proliferation, Sirolimus, TOR Serine-Threonine Kinases, Animals, Analysis of Variance, Homeostasis, Hematopoietic Stem Cells, Stem Cell Transplantation, Mice, Flow Cytometry, Cell Culture Techniques, Lithium Chloride, Wnt Signaling Pathway
Grants: 1-K23-HL-093366-01A1, 1K99HL10774701, 1R01HL110806-01, 1R21HL107968-01, 5P30DK090969-02, R01 HL110806, R21 HL107968, P30 DK090969
Authors: Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS
Cite As: Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med 2012 Dec;18(12):1778-85. Epub 2012 Nov 11.
Hematopoietic stem cell (HSC) self renewal and lineage commitment depend on complex interactions with the microenvironment. The ability to maintain or expand HSCs for clinical applications or basic research has been substantially 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 mTOR pathway, an established nutrient sensor, combined with activation of canonical Wnt-β-catenin signaling, allows for the ex vivo maintenance of human and mouse long-term HSCs under cytokine-free conditions. We also show that the combination of two clinically approved medications that together activate Wnt-β-catenin and inhibit mTOR signaling increases the number (but not the proportion) of long-term HSCs in vivo.