期刊
NATURE MEDICINE
卷 18, 期 12, 页码 1778-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2984
关键词
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资金
- Institute for Translational Medicine and Therapeutics (ITMAT) at the University of Pennsylvania
- US National Institutes of Health [1R21HL107968-01, 1R01HL110806-01, K99, 1K99HL10774701, 1-K23-HL-093366-01A1]
- Leukemia and Lymphoma Society
- University of Pennsylvania
- Human Hematopoietic Stem Cell Center of Excellence at the Children's Hospital of Philadelphia [5P30DK090969-02]
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-beta-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-beta-catenin and inhibit mTOR signaling increases the number (but not the proportion) of long-term HSCs in vivo.
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