title: Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways.
abstract: 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.
authors.affiliation: Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Michelle
authors.initials: M
authors.lastname: Nguyen-McCarty
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Hexner
authors.forename: Gwenn
authors.initials: G
authors.lastname: Danet-Desnoyers
authors.forename: Peter S
authors.initials: PS
authors.lastname: Klein
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D020123:Sirolimus / Q000494:pharmacology; D033581:Stem Cell Transplantation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: D058570:TOR Serine-Threonine Kinases; D018021:Lithium Chloride; D020123:Sirolimus