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

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          Abstract

          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.

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          Most cited references47

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          Wnt signaling and cancer.

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            TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth.

            Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues. TSC2 inhibits cell growth by acting as a GTPase-activating protein toward Rheb, thereby inhibiting mTOR, a central controller of cell growth. Here, we show that Wnt activates mTOR via inhibiting GSK3 without involving beta-catenin-dependent transcription. GSK3 inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation. Inhibition of mTOR by rapamycin blocks Wnt-induced cell growth and tumor development, suggesting a potential therapeutic value of rapamycin for cancers with activated Wnt signaling. Our results show that, in addition to transcriptional activation, Wnt stimulates translation and cell growth by activating the TSC-mTOR pathway. Furthermore, the sequential phosphorylation of TSC2 by AMPK and GSK3 reveals a molecular mechanism of signal integration in cell growth regulation.
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              Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

              Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.
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                Author and article information

                Journal
                9502015
                8791
                Nat Med
                Nat. Med.
                Nature medicine
                1078-8956
                1546-170X
                1 October 2012
                11 November 2012
                December 2012
                01 June 2013
                : 18
                : 12
                : 1778-1785
                Affiliations
                [1 ]Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, PA
                [2 ]Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, PA
                [3 ]Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA
                Author notes
                [4 ]For correspondence: pklein@ 123456mail.med.upenn.edu , 364 Clinical Research Building, 415 Curie Blvd, Philadelphia, PA 19104, (215) 898-2179 (phone), (215) 573-4320 (fax)
                Article
                NIHMS410951
                10.1038/nm.2984
                3518679
                23142822
                a0a192b0-7adb-463a-8420-cea38f0b4bc6

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R21 HL107968 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL110806 || HL
                Categories
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                Medicine
                Medicine

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