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      The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance

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          Adult mouse LSK cells unable to undergo autophagy contain fewer HSCs, accumulate mitochondria, and fail to reconstitute lethally irradiated mice.


          The role of autophagy, a lysosomal degradation pathway which prevents cellular damage, in the maintenance of adult mouse hematopoietic stem cells (HSCs) remains unknown. Although normal HSCs sustain life-long hematopoiesis, malignant transformation of HSCs leads to leukemia. Therefore, mechanisms protecting HSCs from cellular damage are essential to prevent hematopoietic malignancies. In this study, we crippled autophagy in HSCs by conditionally deleting the essential autophagy gene Atg7 in the hematopoietic system. This resulted in the loss of normal HSC functions, a severe myeloproliferation, and death of the mice within weeks. The hematopoietic stem and progenitor cell compartment displayed an accumulation of mitochondria and reactive oxygen species, as well as increased proliferation and DNA damage. HSCs within the Lin Sca-1 +c-Kit + (LSK) compartment were significantly reduced. Although the overall LSK compartment was expanded, Atg7-deficient LSK cells failed to reconstitute the hematopoietic system of lethally irradiated mice. Consistent with loss of HSC functions, the production of both lymphoid and myeloid progenitors was impaired in the absence of Atg7. Collectively, these data show that Atg7 is an essential regulator of adult HSC maintenance.

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          Most cited references 60

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              Self-eating and self-killing: crosstalk between autophagy and apoptosis.

              The functional relationship between apoptosis ('self-killing') and autophagy ('self-eating') is complex in the sense that, under certain circumstances, autophagy constitutes a stress adaptation that avoids cell death (and suppresses apoptosis), whereas in other cellular settings, it constitutes an alternative cell-death pathway. Autophagy and apoptosis may be triggered by common upstream signals, and sometimes this results in combined autophagy and apoptosis; in other instances, the cell switches between the two responses in a mutually exclusive manner. On a molecular level, this means that the apoptotic and autophagic response machineries share common pathways that either link or polarize the cellular responses.

                Author and article information

                J Exp Med
                J. Exp. Med
                The Journal of Experimental Medicine
                The Rockefeller University Press
                14 March 2011
                : 208
                : 3
                : 455-467
                [1 ]Nuffield Department of Clinical Medicine , [2 ]Nuffield Department of Clinical Laboratory Sciences , and [3 ]Haematopoietic Stem Cell Laboratory, Weatherall Institute of Molecular Medicine ; [4 ]Department of Cellular Pathology ; and [5 ]Translational Immunology Laboratory and [6 ]Genetics and Pathology Theme, National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics; John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, England, UK
                [7 ]Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 0XB, Scotland, UK
                Author notes
                CORRESPONDENCE Anna Katharina Simon: katja.simon@

                K.R. Kranc and A.K. Simon contributed equally to this paper.

                © 2011 Mortensen et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at




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