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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.

Original publication

DOI

10.1084/jem.20101145

Type

Journal article

Journal

The Journal of experimental medicine

Publication Date

03/2011

Volume

208

Pages

455 - 467

Addresses

Nuffield Department of Clinical Medicine, Weatherall Institute of Molecular Medicine, UK.

Keywords

Hematopoietic Stem Cells, Mitochondria, Stem Cells, Animals, Mice, Knockout, Mice, Myeloproliferative Disorders, DNA Damage, Reactive Oxygen Species, Microtubule-Associated Proteins, Apoptosis, Cell Proliferation, Autophagy, Female, Male, Autophagy-Related Protein 7