title: The autophagy protein Atg7 is essential for hematopoietic stem cell maintenance.
abstract: 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.
authors.affiliation: Nuffield Department of Clinical Medicine, Weatherall Institute of Molecular Medicine, UK.
authors.forename: Monika
authors.initials: M
authors.lastname: Mortensen
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Soilleux
authors.forename: Gordana
authors.initials: G
authors.lastname: Djordjevic
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tripp
authors.forename: Michael
authors.initials: M
authors.lastname: Lutteropp
authors.forename: Elham
authors.initials: E
authors.lastname: Sadighi-Akha
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Stranks
authors.forename: Julie
authors.initials: J
authors.lastname: Glanville
authors.forename: Samantha
authors.initials: S
authors.lastname: Knight
authors.forename: Sten-Eirik W
authors.initials: SE
authors.lastname: Jacobsen
authors.forename: Kamil R
authors.initials: KR
authors.lastname: Kranc
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D049109:Cell Proliferation; D004249:DNA Damage / Q000502:physiology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D009196:Myeloproliferative Disorders / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D000071193:Autophagy-Related Protein 7