title: Hierarchal Autophagic Divergence of Hematopoietic System.
abstract: Autophagy is integral to hematopoiesis and protects against leukemogenesis. However, the fundamentals of the required molecular machinery have yet to be fully explored. Using conditional mouse models to create strategic defects in the hematopoietic hierarchy, we have shown that recovery capacities in stem cells and somatic cells differ if autophagy is impaired or flawed. An in vivo Atg7 deletion in hematopoietic stem cells completely ablates the autophagic response, leading to irreversible and ultimately lethal hematopoiesis. However, while no adverse phenotype is manifested in vivo by Atg7-deficient myeloid cells, they maintain active autophagy that is sensitive to brefeldin A, an inhibitor targeting Golgi-derived membranes destined for autophagosome formation in alternative autophagy. Removing Rab9, a key regulatory protein, in alternative autophagy, disables autophagy altogether in Atg7-deficient macrophages. Functional analysis indicates that ATG7-dependent canonical autophagy is physiologically active in both hematopoietic stem cells and in terminally differentiated hematopoietic cells; however, only terminally differentiated cells such as macrophages are rescued by alternative autophagy if canonical autophagy is ineffective. Thus, it appears that hematopoietic stem cells rely solely on ATG7-dependent canonical autophagy, whereas terminally differentiated or somatic cells are capable of alternative autophagy in the event that ATG7-mediated autophagy is dysfunctional. These findings offer new insight into the transformational trajectory of hematopoietic stem cells, which in our view renders the autophagic machinery in stem cells more vulnerable to disruption.
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yuan
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhao
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Collaborative Innovation Center of Hematology, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China jrwang@suda.edu.cn.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D002454:Cell Differentiation / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; C544263:rab9 protein, mouse; D020691:rab GTP-Binding Proteins; D000071193:Autophagy-Related Protein 7
keywords: autophagy; hematopoiesis; hematopoietic stem cells; myeloid cell; somatic cells; stem cells