title: Autophagy regulates the cell cycle of murine HSPCs in a nutrient-dependent manner.
abstract: Autophagy is implicated in hematopoiesis, but its role in the regulation of the hematopoietic stem and progenitor cell (HSPC) cycle remains obscure. Here, we show that autophagy is essential to maintain and regulate the cell cycle of HSPCs in a nutrient-dependent manner. The loss of autophagy via conditional deletion of its essential gene atg7 ablated the cell cycle of HSPCs. Under physiologic or nutrient-rich conditions, the in vivo activation of autophagy promoted the cell cycle entry of hematopoietic stem cells and upregulated cyclin D3 expression in HSPCs. In contrast, under poor nutrient conditions, the ex vivo inhibition of early, but not late, autophagy signaling events enhanced the G1/S transition of HSPCs. Cyclin D3 was downregulated in HSPCs in response to nutrient stress. A knockdown of cyclin D3 blocked the G1/S transition in HSPCs. Surprisingly, the ex vivo inhibition of starvation-induced early, but not late, autophagy signaling inhibited the ubiquitin-mediated degradation of cyclin D3 in HSPCs. Furthermore, a conditional autophagy defect also had this effect, leading to an elevated cyclin D3 level in these cells. This suggested a dependency of the proteasomal degradation of cyclin D3 on early, but not late, events in autophagy signaling under nutrient stress in HSPCs. Our results thus indicate a dual role of autophagy in the nutrient-dependent modulation of the cell cycle entry of hematopoietic stem cells and G1/S transition of HSPCs via the regulation of cyclin D3 to maintain a proper cell cycle in HSPCs and normal hematopoiesis during adult life.
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Aihong
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Jinyang
authors.initials: J
authors.lastname: Cai
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Na
authors.initials: N
authors.lastname: Yuan
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Shengbing
authors.initials: S
authors.lastname: Liu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Song
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China.
authors.forename: Shaoyan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China. Electronic address: spzhang@suda.edu.cn.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Hematology Center of Cyrus Tang Medical Institute, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Jiangsu Key Laboratory for Stem Cell Research, Affiliated Children's Hospital, Soochow University School of Medicine, Suzhou 215123, China. Electronic address: jrwang@suda.edu.cn.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D002453:Cell Cycle; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D005502:Food; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D008954:Models, Biological; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D056743:Cyclin D3