Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner.

Autor: Nomura N; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; Department of Hematology, Chugoku Central Hospital, 148-13 Miyuki-cho, Kamiiwanari, Fukuyama, Hiroshima, 720-0001, Japan., Ito C; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Ooshio T; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku Sapporo, Hokkaido, 060-0815, Japan., Tadokoro Y; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Kohno S; Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Ueno M; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Kobayashi M; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Kasahara A; Institute for Frontier Science Initiative, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Takase Y; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; Department of Pediatrics, Nagasaki Harbor Medical Center, 6-39 Shinchi-machi, Nagasaki City, Nagasaki, 850-8555, Japan., Kurayoshi K; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Si S; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan.; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Takahashi C; Division of Oncology and Molecular Biology, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan., Komatsu M; Department of Physiology, Juntendo University Graduate School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan., Yanagawa T; Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan., Hirao A; Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan. ahirao@staff.kanazawa-u.ac.jp.; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa, 920-1192, Japan. ahirao@staff.kanazawa-u.ac.jp.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2021 Jan 18; Vol. 11 (1), pp. 1666. Date of Electronic Publication: 2021 Jan 18.
DOI: 10.1038/s41598-021-81076-z
Abstrakt: Autophagy is a cellular degradation system contributing to homeostasis of tissue stem cells including haematopoietic stem cells (HSCs). It plays pleiotropic roles in HSC characteristics throughout life, but its stage-specific roles in HSC self-renewal are unclear. To investigate the effects of Atg5 deletion on stage-specific HSC functions, we compared the repopulating capacity of HSCs in Atg5 f/f ;Vavi-cre mice from postnatal day (P) 0-7 weeks of age. Interestingly, Atg5 deficiency led to no remarkable abnormality in the HSC self-renewal capacity at P0, but significant defects at P7, followed by severe defects. Induction of Atg5 deletion at P5 by tamoxifen administration to Atg5 f/f ;Rosa26-Cre-ER T2 mice resulted in normal haematopoiesis, including the HSC population, until around 1 year, suggesting that Atg5 in the early neonatal period was critical for haematopoiesis in adults. Mitochondrial oxidative stress was increased by Atg5 loss in neonatal HSC/progenitor cells. Although p62 had accumulated in immature bone marrow cells of Atg5 f/f ;Vavi-cre mice, p62 deletion did not restore defective HSC functions, indicating that Atg5-dependent haematopoietic regulation in the developmental period was independent of p62. This study proposes a critical role of autophagy in HSC protection against harsh environments in the early neonatal stage, which is essential for healthy long-term haematopoiesis.
Databáze: MEDLINE
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