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

• Published in: Scientific reports 2021-01, Vol.11 (1), p.1666-1666, Article 1666
• Main Authors: Nomura, Naho, Ito, Chiaki, Ooshio, Takako, Tadokoro, Yuko, Kohno, Susumu, Ueno, Masaya, Kobayashi, Masahiko, Kasahara, Atsuko, Takase, Yusuke, Kurayoshi, Kenta, Si, Sha, Takahashi, Chiaki, Komatsu, Masaaki, Yanagawa, Toru, Hirao, Atsushi
• Format: Article
• Language: English
• Subjects: 631/136/232; 631/532/1542; 631/80/39; Animals; Animals, Newborn; Autophagy; Autophagy - physiology; Autophagy-Related Protein 5 - genetics; Autophagy-Related Protein 5 - metabolism; Bone marrow; Cell self-renewal; Developmental stages; Disease Models, Animal; Female; Harsh environments; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Homeostasis; Humanities and Social Sciences; Male; Mice; Mice, Knockout; Mitochondria; multidisciplinary; Neonates; Oxidative stress; Oxidative Stress - physiology; Phagocytosis; Progenitor cells; Science; Science (multidisciplinary); Sequestosome-1 Protein - metabolism; Stem cell transplantation; Stem cells; Tamoxifen
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-81076-z

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.