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

Abstract

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 Atg5f/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 Atg5f/f;Rosa26-Cre-ERT2 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 Atg5f/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.

Activation of the p62‐Keap1‐Nrf2 pathway improves pulmonary arterial hypertension in MCT‐induced rats by inhibiting autophagy

“…Inhibition of p62 elevated the level of LC3II/I and ATG5 (Figure 4F). Since p62 is degraded by autophagy, 34 we used CQ to inhibit autophagy, leading to the accumulation of p62. Consistent with p62 overexpression, autophagy inhibitor treatment increased the levels of Nrf2 in PASMCs, while decreasing the levels of Keap1, LC3II/I, and ATG5 (Figure 4F).…”

Single-cell sequencing combined with Bulk RNA-Seq to explore the molecular mechanism of cell communication in atrial fibrillation

“…Our ndings revealed that tissue stem cells exhibited the highest degree of cellular activity and engaged in more frequent interactions with other cell types. Tissue stem cells represent a class of stem cells characterized by self-renewal capacity and the ability to differentiate into various cell lineages to meet tissue demands (34,35). Tissue stem cells are distributed throughout diverse tissues and organs, encompassing bone marrow, skin, muscle, nervous tissue, liver, lung, gastrointestinal tract, and more, each exhibiting distinct characteristics and functions (36, 37).…”

Autophagy and Its Lineage-Specific Roles in the Hematopoietic System

“…Conversely, in malignant hematopoiesis, autophagy leads to excessive cell survival, low glucose consumption, and cell proliferation, which in turn induces malignant invasion by promoting the differentiation of leukemic cells. Besides, impaired autophagy during hematopoiesis may result in damaged organelles, protein aggregation, and excessive ROS and mitochondrial mass accumulation, leading to DNA damage and genomic mutation in the hematopoietic system ( Figure 2 ) [ 91 , 92 ]. Consequently, autophagy deficiency may cause HSC impairment, aberrant myeloproliferation, and severe anemia, while malignant blood cells, such as AML cells, exhibit a higher proliferation rate, apoptosis, and drug (chemotherapy and radiotherapy) resistance [ 93 ].…”

“…However, such a decrease in HSPCs occurs not as a result of impaired differentiation but rather due to reduced cell cycle progression and increased apoptosis. Another study has suggested that the loss of Atg5 increases the mitochondrial oxidative stress in neonatal HSPCs [ 92 ]. Even though p62 accumulates in immature bone marrow cells of Atg5 -deficient mice, p62 deletion does not restore defective HSC functions, which indicates that p62 is not necessary for Atg5 -dependent hematopoietic regulation [ 92 ].…”

“…Another study has suggested that the loss of Atg5 increases the mitochondrial oxidative stress in neonatal HSPCs [ 92 ]. Even though p62 accumulates in immature bone marrow cells of Atg5 -deficient mice, p62 deletion does not restore defective HSC functions, which indicates that p62 is not necessary for Atg5 -dependent hematopoietic regulation [ 92 ]. Autophagy inhibition by mTOR signaling modulates myeloid progenitor-derived macrophage differentiation [ 174 ].…”