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Abstract Excessive protein synthesis upon enhanced cell proliferation frequently results in an increase of unfolded or misfolded proteins. During hematopoietic regeneration, to replenish the hematopoietic system, hematopoietic stem cells (HSCs) are activated and undergo a rapid proliferation. But how the activated HSCs respond to the proliferation pressure is still ambiguous; The proper control of the functional reservoir in the activated HSCs remains poorly understood. Here, we show a significant upregulation of EVA1A protein associated with the increase of ER stress during hematopoietic regeneration. Deletion of Eva1a significantly enhances the regeneration capacity of HSCs by inhibiting the ER stress-induced apoptosis. Mechanistically, the expression of EVA1A protein was upregulated by CHOP, and thereby promoted the ER-mitochondria interlinking via MCL1, which resulted in mitochondria-mediated apoptosis. These findings reveal a pathway for ER stress responses of HSCs by the EVA1A mediated apoptosis, which play an important role in HSCs regeneration.

BackgroundNAD+, nicotinamide adenine dinucleotide, is mostly described to associate with the aging process. We aimed to investigate the association between human whole blood NAD+ contents and aging in a relative large-scale community-based population and further to address the gender impact on this association.MethodsWe recruited 1,518 participants aged over 18 years old and free of cardiovascular and any type of cancer from the Jidong community from 2019 to 2020. Whole blood NAD+ level was measured by cycling assay and LC-mass spectroscopy assay. The chronological age and clinical data were collected using standard questionnaires. The participants were divided into five groups according to their chronological age. General liner regression model was performed to analyze the association between NAD+ contents and aging. In addition, we also conducted subgroup analysis by gender.ResultsThe mean age of included 1,518 participants was 43.0 years, and 52.6% of them were men. The average levels of whole blood NAD+ of total participants was 33.0 ± 5.5 μmol/L. The whole blood NAD+ contents in men were significantly higher than that in women (34.5 vs. 31.3 μmol/L). There was significant difference in the meat diet among NAD+ quartile groups (p = 0.01). We observed a decline trend of NAD+ contents with aging before 50 years in total participants with significant level in 40–49 years old group (β coefficients with 95% confidence interval (95% CI): −1.12 (−2.18, −0.06)), while this trend disappeared after the 50 years. In addition, this association was significantly altered by gender (p for interaction = 0.003). In men, as compared with ≤29 years group, adjusted β coefficient decreased with aging but was only significant in the ≥60 year group (β,−2.16; 95% CI, −4.16 to −0.15). In females, the level of whole blood NAD+ did not significantly differ among five age groups and without the trend as males.ConclusionsAssociation of whole blood NAD+ contents with aging significantly differed in males and females. The loss of blood NAD+ with aging only was observed in males, especially in the male middle-aged population. It is crucial to consider the gender difference in further NAD+ related studies in the future.

Summary: Hematopoietic stem cells (HSCs) regenerate blood cells upon hematopoietic injuries. During homeostasis, HSCs are maintained in a low reactive oxygen species (ROS) state to prevent exhaustion. However, the role of nitric oxide (NO) in controlling HSC regeneration is still unclear. Here, we find increased NO during HSC regeneration with an accumulation of protein aggregation. S-nitrosoglutathione reductase (GSNOR)-deleted HSCs exhibit a reduced reconstitution capacity and loss of self-renewal after chemotherapeutic injury, which is resolved by inhibition of NO synthesis. Deletion of GSNOR enhances protein S-nitrosylation, resulting in an accumulation of protein aggregation and activation of unfolded protein response (UPR). Treatment of taurocholic acid (TCA), a chemical chaperone, rescues the regeneration defect of Gsnor−/− HSCs after 5-fluorouracil (5-FU) treatment. Deletion of C/EBP homologous protein (Chop) restores the reconstitution capacity of Gsnor−/− HSCs. These findings establish a link between S-nitrosylation and protein aggregation in HSC in the context of blood regeneration.