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Single-cell sequencing study of splenocytes and YFP+ B cells to investigate differences between Eif3e cg1cre knockout mice and control mice

ABSTRACT: To gain insights into the cellular mechanisms underlying the lymphoproliferative disorder developed in cKO mice, we performed single cell RNA-seq (scRNA-seq) analysis of YFP+ and total splenocytes from cKO and control mice at the age of 2 months, when lymphocyte activation and proliferation had not yet become obvious.Through our study, we found that Eif3e-deficient B cells are impaired in their development into GCB and PC, becoming blocked at the pre-GCB stage. Additionally, all B cells exhibited high expression of MHC-II. Among CD4+ T cells, the TFH cell population was significantly expanded in cKO mice and showed high expression of IL4. Based on the early-stage phenotype of this mouse model, we hypothesize that Eif3e-deficient B cells promote IL4 expression in CD4+ T cells, which in turn stimulates upregulation of MHC-II on all B cells. The increased MHC-II further enhances CD4+ T cell activation, forming a positive feedback loop.

ORGANISM(S): Mus musculus

PROVIDER: GSE320248 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:BACKGROUND: As an iron-dependent form of regulated cell death caused by lipid peroxidation, ferroptosis has been implicated in ischemic injury, but the underlying mechanisms in acute myocardial infarction (AMI) remain poorly defined. Acetaldehyde dehydrogenase 2 (ALDH2) catalyzes detoxification of lipid aldehydes derived from lipid peroxidation and acetaldehydes from alcohol consumption. The Glu504Lys polymorphism of ALDH2 (rs671, ALDH2*2), affecting around 40% of East Asians, is associated with increased risk of MI. This study aims to investigate the role of ALDH2*2 and ferroptosis in AMI. METHODS: A Chinese cohort of 177 acute heart failure patients with ALDH2 wild type and ALDH2*2 was enrolled. The MI mouse model of left anterior descending (LAD) coronary artery ligation was conducted on wild-type, ALDH2*2, and mice with cardiomyocyte-specific knockdown of eukaryotic translation initiation factor 3 subunit E (eIF3E) by adeno-associated virus. The lipid peroxidation products were measured by mass spectrometry-based lipidomics and metabolomics in human plasma, mouse serum samples, mouse heart tissues, and primary cardiac myocytes. RESULTS: Human ALDH2*2 carriers exhibit more severe heart failure post-AMI with features of ferroptosis in plasma through lipidomic analysis, characterized by increased bioactive lipids and decreased antioxidants, such as Coenzyme Q10 (CoQ10) and tetrahydrobiopterin (BH4). Similar features were observed in MI mouse models of ALDH2*2, whereas ferroptosis inhibition by Fer-1 significantly improved heart functions and reversed ferroptosis markers. Importantly, ALDH2*2 significantly decreased ALDH2 protein levels, while ferroptosis-related markers, including Transferrin receptor (TFRC) and Acyl-CoA synthetase long-chain family member 4 (ACSL4), were notably upregulated in the infarct heart tissues. Mechanistically, ALDH2 physically interacts with the eIF3 complex via the eIF3E factor, which prevents the eIF3E-eIF4G1-mRNA assembly. The ALDH2*2 variant causes ALDH2 deficiency, disrupting its interaction with the eIF3 complex through releasing the bound eIF3E to assemble an eIF3E-eIF4G1-mRNA ternary complex, thereby driving selective translation of mRNAs (e.g., TFRC, ACSL4, and UAP1) containing the GAGGACR (R: represents A/G) motif to promote ferroptosis. Consistently, cardiomyocyte-specific eIF3E knockdown restored ALDH2*2 cardiac function by attenuating ferroptosis in MI. CONCLUSIONS: ALDH2*2 aggravates acute heart failure post-MI through promoting the selective translation of mRNAs containing the GAGGACR motif, thereby driving cardiomyocytes ferroptosis. Targeting ferroptosis represents a potential therapeutic option for mitigating MI injury, especially for ALDH2*2 carriers. Key Words: ALDH2, myocardial infarction, eIF3E, ferroptosis, protein translation

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Single-cell sequencing study of splenocytes and YFP+ B cells to investigate differences between Eif3e cg1cre knockout mice and control mice

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