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OCT4-mediated inflammation induces cell reprogramming at the origin of cardiac valve development and calcification

ABSTRACT: Description Cell reprogramming is at the origin of valve calcification. Cell plasticity plays a key role in embryos by maintaining the differentiation potential of progenitors. Whether postnatal somatic cells revert to an embryonic-like naïve state regaining plasticity and redifferentiate into a cell type leading to a disease remains intriguing. Using genetic lineage tracing and single-cell RNA sequencing, we reveal that Oct4 is induced by nuclear factor κB (NFκB) at embyronic day 9.5 in a subset of mouse endocardial cells originating from the anterior heart forming field at the onset of endocardial-to-mesenchymal transition. These cells acquired a chondro-osteogenic fate. OCT4 in adult valvular aortic cells leads to calcification of mouse and human valves. These calcifying cells originate from the Oct4 embryonic lineage. Genetic deletion of Pou5f1 (Pit-Oct-Unc, OCT4) in the endocardial cell lineage prevents aortic stenosis and calcification of ApoE−/− mouse valve. We established previously unidentified self-cell reprogramming NFκB- and OCT4-mediated inflammatory pathway triggering a dose-dependent mechanism of valve calcification.

SUBMITTER: Farrar E

PROVIDER: S-EPMC8570594 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCardiac valve calcification (CVC) is associated with adverse cardiovascular events. We studied the risk factors of CVC in maintenance hemodialysis (MHD) patients and the value of serum β2-microglobulin (β2-MG) levels in predicting the incidence of CVC. β2-MG is a middle molecular weight toxin. In recent years, researchers found that elevated blood β2-MG was associated with coronary, thoracic, and abdominal aortic calcifications with significant correlations. β2-MG has been emerging as a strong biomarker for cardiovascular mortality in uremic patients but its role in CVC is not well studied. This study looked specifically at CVC occurrence in relation to β2-MG for MHD patients.MethodsPatients who underwent MHD for more than 3 months in the First People's Hospital of Nantong City from November 2012 to November 2019 with complete available data were included in the study. The patients were divided into the CVC group and the non-CVC group. The general information and clinical laboratory indicators of the patients were collected in a retrospective manner. We analyzed the risk factors for developing CVC in MHD patients using binary logistic regression method. Receiver operating characteristic (ROC) curves were used to calculate the cut-off value of β2-MG for predicting CVC. The decision tree (DT) method was used to classify and explore the probability of CVC in patients with MHD.ResultsThe β2-MG in the CVC group was significantly higher than that in the non-CVC group (t=6.750, P<0.001). Multivariate binary logistic regression analysis showed that gender, age, serum β2-MG, and hemodialysis (HD) adequacy (Kt/V urea) were independent risk factors for CVC in MHD patients. ROC analysis showed that a β2-MG value of 25 µg/L was the best cut-off point for predicting CVC in MHD patients. According to binary logistic regression analysis, the β2-MG ≥25 µg/L group was 3.39 times more likely to develop CVC than the β2-MG <25 µg/L group [odds ratio (OR), 3.39; 95% confidence interval (CI), 1.63-7.06; P=0.001]. The DT model determined that serum β2-MG ≥25 µg/L and age >69 years were important determinants for predicting CVC in MHD patients.ConclusionsSerum β2-MG in MHD patients has a positive correlation with the severity and occurrence of CVC.

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OCT4-mediated inflammation induces cell reprogramming at the origin of cardiac valve development and calcification

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