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Single Cell Meta-Analysis of Endothelial to Mesenchymal Transition (EndMT) in Glucose Metabolism of the Digestive Diseases.

ABSTRACT: Background: Endothelial-to-mesenchymal transition (EndMT) is poorly understood in digestive diseases, and the function of metabolism in EndMT is uncertain. Objective: The goal of this study is to elucidate the role of EndMT in digestive diseases and to describe its metabolic state. Method: The GEO database was used to extract single-cell data in order to discover EndMT subpopulations in digestive organs such as premalignant lesions and cancer of the stomach, intestine, and pancreas. Results: By single-cell RNA sequencing in digestive diseases, we generated a single-cell atlas from tissues of patients spanning a cascade of premalignant lesions and cancer. We next established a single-cell network elucidating the cellular and molecular characteristics of endothelial cells (ECs) across many lesions and identified key genes linked with EndMT in premalignant lesions and cancer lesions. The EndMT activation of a wide variety of metabolic signaling pathways was discovered in ECs, and further study of premalignant lesions and cancer tissue indicated that glucose metabolism increased in premalignant lesions and reached a maximum in cancer tissue. Finally, it was shown that INSR and LDHA might be used as prognostic markers for developing premalignant lesions to cancer involving glucose metabolism in digestive diseases. Conclusion: For the first time, we discovered EndMT's role in digestive diseases and described its metabolism, underscoring its crucial role in glucose metabolism in the disease. We found several targets via gene screening that are beneficial for predicting premalignant lesions that progress to cancer.

SUBMITTER: Zhou Q

PROVIDER: S-EPMC9216733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveImaging endothelial cell behaviour under physiological conditions, particularly those associated with chronic fibrotic pathologies, is an incredibly challenging endeavour. While short-term assessments (hours) can be achieved with techniques such as intravital microscopy, vascular changes often occur over days and weeks which is unfeasible with current imaging techniques. These challenges are exemplified within the liver where liver sinusoidal endothelial cells (LSECs) are known to undergo dramatic changes termed endothelial-to-mesenchymal transition (EndMT) during fibrotic liver disease. Despite the established presence of EndMT in liver disease, the inaccessibility of viable liver tissue, and simplicity of 2D culture techniques has meant, the role of EndMT during disease progression remains largely undetermined. This study describes the development of novel fluorescent EndMT reporters to identify, track, and characterise the migratory behaviour of EndMT cells. We show that liver-on-a-chip (LOAC) platforms provide a flexible, optically accessible, and physiologically relevant microenvironment to study the vascular dynamics of EndMT during liver disease.MethodsIdentification, creation, and application of an EndMT-specific fluorescent reporter construct (EndMT-Rep). Transduction of EC using lentiviral packaged CNN1-eGFP construct as an inducible EndMT-Rep (CNN1-Rep) to 2D, 3D, and 4D imaging techniques for fixed and live cell imaging. Combined application of live and fixed imaging technologies to measure EndMT using CNN1-Rep on LOAC platform under physiological conditions. Demonstration of the high-resolution single-cell EndMT tracking by live cell time-lapse microscopy and with post-acquisition processing to perform a comparative study of CNN1-Rep and healthy LSECs within a NASH-like LOAC microenvironment.ConclusionsLOAC enables prolonged, multi-platform imaging of endothelial cell sub-populations such as those undergoing EndMT in 2D and 3D cultures. Our study highlights the application of EndMT reporters, such as CNN1-Rep, to provide high-resolution imaging of EndMT behaviour for the first time under physiologically relevant liver microenvironment. Overall, these methods reveal the adaptability and impact of live-cell imaging on uncovering vascular behaviours, such as EndMT, that are unattainable in viable tissue or conventional 2D in vitro experiments.Supplementary informationThe online version contains supplementary material available at 10.1007/s44164-022-00034-9.

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Single Cell Meta-Analysis of Endothelial to Mesenchymal Transition (EndMT) in Glucose Metabolism of the Digestive Diseases.

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