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Title: Molecular and cellular investigation of the endothelial-mesenchymal transition
Author: Ummarino, Dario
ISNI:       0000 0004 6349 3287
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2016
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Recent biomedical literature has proposed that the Endothelial-Mesenchymal Transition (EndMT) is a critical cellular process involved in the pathophysiology of a number of diseases, including cardiovascular conditions such as atherosclerosis and cardiac fibrosis. Classified as a subtype of Epithelial-Mesenchymal Transition (EMT) due to similarities in molecular events, EndMT is characterized by endothelial cells (ECs) turning into a different cell lineage through suppression of endothelial-specific genes and activation of mesenchymal-specific ones. Members of the Transforming Growth Factor β (TGFβ) superfamily have been shown to play a major role in the initiation of this process. HDAC3α, an alternative splicing isoform of the mouse gene HDAC3, has been previously found to be involved in the EndMT. Through the overexpression of HDAC3α in human ECs and a pressure-overload mouse model, the present research project aimed at characterizing the molecular mechanisms underlying the function of HDAC3α in EndMT and its role in cardiac fibrosis. Results indicate that HDAC3α induces an EndMT phenotype through the upstream activation of TGFβ signalling, a mechanism that is potentially mediated by increased secretion of proteases. Furthermore, HDAC3α expression is increased in fibrotic hearts but its direct role in EndMT in vivo needs further investigation. Subsequently, experiments aiming at modelling the EndMT in vitro in human ECs revealed that EndMT-like responses (morphological changes, altered gene/protein expression) were induced by inflammatory cytokines, with little evidence of the typical endothelial markers-DOWN/mesenchymal markers-UP molecular pattern triggered by TGFβ ligands. Further cellular and molecular data led to interpret the phenotypic changes of ECs in vitro as inflammatory-induced responses such as vascular leakage and angiogenichealing, rather than a differentiation into a distinct cell type. Taken together, these results challenge the EndMT concept in adult tissues.
Supervisor: Zeng, Lingfang Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available