Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.693973
Title: The instructive role of cardiac transcription factors in triggering transition of cardiac progenitor cells into the cardiac muscle fate
Author: Belian, Elisa
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Abstract:
The mechanisms that maintain cardiac progenitor cells (CPCs) in a state of arrested development and prevent their spontaneous differentiation are unknown. This study is aimed at investigating potential mechanisms responsible for the striking paradox of cardiac transcription factors' expression without activation of their direct cardiomyocyte-specific target genes. Expression analysis of a range of CPC-derived clonal lines, characterised by Sca-1 expression and the SP phenotype, showed that all analysed cardiac transcription factors are expressed as nuclear-localised proteins. Hence, the absence of nucleartargeted protein expression is not the reason for lack of transcriptional activity. Interestingly, none of the clones expressed the complete triad of Gata4, Mef2c and Tbx5 (GMT) that reportedly reprograms cardiac fibroblasts into cardiomyocytes. However, forced expression of the respective missing factor(s) in CPCs induced few of the tested cardiac markers, indicating that lack of co-expression of these three factors is not the reason for the cells' failure to undergo differentiation. As a third potential barrier, the cardiac muscle-specific isoform of the transcriptional coactivator Myocardin (Myocd) was investigated and found to be absent in all analysed clones. Conversely, rescue with exogenous Myocd plus Tbx5 was found to robustly activate nearly all tested RNA and protein markers diagnostic of the cardiomyocyte lineage. In summary, this study demonstrates that rescuing the lack of Myocd in combination with other cardiac transcription factors is sufficient to induce expression of a range of cardiac genes and proteins characteristic of differentiated cardiomyocytes, suggesting that the lack or insufficient level of these factors is a limiting mechanism maintaining CPCs in the undifferentiated state. Evidence presented in this study indicates that Myocd is not only crucial in regulating cardiac muscle formation during embryogenesis but pivotal to induce the transition of adult cardiac progenitor cells toward the cardiac muscle fate.
Supervisor: Schneider, Michael Sponsor: National Heart and Lung Institute
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.693973  DOI: Not available
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