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Title: Systems biology analysis of gene expression in cardiopoiesis
Author: Leja, Tomasz
ISNI:       0000 0004 9356 6336
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Myocardial infarction causes an irreversible loss of cardiac cells, frequently resulting in heart failure. Cardiac cell therapies using embryonic or adult stem cells offer promise to restore heart function. However, the convolution of molecular cues that guide cell differentiation and cardiogenesis hinders the use of appropriate regenerative strategies. The application of high-throughput, genome-wide and single-cell profiling methods provides quantitative insight into the regulatory mechanisms of tissue development. Systems biology methods are consequently required to decipher the spatial and temporal complexity of those regulatory circuits. Here, a quantitative systems approach is utilised to unravel the intricate network of genetic cues involved in cardiopoiesis, both from embryonic and adult stem cells. A new computational platform is presented for graph theoretical analysis of complex gene networks. The implemented methods for network reconstruction and dynamic graph partitioning are collectively tailored to uncover regulatory interactions from transcriptomic data. The addition of an integrated web-based interface meets the analytical challenges in systems biology, by complementing the execution workflow with an interactive visual network analysis. A systems analysis of genome-wide temporal expression profiles from differentiating embryonic stem cells is demonstrated. Graph theoretical principles were applied to obtain a Sox17-gene regulatory network, and to elucidate the endoderm-derived cardiokine signalling. Sox17 was shown to be essential in regulating Mesp1 induction, and a Sox17-Hhex-Cer1 circuit was further identified in mediating cardiac mesoderm specification. A bioinformatic framework is proposed to decouple the transcriptional heterogeneity among adult progenitor cells. A single-cell study of endogenous Lin−/Sca1+ cardiac precursor cells revealed heterogeneous expression of cardiogenic transcription factors, namely Gata4/6, Tbx2/20 and Hand2. The presence of Pdgfrα defined a discrete cellular fraction enriched with cardiogenic genes, representing an attractive target for heart regenerative therapies. Keywords: Regenerative medicine, cardiogenesis, embryonic stem cells, cardiac progenitor cells, systems biology, graph theoretical analysis.
Supervisor: Schneider, Michael ; Barahona, Mauricio Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral