How the Heart Grows: From Multi-scale Data to a Multi-scale Model

The heart is the first organ to form and the first to function during early development. Embryological heart development consists of a series of events believed to be highly conserved in vertebrates. Cardiac precursor cells form a cardiac crescent at the embryonic midline. Fusion of the cardiac crescent results in the linear heart tube formation. The heart tube then undergoes a bending, elongation and twisting prior to further bending and helical torsion to form a looped heart. The looping phase is then followed by septation and valve formation giving rise to a four chambered heart in avians and mammals. The looping phase plays a central role in heart development. Successful looping is essential for proper alignment of the future cardiac chambers and tracts. Since aberrant looping results in various congenital heart diseases, cardiac looping has been studied for several decades by various disciplines. Many groups have studied the biology, genetics, and mechanical processes during heart looping. These studies have been carried out at different levels of subcellular, cell, tissue, and organ. However, looping is a very complex process and, despite a great deal of experimental data and research, the underlying mechanisms controlling the looping phase are unclear. In this thesis, a novel workflow is developed to investigate C-looping (the first phase of the entire looping process) using a multi-scale and multi-disciplinary approach. First, an experimental pipeline was developed to obtain data at different biological scales from cell to organism in a single embryo. Utilising the pipeline on embryos at different time-points resulted in a time-course dataset. Secondly, a three-dimensional shape model of developing hearts was generated using the experimental data, able to capture the spatial and temporal dynamics of C-looping at the tissue level. Thirdly, a state-of-the-art convolutional neural network approach was utilised to segment individual myocardial cells within the hearts. The individual segmented cells were mapped onto the geometric model of heart to generate a spatio-temporal cellular dataset. In the cellular dataset, the locations of all myocardial cells within each heart were identified and different cellular features were quantified. Finally, the generated tissue and cellular datasets were used for a spatio-temporal analysis of growth during C-looping at the tissue and cellular levels, and with respect to each other. The experimental pipeline used in the chicken and rat embryo models resulted in time-course, multi-scale datasets. The chicken embryo dataset was then utilized in the study for analysis and modelling. Finite element modelling, anatomical landmarking and temporal staging generated a dynamic shape model of the C-looping heart which provided the basis to link the cellular, tissue, and organ levels. At the cellular level the developed workflow, which consisted of various parts including qualification of cellular features and mapping cells with their quantified features onto the finite element mesh, generated a spatio-temporal dataset of cellular features. A cellular analysis of the dataset provided further quantitative information of cellular features both spatially and temporally during C-looping. Results from kinematic and statistical analyses revealed link between the volume and directional changes of tissue deformation and cellular features. Results showed a good agreement with previous work, but also further contributed to the field by providing more data. This thesis successfully presented a quantitative framework for a spatio-temporal analysis of C-looping, providing insights into differential growth during this phase. The workflow also provides a sound basis for further investigation into new research questions regarding C-looping. The conclusions from the spatio-temporal analysis may serve as the foundation for future experimental and modelling investigations.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Bioengineering

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2020

Author dc:creator

• Ebrahimi, Nazanin

Advisors dc:contributor.advisor

• Hunter, PJ
• Bradley, CP
• Kubke, MF

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/50142

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/50142