Magnussen, Michael;
(2022)
Engineering Cardiogenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Cellular and tissue asymmetry are hallmarks of human development, regulation of which is responsible for transforming simple largely symmetrical structures of few cells into vastly complex tissues and organs that define organisms. Correct tissue morphogenesis is reliant on cellular orientation, spatiotemporal arrangement, and cell and tissue asymmetry during organogenesis. The embryonic myocardium of the primary heart tube is one such tissue that undergoes rapid and asymmetrical architectural transformation, initiated by polarising cues from the adjacent endocardium and the Extracellular Matrix (ECM). Applying three-dimensionality to stem cell-derived cellular models is the only way to generate physiologically relevant tissue for in vitro study with a view to study cardiogenesis in humans. Using human induced pluripotent stem cell (hiPSC)-derived cardiac mesoderm cells (CMP) seeded onto multiphoton-bioprinted cardiac jelly-mimicking scaffolds I have engineered the embryonic heart tube to explore how the myocardium becomes polarised in utero. Scaffolds are designed with geometries, composition and biophysical properties of embryonic heart ECM, upon which hiPSC-CMP on-scaffold differentiation to cardiomyocytes closely mimics heart tube formation; namely transmural matrix contact and exogenous simulations of endocardial-to-myocardial signalling in a highly biomimetic model. Motile CMPs seeded onto bioprinted scaffolds differentiate functionalised contractile tubular tissues, maintaining lumens that occlude with contractions and displaying organised sarcomeric alignment. Engineered Cardiac Tubes host spontaneous hyaluronan (HA) secretions reminiscent of cardiogenesis, and exhibit a morphogenic priming in the form of proliferation and trabecular fate bias in response to the endocardial signalling mitogen Neuregulin-1β (NRG1β). For future work it is anticipated that reverse engineering the human embryonic heart will emerge as a versatile method for uncovering human data in a field populated almost exclusively by animal studies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Engineering Cardiogenesis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10161422 |
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