Abstract
Cardiovascular disease is the leading cause of mortality worldwide, with the most significant contributor being ischemic heart disease following a myocardial infarction. Recent advancements towards a curative treatment demonstrate the plausibility of introducing therapeutic cells into an infarcted heart and manipulating their ion channel expression to prevent graft automaticity and promote beating in tune with the host environment. However, this has yet to become a reality for patients whose current treatment strategy is symptom management or transplant, with current studies citing the need for a more suitable test environment for potential therapeutic cells. This process naturally occurs within the developing embryonic heart, with cells from the secondary heart field being recruited into the existing beating heart tube, where they integrate into their host environment and beat in tune. This poses the question of whether an embryonic environment, specifically the chicken, due to its accessibility and established history of grafting experiments, would provide a cheap and mass-replicable test environment.Given the emerging importance of ion channels and pumps in allowing cells to beat in tune with their host environment, we used existing single-cell sequencing databases alongside in situ hybridisation within the chicken to establish the ion channel setup preceding the first heartbeat through the window where cells are recruited in from the SHF. The sites were then identified in which cells could be introduced into the early embryonic heart and recruited later from the SHF. Through a host of methods, we also demonstrated that the FHF and SHF are initially a continuum and demonstrated that the SHF is a lateral head mesoderm derivative. Subsequently, through in vivo and invitro graftings of the cardiogenic tissues of the embryo, it was demonstrated that the early cardiogenic mesoderm between Hamburger Hamilton stages five to eight provides the most cardiogenic environment within the embryo and that there is a distinct change in the commitment of the early and late SHF. Through molecular analysis, these differences were further explored through in vivo graft gene expression alongside bulk RNA sequencing of the early and late SHF, revealing a distinct shift in the intrinsic molecular properties of the SHF as the embryo develops.
| Date of Award | 2 Sept 2025 |
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| Original language | English |
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| Supervisor | Susanne Dietrich (Supervisor), Anthony Lewis (Supervisor) & Katerina Lalatsa (Supervisor) |