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Supervisors names
Kenzo Ivanovitch
De Coppi, Paolo
Background:
In this project, you will address how embryonic cells develop into distinct cardiac cell types and form a heart. Addressing this question has important implications for our understanding of congenital heart diseases -affecting ~1% of newborns- and the design of regenerative methods targeting specific populations of heart cells.
Our heart comprises four chambers, two ventricles and two atria, driving blood from the body to the lungs and through the rest of the body. We recently demonstrated ventricular and atrial cardiac progenitors have distinct spatial and temporal origins in the primitive streak (1). See Sheng et al. 2021 for a definition of the primitive streak (2). We further demonstrated that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the atria. Anterior regions of the primitive streak -expressing low levels of the T-box transcription factor T- contribute to the ventricles. In contrast, the posterior primitive streak -expressing high levels of T- contributes to the atria. These observations suggest cardiac progenitors are already prespecified in the streak, and this may prefigure their allocation to distinct anatomical structures of the heart.
Aims:
You will test if the specification of ventricular or atrial cardiomyocyte (transcriptionally and functionally distinct) depends on initial molecular conditions set in the primitive streak. You will first generate distinct populations of primitive streak-like cells expressing low or high levels of T using mouse embryonic stem cell differentiation protocols we recently established in the laboratory. You will then test their ventricular and atrial differentiation potential. In the low T condition, you will overexpress T using an inducible overexpressing cell line (TTET-ON line) and analyse the putative changes in differentiation potential induced by T overexpression. You may extend the analysis to other genes differentially expressed in the Tlow versus Thigh primitive streak.
You would then be expected to have intellectual freedom to pursue your findings. Depending on your interest, you could further address the molecular mechanisms mediating such commitment of the mesodermal cells (e.g. by assessing for chromatin accessibility and epigenetic modifications at single-cell resolution).
Alternatively, you could exploit a 3D mouse stem cell-based model resembling natural embryos (embryoids) developed by Prof. Zernicka-Goetz's team and Colleagues to address mechanisms of lineage specification and morphogenesis further (3-4). Using embryoids, you could test if overexpression of transcription factors in the primitive streak (e.g., T or others) can:
a) modulate the proportions of ventricular vs. atrial cardiomyocytes and
b) result in atrial progenitors being generated precociously in the embryoids, consequently disrupting heart tube morphogenesis.
Embryonic development is robust to perturbations and molecular mechanisms, ensuring coordinated cell fate specification and morphogenesis in time and space may exist. You will collaborate with Prof. Magdalena Zernicka-Goetz’s team (University of Cambridge) to implement the embryoids.
Timeline:
Aim 1: months 3-18.
Aim 2: months 19-36, including submission of publications.
You will have the opportunity to teach.
References:
1.Ivanovitch et al. PLoS Biology 2021 doi.org/10.1371/journal.pbio.3001200
2.Sheng et al. Science 2021 10.1126/science.abg1727
3.Amadei et al. Nature 2021 Doi: 10.1038/s41586-022-05246-3.
4.Tarazi et al. Cell 2021 doi.org/10.1016/j.cell.2022.07.028.
Contact
Kenzo Ivanovitch k.ivanovitch@ucl.ac.uk