Inge, Oliver CK; (2023) Combinatorial signalling and cell state transitions during human gastrulation. Doctoral thesis (Ph.D), UCL (University College London).

Text OliverInge_PhD_Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 January 2026. Download (59MB)

Abstract

Cell fate decisions during development are dictated by the interplay between combinatorial signals which direct cells through specific cell state transitions in gene expression space. How signalling inputs drive these transitions is a complex and challenging area of study. To explore this, we combined single-cell experimental approaches with computational analyses and utilised human embryonic stem cell (hESC) as a tractable model to study how signalling inputs (BMP4 and Activin) are integrated to mediate lineage choice during early human development. BMP4 and Activin signalling have been implicated in the specification of multiple cell types, but how exactly cells respond to these cues in dose and time is not well understood. By challenging hESCs with dynamic and combinatorial inputs of BMP4 and Activin we quantitatively dissected the concentration and duration thresholds required for entry into different cellular states. We find that different cell types use different integration strategies to respond to BMP4 and Activin, with some cell types responding to these cues in a synergistic manner while other cell types exhibit antagonistic control. Furthermore, we identified defined commitment points in time during the specification of different developmental lineages. Using mathematical modelling we predicted underlying cell state transitions that could explain our experimental observations. Using scRNAseq and a combination of trajectory inference methods, we predicted a novel developmental transition suggesting that the endoderm lineage may originate from a subset of mesoderm cells during gastrulation. Finally, using in silico screening to predict drivers of fate decisions followed by genetic perturbations in hESCs, we identified candidate regulators of endoderm and mesoderm specification. The work presented in this thesis builds on our understanding of the interplay between signalling inputs and cell state transitions and provides new insights into the regulation of a critical window of human development.

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