Haematopoiesis across Scales, Species and Time: a Foundational Approach to Study Stem Cell Biology and Disease (360G-Wellcome-309075_Z_24_Z)

The full complexity of biological systems can only be unravelled by working across scales. Here we propose to traverse molecular, cellular and organ scales, as well as working across species and time, to unveil the dynamic system properties defining native and perturbed haematopoiesis. We will build on our recent breakthrough where we combined persistent labelling of stem cells with time-series single-cell genomics to construct computer models of mouse haematopoiesis. Unlike conventional single cell genomics which relies on snapshot data to infer differentiation processes, our approach directly links molecular states with dynamic cellular behaviour at single-cell resolution. The specific objectives of this proposal include defining individual HSC behaviour types in unperturbed mouse in vivo and mouse and human in vitro haematopoiesis, developing computational flux models for precise clonal-level quantification of perturbations, decoding molecular programs governing cell population dynamics, establishing a pipeline to infer unmeasurable human data, and assessing how differentiation speed impacts the fidelity of cell production. Working across scales, time and species, our approach to reveal the dynamic system properties of native and perturbed haematopoiesis represents a real step change for haematopoiesis research, with broad applicability across organs and diseases, including processes that cannot be directly studied in humans.