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The paradigmatic tree model of hematopoiesis is increasingly recognized to be limited as it is based on heterogeneous populations and largely inferred from non-homeostatic cell fate assays. Here, we combine persistent labeling with time-series single-cell RNA-Seq to build the first real-time, quantitative model of in vivo tissue dynamics for any mammalian organ. We couple cascading single-cell expression patterns with dynamic changes in differentiation and growth speeds. The resulting explicit linkage between single cell molecular states and cellular behavior reveals widely varying self-renewal and differentiation properties across distinct lineages. Transplanted stem cells show strong acceleration of neutrophil differentiation, illustrating how the new model can quantify the impact of perturbations. Our reconstruction of dynamic behavior from snapshot measurements is akin to how a Kinetoscope allows sequential images to merge into a movie. We posit that this approach is broadly applicable to empower single cell genomics to reveal important tissue scale dynamics information.
Professor Bertie Göttgens is the Director of the Wellcome – MRC Cambridge Stem Cell Institute, a Fellow of the Academy of Medical Sciences, Member of the European Molecular Biology Organisation (EMBO), Wellcome Investigator and former President of the International Society for Experimental Haematology. Bertie’s post-doctoral research delivered the first molecular understanding of key regulatory processes that define blood stem cell identity. After starting his own group, he continued work to decipher the blood stem cell regulatory code and then exploited this knowledge to generate computer models that faithfully capture the behaviour of normal blood stem cells, and model dysregulation of stem cell function in leukaemia. Throughout the past 6 years, his group has performed internationally leading research in using new single cell profiling technologies. By expanding their scope beyond blood development, the group is now charting cellular diversification in mammalian embryos, all the way from pluripotent stem cells to the progenitors of all major organs.