Stem cell identity and lineage: insights from network theory and dynamical systems

What is a (adult) stem cell? This question is still, after decades of debate, not settled yet. In recent years, high-throughput single-cell RNA-sequencing (scRNA-seq) thought to settle this issue by identifying all cell states and differentiation trajectories, yet the thereby discovered high degree of tissue cell heterogeneity even complicated our picture about stem cells and cell lineages. In this talk, I will show how a graph-theoretical view, combined with novel findings from dynamical and stochastic systems, allows to define cell types in a way that greatly simplifies and brings order to the complex web of cell trajectories as yielded by scRNA-seq. It turns out that with this definition many discoveries from stem cell and developmental biology follow "for free", such as an adult stem cell being at the apex of a lineage hierarchy, and the universal features of asymmetric vs. symmetric stem cell divisions that emerge in the form of very few experimentally observed shapes of clone size distributions. Furthermore, we show that in the presence of homeostatic control (crowding feedback), the identity of a stem cell is fully determined by its controlling environment, and theefore cannot be a cell-intrinsic property.