Lineages of embryonic stem cells show non-Markovian state transitions

Pluripotent embryonic stem cells (ESCs) constitute the cell types of the adult vertebrate through a series of developmental state transitions. These states can be defined by expression levels of marker genes, such as Nanog and Sox2. In culture, ESCs reversibly transition between states. However, whether ESCs retain memory of their previous states or transition in a memoryless (Markovian) process remains relatively unknown. Here, we show some highly dynamic lineages of ESCs do not exhibit the Markovian property: their previous states and kin relations influence future choices. Unexpectedly, the distribution of lineages across their composition between states is constant over time, contrasting with the predictions of a Markov model. Additionally, highly dynamic ESC lineages show skewed cell fate distributions after retinoic acid differentiation. Together, these data suggest ESC lineage is an important variable governing future cell states, with implications for stem cell function and development.