Reconstruction of hierarchical differentiation processes based on the temporal clonal readout in distinct hematopoietic lineages: part II

The differentiation process of hematopoietic stem cells towards mature blood cells is generally depicted as a hierarchical decision process. Although the principle structure of such a branching tree is widely accepted, increasing evidence about complementary and alternative differentiation pathways question the concept of a fixed hierarchy. Clonal tracing studies allow quantifying to which extend and in which lineages marked hematopoietic stem cells contribute to the production of mature blood cells. However, the reconstruction of a hierarchical decision tree based on the temporal clonal readout in distinct blood lineages is computationally challenging. We use a computational approach to investigate how and under which conditions the original branching tree can be faithfully reconstructed. To this end we use a mathematically model to generate prototypic differentiation processes through a hierarchical decision tree and produce clonal readouts in different lineages over time that closely resample the data available from corresponding experimental and clinical studies. Applying a numerical optimization procedure, we estimate the extend of necessary data (e.g. with respect to measured compartments and timing of subsequent measures) that is needed for the reconstruction process in order to obtain identifiable results. We complement the model-based investigations with available data from clonal tracing studies and test our suggested approaches for reconstruction of hierarchical decision trees in real-world settings. Our analysis is a necessary and complementary prerequisite to support experimental approaches for the reconstruction of hierarchical, hematopoietic decision trees. In particular, the modeling approach allows, based on the available data, to estimate whether certain decision processes can be uniquely reconstructed or not.