Clonal abundance patterns in hematopoiesis: Mathematical modeling and parameter estimation

Abstract

Hematopoiesis has been studied via stem cell labeling using barcodes, viral integration sites (VISs), or in situ methods. Subsequent proliferation and differentiation preserve the tag identity, thus defining a clone of mature cells across multiple cell type or lineages. By tracking the population of clones, measured within samples taken at discrete time points, we infer physiological parameters associated with a hybrid stochastic-deterministic mathematical model of hematopoiesis. We analyze clone population data from Koelle et al. (Koelle et al., 2017) and compare the states of clones (mean and variance of their abundances) and the state-space density of clones with the corresponding quantities predicted from our model. Comparing our model to the tagged granulocyte populations, we find parameters (stem cell carrying capacity, stem cell differentiation rates, and the proliferative potential of progenitor cells, and sample sizes) that provide reasonable fits in three out of four animals. Even though some observed features cannot be quantitatively reproduced by our model, our analyses provides insight into how model parameters influence the underlying mechanisms in hematopoiesis. We discuss additional mechanisms not incorporated in our model.

Dynamically adjusted cell fate decisions and resilience to mutant invasion during steady state hematopoiesis revealed by an experimentally parameterized mathematical model

“…The biology of hematopoietic stem cells has been subject to much investigation, and an increasingly detailed picture has been emerging, which includes the hierarchical structure of the hematopoietic system [1], the mechanisms underlying the associated cell fate decisions [2][3][4][5][6], and the kinetics of these processes [7][8][9][10][11][12][13][14]. At the same time, it has become clear that the dynamics within the hematopoietic system are characterized by complex interactions among cells, involving homeostatic control mechanisms [15,16].…”