Early dynamic rate changes in myeloid-primed progenitors contribute to their expansion. (A) Schematic of HSPC population dynamics model that uses PDEs to capture a continuum of cell-states along hematopoietic differentiation described by the pseudotime analysis. refers to the cell-density at pseudotime value at time . (B) Top model fits obtained for 1000 optimization runs of each replicate (each with a different estimate of the experimental cell densities). Normalized root mean square deviation (Norm. RMSD) was calculated by dividing each optimized objective value by the average experimental IκB− cell-density for that replicate. (C) Difference in branching ratio (left) and lineage developmental-flux functions (right) between IκB− and WT given by parameters underlying model fits. Error bars and shaded regions denote range. The branching ratio describes how much the HSCs contribute to each primed progenitor lineage at the branch-point. The developmental-flux function is composed of the net proliferation and differentiation rates, and its difference between IκB− and WT can be increased if IκB− net proliferation is increased or differentiation is decreased, and vice versa. (D) Difference in IκB− and WT branching ratio (left) and average difference in IκB− and WT developmental-flux functions over the domain from the branch-point to pseudotime value 0.5 (right) for model fits with different values for the branch-point. Lines connect median values and error bars denote maximum/minimum values across 500 fits. (E) Predicted difference between IκB− and WT differentiation (left) and net proliferation (right) rates relative to magnitude of WT rates from minimizing difference between IκB− and WT rates while satisfying the steady-state constraint of differences in developmental-flux functions. Results from replicate 1 where difference in flux functions determined with greater certainty.
