Modeling Complex Neutrophil Dynamics in the Grey Collie

Observations on the Pathophysiology and Mechanisms for Cyclic Neutropenia

“…It seemed more likely that the oscillations of CN originate from the hematopoietic stem cell population as was originally proposed in earlier work by [51,52]. Then, [55] modified the general model of [54] by writing out explicitly the form of the control mechanism. In particular, they explicitly estimated the amplification rate of cells entering the recognizable neutrophil precursor pool (including apoptosis) as well as the form of the negative feedback loop mediated by endogenous G-CSF.…”

“…This would also explain the fact that in CN, other cell lineages oscillate with the same period as the neutrophils [34,55].…”

“…The aim of this work was to better understand the origin of cyclic neutropenia in the HSC compartment. In particular, they were interested in the mechanisms by which the oscillatory input suggested in [55] could account for the oscillations seen in cyclic neutropenia. They built a two dimensional delay differential equations (DDE) system in which they replace the previous oscillating input by a stem cell compartment regulated by a negative feedback loop.…”

“…Using bifurcation analysis, they showed that the origin of cyclic neutropenia is probably due an increased apoptosis rate in the recognizable and committed neutrophil precursors, leading to a destabilization of the hematopoietic stem cell compartment through a Hopf bifurcation. As a result, the HSCs start oscillating, which provides the kind of oscillatory input to the neutrophil compartment postulated by [55].…”

“…In [60] this model was applied to cyclic neutropenia. The goal was to test whether the hypothesis of [54] and [55] still holds in this new system. The authors used a simulated annealing approach to automated fitting of model simulations to clinical data for both human and gray collie serial neutrophil and platelet counts.…”