Abstract
BackgroundHematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. This complexity stimulated various models with different scopes and applications. A combination of complementary models promises to provide their mutual confirmation and to explain a broader range of scenarios. Here we propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agent-based model (ABM) of hematopoietic stem cell (HSC) organization. The first describes the dynamics of bone marrow cell stages and circulating cells under various perturbations such as G-CSF treatment or chemotherapy. In contrast to the ODE model describing cell numbers, our ABM focuses on the organization of individual cells in the stem population.ResultsWe combined the two models by replacing the HSC compartment of the ODE model by a difference equation formulation of the ABM. In this hybrid model, regulatory mechanisms and parameters of the original models were kept unchanged except for a few specific improvements: (i) Effect of chemotherapy was restricted to proliferating HSC and (ii) HSC regulation in the ODE model was replaced by the intrinsic regulation of the ABM. Model simulations of bleeding, chronic irradiation and stem cell transplantation revealed that the dynamics of hybrid and ODE model differ markedly in scenarios with stem cell damage. Despite these differences in response to stem cell damage, both models explain clinical data of leukocyte dynamics under four chemotherapy regimens.ConclusionsABM and ODE model proved to be compatible and were combined without altering the structure of both models. The new hybrid model introduces model improvements by considering the proliferative state of stem cells and enabling a cell cycle-dependent effect of chemotherapy. We demonstrated that it is able to explain and predict granulopoietic dynamics for a large variety of scenarios such as irradiation, bone marrow transplantation, chemotherapy and growth factor applications. Therefore, it promises to serve as a valuable tool for studies in a broader range of clinical applications, in particular where stem cell activation and proliferation are involved.
Highlights
Hematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines
Qualitative model behavior Depletion of the granulocyte compartment First, we considered an initial depletion of granulocytes setting CGRA 1⁄4 10−15CnGoRrA and initializing all other compartments with their equilibrium number Cnor
Simulations of bone marrow transplantation Because the differences between the models lie in the two stem cell compartment (SCC), we addressed them directly by simulations mimicking bone marrow transplantation with granulocyte colony stimulating factor (G-CSF) support after myeloablative conditioning
Summary
Hematopoiesis is a complex process involving different cell types and feedback mechanisms mediated by cytokines. We propose a combination of an ordinary differential equation (ODE) model of human granulopoiesis and an agentbased model (ABM) of hematopoietic stem cell (HSC) organization. The process of hematological homeostasis is characterized by a relative stability of the (small) stem cell pool and a massive amplification along. This concept represents a core assumption of most mathematical models for hematopoiesis that have been formulated complementary to experiments. A few models do consider structured cell populations and introduce an additional cellular feature [14] All these models share the concept of unidirectional cell flux towards differentiated states
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