Dataset Information

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

ABSTRACT:

Background

Hematopoiesis 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.

Results

We 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.

Conclusions

ABM 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.

SUBMITTER: Krinner A

PROVIDER: S-EPMC4228322 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

Krinner Axel A Roeder Ingo I Loeffler Markus M Scholz Markus M

BMC systems biology 20131101

<h4>Background</h4>Hematopoiesis 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 c ...[more]

PMID: 24180697

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Project description:BackgroundReproducing cell processes using an in silico system is an essential tool for understanding the underlying mechanisms and emergent properties of this extraordinary complex biological machine. However, computational models are seldom applied in the field of intracellular trafficking. In a cell, numerous molecular interactions occur on the surface or in the interior of membrane-bound compartments that continually change position and undergo dynamic processes of fusion and fission. At present, the available simulation tools are not suitable to develop models that incorporate the dynamic evolution of the cell organelles.ResultsWe developed a modeling platform combining Repast (Agent-Based Modeling, ABM) and COPASI (Differential Equations, ODE) that can be used to reproduce complex networks of molecular interactions. These interactions occur in dynamic cell organelles that change position and composition over the course of time. These two modeling strategies are fundamentally different and comprise of complementary capabilities. The ODEs can easily model the networks of molecular interactions, signaling cascades, and complex metabolic reactions. On the other hand, ABM software is especially suited to simulate the movement, interaction, fusion, and fission of dynamic organelles. We used the combined ABM-ODE platform to simulate the transport of soluble and membrane-associated cargoes that move along an endocytic route composed of early, sorting, recycling and late endosomes. We showed that complex processes that strongly depend on transport can be modeled. As an example, the hydrolysis of a GM2-like glycolipid was programmed by adding a trans-Golgi network compartment, lysosomal enzyme trafficking, endosomal acidification, and cholesterol processing to the simulation model.ConclusionsThe model captures the highly dynamic nature of cell compartments that fuse and divide, creating different conditions for each organelle. We expect that this modeling strategy will be useful to understand the logic underlying the organization and function of the endomembrane system.ReviewersThis article was reviewed by Drs. Rafael Fernández-Chacón, James Faeder, and Thomas Simmen.

Dataset Information

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

Background

Results

Conclusions

Publications

Merging concepts - coupling an agent-based model of hematopoietic stem cells with an ODE model of granulopoiesis.

Similar Datasets

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