Mathematical Analysis of Cytokine-Induced Differentiation of Granulocyte-Monocyte Progenitor Cells

Front Immunol. 2018 Sep 18;9:2048. doi: 10.3389/fimmu.2018.02048. eCollection 2018.

Abstract

Granulocyte-monocyte progenitor (GMP) cells play a vital role in the immune system by maturing into a variety of white blood cells, including neutrophils and macrophages, depending on exposure to cytokines such as various types of colony stimulating factors (CSF). Granulocyte-CSF (G-CSF) induces granulopoiesis and macrophage-CSF (M-CSF) induces monopoiesis, while granulocyte/macrophage-CSF (GM-CSF) favors monocytic and granulocytic differentiation at low and high concentrations, respectively. Although these differentiation pathways are well documented, the mechanisms behind the diverse behavioral responses of GMP cells to CSFs are not well understood. In this paper, we propose a mechanism of interacting CSF-receptors and transcription factors that control GMP differentiation, convert the mechanism into a set of differential equations, and explore the properties of this mathematical model using dynamical systems theory. Our model reproduces numerous experimental observations of GMP cell differentiation in response to varying dosages of G-CSF, M-CSF, and GM-CSF. In particular, we are able to reproduce the concentration-dependent behavior of GM-CSF induced differentiation, and propose a mechanism driving this behavior. In addition, we explore the differentiation of a fourth phenotype, monocytic myeloid-derived suppressor cells (M-MDSC), showing how they might fit into the classical pathways of GMP differentiation and how progenitor cells can be primed for M-MDSC differentiation. Finally, we use the model to make novel predictions that can be explored by future experimental studies.

Keywords: cytokines; differentiation; granulopoiesis; mathematical modeling; monocytic myeloid-derived suppressor cells; monopoiesis; temporal dynamics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Dose-Response Relationship, Immunologic
  • Granulocyte Colony-Stimulating Factor / metabolism*
  • Granulocyte-Macrophage Progenitor Cells / physiology*
  • Humans
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Macrophages / physiology*
  • Models, Theoretical*
  • Myeloid-Derived Suppressor Cells / physiology*
  • Neutrophils / physiology*
  • Systems Analysis

Substances

  • Granulocyte Colony-Stimulating Factor
  • Macrophage Colony-Stimulating Factor