Journal of Mathematical Biology

, Volume 70, Issue 1–2, pp 71–97 | Cite as

The role of spatial organization of cells in erythropoiesis

  • N. Eymard
  • N. Bessonov
  • O. Gandrillon
  • M. J. Koury
  • V. Volpert
Article

Abstract

Erythropoiesis, the process of red blood cell production, occurs mainly in the bone marrow. The functional unit of mammalian erythropoiesis, the erythroblastic island, consists of a central macrophage surrounded by adherent erythroid progenitor cells (CFU-E/Pro-EBs) and their differentiating progeny, the erythroblasts. Central macrophages display on their surface or secrete various growth or inhibitory factors that influence the fate of the surrounding erythroid cells. CFU-E/Pro-EBs have three possible fates: (a) expansion of their numbers without differentiation, (b) differentiation into reticulocytes that are released into the blood, (c) death by apoptosis. CFU-E/Pro-EB fate is under the control of a complex molecular network, that is highly dependent upon environmental conditions in the erythroblastic island. In order to assess the functional role of space coupled with the complex network behavior in erythroblastic islands, we developed hybrid discrete-continuous models of erythropoiesis. A model was developed in which cells are considered as individual physical objects, intracellular regulatory networks are modeled with ordinary differential equations and extracellular concentrations by partial differential equations. We used the model to investigate the impact of an important difference between humans and mice in which mature late-stage erythroblasts produce the most Fas-ligand in humans, whereas early-stage erythroblasts produce the most Fas-ligand in mice. Although the global behaviors of the erythroblastic islands in both species were similar, differences were found, including a relatively slower response time to acute anemia in humans. Also, our modeling approach was very consistent with in vitro culture data, where the central macrophage in reconstituted erythroblastic islands has a strong impact on the dynamics of red blood cell production. The specific spatial organization of erythroblastic islands is key to the normal, stable functioning of mammalian erythropoiesis, both in vitro and in vivo. Our model of a simplified molecular network controlling cell decision provides a realistic functional unit of mammalian erythropoiesis that integrates multiple microenvironmental influences within the erythroblastic island with those of circulating regulators of erythropoiesis, such as EPO and glucocorticosteroids, that are produced at remote sites.

Keywords

Erythropoiesis Erythroblastic island Hybrid model Comparison with experiments 

Mathematics Subject Classification (2010)

92C37 68U20 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • N. Eymard
    • 1
  • N. Bessonov
    • 2
  • O. Gandrillon
    • 3
    • 4
  • M. J. Koury
    • 5
  • V. Volpert
    • 1
    • 4
    • 6
  1. 1.Institut Camille Jordan, UMR 5208 CNRSUniversity Lyon 1VilleurbanneFrance
  2. 2.Institute of Mechanical Engineering ProblemsSaint PetersburgRussia
  3. 3.Centre de Génétique et de Physiologie Moléculaire et Cellulaire, CNRS UMR 5534University Lyon 1Villeurbanne France
  4. 4.INRIA Team DraculaINRIA Antenne Lyon la DouaVilleurbanneFrance
  5. 5.Medicine, Veterans Affairs Tennessee Valley Healthcare System and Vanderbilt University Medical CenterNashvilleUSA
  6. 6.European Institute of Systems Biology and MedicineLyon France

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