The Role Of Spatial Organization Of Cells In Erythropoiesis

The functional unit of definitive mammalian erythropoiesis, the erythroblastic island, consists of a central macrophage surrounded by adherent erythroid progenitor cells at the colony-forming unit/proerythroblast (CFU-E/Pro-EB) stages of differentiation 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 through the erythroblast stages into reticulocytes that are released into the blood, c) death by apoptosis. CFU-E/Pro-EB fate is under the control of a complex intracellular molecular network that is highly dependent upon environmental conditions in the erythroblastic island. Direct examination of erythroblastic island function in vivo has been limited in mice and unfeasible in humans. In order to assess the functional role of spatial organization coupled with the complex network behavior in erythroblastic islands, we developed hybrid discrete-continuous models of erythropoiesis. A mathematical model was developed in which the cells of the erythroblastic island are considered as individual physical objects, intracellular regulatory networks are modeled with ordinary differential equations, and extracellular concentrations of cytokines or hormones are modeled by partial differential equations. The concentrations of the cytokines Fas-ligand and bone morphogenetic protein-4, which are produced locally in the erythroblastic island, and the hormones erythropoietin and glucocorticosteroid hormone, which are produced at remote locations in the body, are included in the model. We used the model in simulations that investigated the impact of an important difference between humans and mice in which mature late-stage erythroblasts produce the most Fas-ligand in humans, and 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 recovery time of hematocrits and erythrocyte numbers to their baselines following the development of acute anemia in humans as compared to mice. These simulation results with the model were consistent with the more rapid recovery to baseline in mice that were bled to about one-half of their normal hematocrit compared to two patients who had acute blood loss to about one-half of their respective baseline hematocrits and recovered without erythrocyte transfusions. Our modeling approach was also very consistent with the previously reported results of in vitro cultures, where the central macrophages in reconstituted erythroblastic islands of mice had a strong impact on the dynamics of erythroid cell proliferation. The spatial organization of cells in erythroblastic islands is important for the normal, stable functioning of mammalian erythropoiesis, both in vitro and in vivo. Our model of a simplified molecular network controlling erythroid progenitor cell decision and fate provides a realistic functional unit of mammalian erythropoiesis that integrates factors within the microenvironment of the erythroblastic island with those of circulating regulators of erythropoiesis. Our model highlights the need for proper inclusion of the spatial relationships of erythropoietic cells and allowing decisions to be made at the level of individual erythroid cells in the modeling process.