The role of spatial organization of cells in erythropoiesis

International audienceErythropoiesis, the process of red blood cell production, occurs mainly inthe bone marrow. The functional unit of mammalian erythropoiesis, the erythroblasticisland, consists of a central macrophage surrounded by adherent erythroid progenitorcells (CFU-E/Pro-EBs) and their differentiating progeny, the erythroblasts. Centralmacrophages display on their surface or secrete various growth or inhibitory factorsthat influence the fate of the surrounding erythroid cells. CFU-E/Pro-EBs havethree 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 ishighly dependent upon environmental conditions in the erythroblastic island. In orderto assess the functional role of space coupled with the complex network behavior inerythroblastic islands, we developed hybrid discrete-continuous models of erythropoiesis.A model was developed in which cells are considered as individual physicalobjects, intracellular regulatory networks are modeled with ordinary differential equationsand extracellular concentrations by partial differential equations. We used themodel to investigate the impact of an important difference between humans and mice inwhichmature late-stage erythroblasts produce themost Fas-ligand in humans,whereasearly-stage erythroblasts produce the most Fas-ligand in mice. Although the globalbehaviors of the erythroblastic islands in both species were similar, differences werefound, including a relatively slower response time to acute anemia in humans. Also,our modeling approachwas very consistent with in vitro culture data, where the centralmacrophage in reconstituted erythroblastic islands has a strong impact on the dynamicsof red blood cell production. The specific spatial organization of erythroblasticislands is key to the normal, stable functioning of mammalian erythropoiesis, both invitro and in vivo. Our model of a simplified molecular network controlling cell decisionprovides a realistic functional unit of mammalian erythropoiesis that integratesmultiple microenvironmental influences within the erythroblastic island with those ofcirculating regulators of erythropoiesis, such as EPO and glucocorticosteroids, thatare produced at remote sites