The hormone Epo is the key regulator of definitive erythropoiesis that is a unidirectional proliferation and maturation process ensuring renewal of red blood cells. Erythropoiesis represents one of the best understood differentiation processes in the human body and thus serves as an ideal test case for data-based mathematical modeling to provide insights into mechanisms regulating cell fate decisions and to quantitatively predict targeted perturbations.
As a single, non-redundant factor Epo critically regulates cell fate decisions of committed erythroid progenitor cells at the colony forming unit erythroid (CFU-E) stage and inhibits apoptosis, induces proliferation and facilitates terminal differentiation. In response to binding to its cognate receptor, the EpoR, Epo activates three major signaling cascades: it inhibits apoptosis primarily through the JAK2-STAT5 pathway, while proliferation is jointly controlled through the PI3K/AKT and the MEK/ERK cascade. Identifiable mathematical models based on coupled ordinary differential equations for information processing through the EpoR (Becker et al., Science 2010) and for the three major signaling pathways have been established by members of the SBEpo consortium (Schilling et al., Mol Syst Biol 2009; Bachmann et al., in revision; She et al, in preparation). The aim of SBEpo is to integrate these dynamic pathway models and link them to gene regulatory networks and cell fate decisions in erythroid progenitor cells, thus coupling events that are regulated by multiple feedbacks and occur at very different time-scales. The final goal is to define a model-based rational strategy for optimal expansion of human erythroid progenitor cells ex vivo.
The integrative multi-level mathematical model of erythropoiesis will be used to predict strategies for increasing the proliferative capacity of erythroid progenitor cells. Members of the SBEpo consortium have demonstrated that Epo determines the window for proliferation of erythroid progenitor cells. Co-stimulation with other ligands shortens this window resulting in reduced proliferation and accelerated differentiation. Time-resolved genome wide expression profiling performed by SBEpo consortium members revealed the induction of autocrine factors such that may amplify the Epo response and thereby extent the proliferative window.
This ample knowledge available for cell fate decisions in murine erythroid progenitor cells will be used to employ optimal experimental design to select a minimal set of most informative measurements to adapt the integrative multi-level mathematical model to the human system. The establishment of transferability will permit to rapidly test in silico innovative treatment regimes that promise to amplify expansion of erythroid progenitor cells. Applying these insights for the ex vivo expansion of erythroid progenitor to erythrocytes will provide an important example demonstrating the potential of systems biology to guide manufacturing blood cells from hematopoietic stem cells or progenitor cells. This is in high demand due to the shortage in blood transfusions and safety concerns and can contribute significantly to an improved quality of life for patients suffering from anemia.