Erythropoiesis: from molecular pathways to system properties.

Erythropoiesis is regulated through a long-range negative feedback loop, whereby tissue hypoxia stimulates erythropoietin (Epo) secretion, which promotes an increase in erythropoietic rate. However, this long-range feedback loop, by itself, cannot account for the observed system properties of erythropoiesis, namely, a wide dynamic range, stability in the face of random perturbations, and a rapid stress response. Here, we show that three Epo-regulated erythroblast survival pathways each give rise to distinct system properties. The induction of Bcl-xL by signal transducer and activator of transcription 5 (Stat5) is responsive to the rate of change in Epo levels, rather than to its absolute level, and is therefore maximally but transiently activated in acute stress. By contrast, Epo-mediated suppression of the pro-survival Fas and Bim pathways is proportional to the levels of stress/Epo and persists throughout chronic stress. Together, these elements operate in a manner reminiscent of a "proportional-integral-derivative (PID)" feedback controller frequently found in engineering applications. A short-range negative autoregulatory loop within the early erythroblast compartment, operated by Fas/FasL, filters out random noise and controls a reserve pool of early erythroblasts that is poised to accelerate the response to acute stress. Both these properties have previously been identified as inherent to negative regulatory motifs. Finally, we show that signal transduction by Stat5 combines binary and graded modalities, thereby increasing signaling fidelity over the wide dynamic range of Epo found in health and disease.