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In this study, we have investigated the synergistic generation of erythroid cells in response to erythropoietin (EPO) and stem cell factor (SCF). We have used a quantitative approach to determine if the effects of EPO and SCF superpose in a supra\u2010additive fashion on the cell proliferation rate or on the death rate, suggesting a contribution from a joint cytokine effect (co\u2010signaling). Primary mouse bone marrow hematopoietic cells and the stem cell\u2010like FDCP\u2010mix cell line were used to investigate the effects of EPO and SCF (individually or in combination) on erythroid output. Carboxyfluorescein diacetate succinimidyl ester (CFSE)\u2010based cell\u2010division tracking and mathematical modeling were used to measure cell type\u2010specific proliferation and death rates. We observed a significant synergistic effect of EPO and SCF on the net generation of benzidine positive (erythroid) colony\u2010forming cells, CD71<jats:sup>++<\/jats:sup> (early erythroblasts) cells and TER\u2010119<jats:sup>+<\/jats:sup> (late erythroblasts and reticulocytes) cells in culture. When the observed increases in cell number were decomposed into proliferation and death rates, the cytokines were shown to act independently at different stages of erythroid development; SCF promoted the early proliferation of primitive cells, while EPO primarily promoted the survival of differentiating erythroid progenitor cells. Our analysis demonstrates that EPO and SCF have distinct and predominantly sequential effects on erythroid differentiation. This study emphasizes the necessity to separate proliferation rates from death rates to understand apparent cytokine synergies. Biotechnol. Bioeng. 2008;99: 1261\u20131272. \u00a9 2007 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/bit.21677","type":"journal-article","created":{"date-parts":[[2007,10,29]],"date-time":"2007-10-29T20:17:42Z","timestamp":1193689062000},"page":"1261-1272","source":"Crossref","is-referenced-by-count":17,"title":["Synergy between erythropoietin and stem cell factor during erythropoiesis can be quantitatively described without co\u2010signaling effects"],"prefix":"10.1002","volume":"99","author":[{"given":"WeiJia","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel N.","family":"Horner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Li Kelly","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter 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