Pleiotropic Cytokine Effects Drive Synchronized Proliferation and Emergent Chaos in Hematopoiesis 2309108

Abstract Introduction Hematopoiesis is an inherently dynamic process with variations shaping differential immune responsiveness. Our previous work demonstrated that homeostatic hematopoiesis operates as a chaotic system with large fluctuations in cell frequencies, enabling robust adaptability. However, the underlying biological mechanism remains unclear. We hypothesize that pleiotropic cytokine signaling drives variable cell kinetics that generate chaotic hematopoietic dynamics. Methods We performed pulse-labeling experiments using 5-iodo-2’- deoxyuridine (IdU) in 39 healthy C57BL/6 mice, followed by mass cytometry analysis of bone marrow, blood and spleen. We also treated isolated bone marrow cells with 30 individual cytokines for 24h and 48h, and quantified changes in proliferative subset (%Ki-67+) across leukocyte subsets by spectral flow cytometry. These measurements were integrated into a mathematical model simulating cytokine effect on hematopoietic dynamics. Results Proliferation rates of all cell types between left and right femurs within individual mice showed high similarity (slope = 0.98, R² = 0.97), confirming observed fluctuations reflect biological variation, rather than experimental artifact. All leukocyte types exhibited substantial proliferation variability (coefficient of variation ≈ 1). Strikingly, we observed globally synchronized cell proliferation. Individual cytokines simultaneously upregulated the %Ki-67+ subsets across multiple cell types, revealing pleiotropic proliferative effects. Even cell populations with strongly negative correlations in numbers (e.g., neutrophils and B cells) showed positively correlated proliferation rates. Mathematical modeling confirmed such cytokine-driven synchronized proliferation is sufficient to generate observed chaotic fluctuations in hematopoiesis. Conclusion Our findings reveal that pleiotropic cytokine signaling drives synchronized proliferation across cell types, which paradoxically generates chaotic population dynamics through nonlinear interactions. Funding Source This work was supported by the intramural research program of the NCI. Topic Categories Hematopoiesis and Immune System Development (HEM)