Novel cytokine interactions identified during perturbed hematopoiesis

Hematopoiesis is a dynamic process involving the up- and down-regulation of genes, as well as feed-back loops that stimulate or suppress circulating cytokine concentrations. More complete pictures of the gene regulatory networks that control the production of the blood system have emerged with the advent of single-cell sequencing techniques and refinements to the capabilities of immunoassays. However, information about the regulatory networks of cytokines is still lacking. A novel mathematical technique (convergent cross-mapping, or CCM) allows for the extraction of causal relationships from data, which is of crucial importance for understanding these networks. To reconstruct the cytokine networks within the hematopoietic system we measured the concentrations of 62 cytokines, platelets, and thrombopoietin from an individual with cyclic thrombocytopenia (regular oscillations in the megakaryocytes and platelets) over 84 days. Using CCM, we identified 61 previously unreported cytokine relationships. Our approach is the first broad-scale investigation into causal relationships between cytokines in the blood and suggests a new paradigm for understanding how dynamic regulation occurs during hematopoiesis.