Phenotypic variability, not noise, accounts for most of the cell-to-cell heterogeneity in IFN-γ and oncostatin M signaling responses.

Topolewski, Piotr; Zakrzewska, Karolina E.; Walczak, Jarosław; Nienałtowski, Karol; Müller-Newen, Gerhard; Singh, Abhyudai; Komorowski, Michał

Cellular signaling responses show substantial cell-to-cell heterogeneity, which is often ascribed to the inherent randomness of biochemical reactions, termed molecular noise, wherein high noise implies low signaling fidelity. Alternatively, heterogeneity could arise from differences in molecular content between cells, termed molecular phenotypic variability, which does not necessarily imply imprecise signaling. The contribution of these two processes to signaling heterogeneity is unclear. Here, we fused fibroblasts to produce binuclear syncytia to distinguish noise from phenotypic variability in the analysis of cytokine signaling. We reasoned that the responses of the two nuclei within one syncytium could approximate the signaling outcomes of two cells with the same molecular content, thereby disclosing noise contribution, whereas comparison of different syncytia should reveal contribution of phenotypic variability. We found that ~90% of the variance in the primary response (which was the abundance of phosphorylated, nuclear STAT) to stimulation with the cytokines interferon-γ and oncostatin M resulted from differences in the molecular content of individual cells. Thus, our data reveal that cytokine signaling in the system used here operates in a reproducible, high-fidelity manner. Not-so-noisy cytokines: The same signaling stimulus can induce variable outcomes among the same cell type in a group of cells or tissue, prompting the notion that signaling is influenced by random biochemical reactions, or molecular "noise." Topolewski et al. generated multinuclear fibroblasts to explore whether heterogeneity in the cellular response to cytokines was the result of stochastic noise in the system or of cell-to-cell variability in molecular content. The results suggest that, at least in this experimental system, molecular phenotypic variability makes the greater contribution.

ONCOSTATIN M; PHENOTYPIC plasticity; HETEROGENEITY; NOISE; CELL communication

Science Signaling, 2022, Vol 15, Issue 721, p1

1945-0877

Academic Journal

10.1126/scisignal.abd9303