Population robustness arising from cellular heterogeneity

Abstract

Heterogeneity between individual cells is a common feature of dynamic cellular processes, including signaling, transcription, and cell fate; yet the overall tissue level physiological phenotype needs to be carefully controlled to avoid fluctuations. Here we show that in the NF-κB signaling system, the precise timing of a dual-delayed negative feedback motif [involving stochastic transcription of inhibitor κB (IκB)-α and -ε] is optimized to induce heterogeneous timing of NF-κB oscillations between individual cells. We suggest that this dual-delayed negative feedback motif enables NF-κB signaling to generate robust single cell oscillations by reducing sensitivity to key parameter perturbations. Simultaneously, enhanced cell heterogeneity may represent a mechanism that controls the overall coordination and stability of cell population responses by decreasing temporal fluctuations of paracrine signaling. It has often been thought that dynamic biological systems may have evolved to maximize robustness through cell-to-cell coordination and homogeneity. Our analyses suggest in contrast, that this cellular variation might be advantageous and subject to evolutionary selection. Alternative types of therapy could perhaps be designed to modulate this cellular heterogeneity.network topology | NF-κB | biological oscillations | feedback regulation | paracrine signaling

Physiological levels of TNFα stimulation induce stochastic dynamics of NF-κB responses in single living cells

“…This suggests that further development of models for cellular communication and propagation of inflammatory signals between cells should be a priority to allow a better understanding of the tissue-level switch between amplification and resolution of inflammation. Recent data (Paszek et al, 2010) has suggested that cell-to-cell heterogeneity is an intrinsic feature of the NF-B system. Therefore, the variability in response to low-dose stimulation might also be a fundamental property of the NF-B inflammatory response.…”

Transcription factor heterogeneity in pluripotent stem cells: a stochastic advantage

“…A model for pulsatile stimulation has been described for the signalling response to NF-κB, whereby a population of cells shows a more efficient response in downstream transcriptional activation to repeated pulses of TNFα stimulation as opposed to a continuous stimulus (Ashall et al, 2009). A broader conclusion from these observations is that the cellular heterogeneity that arises from pulsatile transcriptional responses confers robustness to a cell population (Paszek et al, 2010). In other words, generating enhanced cell heterogeneity at the single-cell level can control the stability of a population of cells by decreasing fluctuations over time at the population level.…”

“…In other words, generating enhanced cell heterogeneity at the single-cell level can control the stability of a population of cells by decreasing fluctuations over time at the population level. This might confer an advantage by both preserving the identity of the population and simultaneously enabling the population to respond to signalling stimuli (Paszek et al, 2010). In this scenario, fluctuating gene expression may enable a faster response to signalling.…”

Sources of Cell-to-cell Variability in Canonical Nuclear Factor-κB (NF-κB) Signaling Pathway Inferred from Single Cell Dynamic Images

“…In response to tonic TNF␣ stimulation, an initial synchronous pulse of NF-B translocation is followed either by nuclear persistence (monophasic activation) or in a minority of cells by dampened oscillatory profiles (22,24). Individual cells producing asynchronous oscillatory responses produce population robustness, a phenomenon that is predicted to reduce tissue sensitivity to paracrine stimuli (26).…”