The PN t -Methodology: a top-down network modelling approach to estimate dose- and time-dependent cell responses to complex multifactorial environments

Abstract Current methodologies to estimate cell responses usually focus on bottom-up intracellular network modeling, accompanied by limitations regarding the network topology and regarding the consideration of transient changes in cell responses due to chronic, dose-dependent stimulus exposure. Here we present a novel high-level top-down network modelling approach to simulate dose- and time-dependent cell responses within heterogeneous multifactorial, multicellular environments. Through the representation of cell activities as time-dependent parallel networks (PNt), the PNt-Methodology provides relative, interrelated cell responses for heterogeneous stimulus environments. The methodology is based on a systematic use of experimental findings, both data- and knowledge-based. Applied to intervertebral disc multicellular systems, the PNt-Methodology allows for the first time to obtain qualitatively validated cell responses for daily human moving activities and exposure to microgravity. The PNt-Methodology is not tissue specific per-se and is designed to be easily scalable. Eventually, it provides a one-of-a-kind network modeling approach to approximate complex multicellular systems.