Biology subjects

Noailly, J.

Publications and source records attributed to Noailly, J..

4 recordsLinked to original sources

bioRxiv2024

Nucleus Pulposus Cell Network Modelling in the Intervertebral Disc

Intervertebral disc degeneration (IDD) arises from an intricate imbalance between the anabolic and catabolic processes governing the extracellular matrix (ECM) within the disc. Biochemical processes are complex, redundant and feedback-looped, thus improved integration of knowledge is needed. To address this, a literature-based regulatory network model (RNM) for nucleus pulposus cells (NPC) is proposed, representing the normal state of the intervertebral disc (IVD) cells, in which proteins are represented by nodes that interact with each other through activation and/or inhibition edges. This model includes 32 different proteins and 150 edges by incorporating critical biochemical interactions in IVD regulation, tested in vivo or in vitro in human and animal NPC, alongside non-tissue-specific protein-protein interactions. We used the network to calculate the dynamic regulation of each node through a semi-quantitative method. The basal steady state successfully represented the activity of a normal NPC, and the model was assessed through the published literature, by replicating two independent experimental studies in human normal NPC. Pro-catabolic or pro-anabolic shifts of the network activated by nodal perturbations could be predicted. Sensitivity analysis underscored the significant influence of transforming growth factor beta (TGF-{beta}) and interleukin-1 receptor antagonist (IL-1Ra) on the regulation of structural proteins and degrading enzymes within the system. Given the ongoing challenge of elucidating the mechanisms that drive ECM degradation in IDD, this unique IVD RNM holds promise as a tool for exploring and predicting IDD progression, shedding light on IVD phenotypes and guiding experimental research efforts.

systems biology↗

bioRxiv2024

Parallel networks to predict TIMP and protease cell activity of Nucleus Pulposus cells exposed and not exposed to pro-inflammatory cytokines

BackgroundIntervertebral disc (IVD) degeneration is characterized by a disruption of the balance between anabolic and catabolic cellular processes. Within the Nucleus Pulposus (NP), this involves increased levels of the pro-inflammatory cytokines Interleukin 1beta (IL1B) and Tumor Necrosis Factor (TNF) and an upregulation of the protease families MMP and ADAMTS. Primary inhibitors of those proteases are the tissue inhibitors of matrix metalloproteinases (TIMP). This work aims at contributing to a better understanding of the dynamics among proteases, TIMP and proinflammatory cytokines within the complex, multifactorial environment of the NP. MethodsThe Parallel Network (PN)-Methodology was used to estimate relative mRNA expressions of TIMP1-3, MMP3 and ADAMTS4 for five simulated human activities; walking, sitting, jogging, hiking with 20 kg extra weight, and exposure to high vibration. Simulations were executed for nutrient conditions in non- and early-degenerated IVD approximations. To estimate the impact of cytokines, the PN-Methodology inferred relative protein levels for IL1B and TNF, re-integrated as secondary stimuli into the network. ResultsTIMP1 and TIMP2 expression were found to be overall lower than TIMP3 exp. In absence of pro-inflammatory cytokines, MMP3 and/or ADAMTS4 expression were strongly downregulated in all conditions but vibration and hiking with extra weight. Pro-inflammatory cytokine exposure resulted in an impaired inhibition of MMP3, rather than of ADAMTS4, progressively rising with increasing nutrient deprivation. TNF mRNA was less expressed than IL1B. However, at the protein level, TNF was mainly responsible for the catabolic shift in the simulated pro-inflammatory environment. Overall, results agreed with previous experimental findings. ConclusionsThe PN-Methodology successfully allowed the exploration of the relative dynamics of TIMP and protease regulations in different mechanical, nutritional, and inflammatory environments, in the NP. It shall stand for a comprehensive tool to integrate in vitro model results in IVD research and approximate NP cell activities in complex multifactorial environments.

systems biology↗

bioRxiv2022

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

BackgroundNetwork models are convenient to represent in a mechanistic way the complexity of cell biological activity. Dynamic simulations of such networks might require approximations of equation parameters through reverse engineering, numerous and costly experimental research, and/or have limited capacity to explore cell responses to chronic, dose-dependent stimulus exposure. Here we present a mechanistic methodology allowing the simulation of interrelated cell responses of multicellular systems to multifactorial stimuli with dose-and time dependent network links. Methodsa mathematical framework to approach systems biology research questions is presented, the Parallel Networks (PN)-Methodology. It consists of a novel concept, where multicellular systems are described as many relatively small feed-forward networks acting in parallel. Each parallel network is calculated through a specifically designed ordinary differential equation (ODE). Through a unique approach to feed the ODE with interrelated parameters, a system of decoupled, analytically resolvable ODE was obtained. ResultsApplied to intervertebral disc multicellular systems, virtual environments of multifactorial stimuli and multiple cell responses simulating daily moving activities, and to microgravity could successfully be created. ConclusionsThe PN-Methodology stands for a one-of-a-kind mathematical methodology to approximate dynamics of complex multicellular systems over long periods of time at low computational costs.

systems biology↗

bioRxiv2019

Simulating intervertebral disc cell behavior within 3D multifactorial environments

MotivationLow back pain is responsible for more global disability than any other condition. Its incidence is closely related to intervertebral disc (IVD) failure, which is likely caused by an accumulation of microtrauma within the IVD. Crucial factors in microtrauma development are not entirely known yet, probably because their exploration in vivo or in vitro remains tremendously challenging. In-silico modelling is, therefore, definitively appealing, and shall include approaches to integrate influences of multiple cell stimuli at the microscale. Accordingly, this study introduces a hybrid Agent-based (AB) model in IVD research and exploits network modelling solutions in systems biology to mimic the cellular behavior of Nucleus Pulposus cells exposed to a 3D multifactorial biochemical environment, based on mathematical integrations of existing experimental knowledge. Cellular activity reflected by mRNA expression of Aggrecan, Collagen type I, Collagen type II, MMP-3 and ADAMTS were calculated for inflamed and non-inflamed cells. mRNA expression over long periods of time is additionally determined including cell viability estimations. Model predictions were eventually validated with independent experimental data. ResultsAs it combines experimental data to simulate cell behavior exposed to a multifactorial environment, the present methodology was able to reproduce cell death within 3 days under glucose deprivation and a 50% decrease in cell viability after 7 days in an acidic environment. Cellular mRNA expression under non-inflamed conditions simulated a quantifiable catabolic shift under an adverse cell environment, and model predictions of mRNA expression of inflamed cells provide new explanation possibilities for unexpected results achieved in experimental research. Contactlaura.baumgartner@upf.edu

systems biology↗