Differentiation of ReNcell VM197 cells is induced solely by growth factor removal and proceeds without any additional external stimulation.

This cell line differentiates into neurons and glial cells within 72 hours after growth factor removal, which might explain the faster time scale of our model compared to the Lee model.

It is the combination of these two WNT stimuli, that allows the cell to first generate an immediate response to the perturbation (removal of growth factor ) and in the following to keep the activation on a constant, but moderately incremented level (cf.

In response to growth factor removal, a transient increase of the intracellular ROS level activates DVL in a redox-dependent manner.

Thus in contrast to the previous model configuration we replaced the initial amount of WNT molecules with a onetime release of ROS molecules (nRos = 10000) in response to growth factor removal.

Within three days after growth factor removal, ReNcell VM197 cells differentiate into neurons, astrocytes, and oligodendrocytes without any additional exogenous stimulation.

Accordingly proliferating ReNcell VM197 cells were used as reference (Oh), whereas all following time points were measured after initiating the differentiation by growth factor removal.

Cells were kept in proliferative state by applying 10 ng/mL basic fibroblast growth factor (bFGF, Invitrogen) and 20 ng/mL epidermal growth factor (EGF, Sigma-Aldrich, Steinheim, Germany).

Upon growth factor removal ReNcell VM197 cells differentiate into neurons and glial cells within a few days and without any additional external stimulation.

However further evidence was provided in our previous study on ReNcell VM197 cells, as an early increase of mitochondrial ROS metabolism after growth factor removal was found to modulate DVL-mediated WNT/fi-catenin pathway and neurogenesis [21].

Here, we report a novel hybrid mathematical modeling strategy to systematically unravel hepatocyte growth factor (HGF) stimulated phosphoinosi-tide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling, which critically contribute to liver regeneration.

We combine interaction graph and dynamic modeling with quantitative experimental data to study the hepatocyte growth factor induced signaling network in primary mouse hepatocytes.

Examples include that of periodic calcium spikes after growth factor or hormone stimulation [54] and the MAPK system, where positive and negative feedback loops allow the system to switch between monostable and bistable regimes and, therefore, to flexibly adapt the response to different stimuli [55].

An important factor that contributes to liver regeneration and has been implicated in the context of resistance to targeted tumor therapy is hepatocyte growth factor (HGF).

Insulin-like growth factor binding proteins (IGFBPs), which have a high affinity for IGFs, control IGF bioavailability.

Bound complex of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 2 (IGFI-IGFBP2)complex complex

Insulin-like growth factor 1 (IGFI) and insu-lin-like growth factor 1 receptor (IGFIR) are an integral part of normal fetal and postnatal growth of the brain [19].

The activation of ErbB receptors by epidermal growth factor (EGF) or heregulin (HRG) in the MCF7 breast cancer cell line exemplifies the impact of such transient or sustained signalling on cell fate [3, 4].

They are normally growth-quiescent in the normal adult vessels, but are activated by injury, or exposure to growth factors (including FGF2) and pro-inflamma-tory cytokines (including IL1b).

Pathways associated with the early peak signature included the transforming growth factor (TGF) beta signalling pathway, and the platelet derived growth factor (PDGF) signalling pathway, which play critical roles in cellular proliferation and development [24] and shares the downstream targets with the ErbB receptor signalling pathway, the receptors for EGF and HRG and all those belong to the members of receptor tyrosine kinases (RTK) family.