A computational Model to Assess the Contribution of Growth Factors to Phenotype Stability in Chondrocytes

Cell-based tissue engineering constructs are an interesting expansion of the surgeon’s toolkit in treating long bone defects. However, the outcome of interventions with these constructs suffers from high variability barring their regular appearance in the clinic, in no small part due to the inter-patient variability in cell behaviour. In the paradigm of ‘developmental engineering’ a solution to this problem is envisioned by mimicking robust developmental processes in combination with a rigorous analysis thereof through the construction of computational models. From our knowledge of developmental biology we can form a computational model to facilitate understanding of how growth factors and transcription factors influence cell fate decisions in the growth plate and consequently answer the question whether – and how – they can boost bone healing. The model presented in this study includes 46 factors and 146 interactions between them. The dynamics of the system were simulated in a simplified manner that differentiates between slow and fast interactions. Through a Monte Carlo approach the importance of each factor in the stability of chondrocytic phenotypes (proliferating, hypertrophic) is assessed. The hypertrophic state was found to be more stable than that of the proliferating chondrocyte. This higher stability in random initial conditions seems to be conferred by faster reactions that favor the hypertrophic phenotype. Overall, the model allows the importance of several important factors in the fate decision of chondrocytes to be quantitatively assessed and can make suggestions as to how an in vitro bone forming process could be steered.status: publishe