Stepwise modelling of iPSC differentiation towards chondrocytes
Lucas F. Jansen Klomp1,2, Ricco A. Zeegelaar2, Hil G.E. Meijer1 and Janine N. Post2
1Department of Applied Mathematics, University of Twente, Enschede, The Netherlands
2Developmental BioEngineering, University of Twente, Enschede, The Netherlands
E-mail: l.f.jansenklomp@utwente.nl, r.a.zeegelaar@utwente.nl, h.g.e.meijer@utwente.nl, j.n.post@utwente.nl
Abstract
Introduction
Induced pluripotent stem cells (iPSCs) provide a promising avenue for the development of innovative treatments for osteoarthritis (OA). We use computational models to better understand differentiation of iPSCs towards chondrocytes, the main cell type in cartilage.
Results
We have constructed dynamic models of signalling networks for cell fate decision processes in the early stages of differentiation towards chondrocytes. These prior knowledge signalling networks consist of two parts. First, a network of signal transduction pathways describes how cells respond to specific experimental inputs. Second, a gene regulatory network describes how the target transcription factors for specific cell fates respond to these inputs. We have imposed nonlinear ordinary differential equations on the subnetworks constructed for each decision point that results in a specific cell fate. This allows investigating temporal changes in gene expression and protein activity when experimental inputs are applied to the model.
Our analysis of the models shows various regions of bistability and other interesting dynamic behaviour. These regions of bistability indicate where cell fate decisions depend on a cell’s current state, and where population cell differentiation is more heterogeneous and influenced by experimental factors.
Conclusion
Our model accurately describes the early steps of differentiation from iPSCs towards chondrocytes. Changes in experimental inputs can be assessed in-silico, enabling predicting optimal conditions for cell fate decisions in health and OA. Our model can lead to new protocols for stem cell differentiation and potential therapeutic targets of OA cartilage that will be assessed in wet-lab experiments.
Funding: OCENW.GROOT.2019.079, collaboration with the Molecular Epidemiology group at LUMC led by Ingrid Meulenbelt.