PhD Defence Lucas Jansen Klomp | Computational modelling of stem cell differentiation towards chondrocytes

Computational modelling of stem cell differentiation towards chondrocytes

Lucas Jansen Klomp is a PhD student in the department Applied Mathematics. (Co)Promotors are prof.dr. C. Brune; dr.ing. J.N. Post and dr. H.G.E.Meijer from the Faculty of Electrical Engineering, Mathematics and Computer Science (EEMCS), University of Twente.

Osteoarthritis is a disease that affects cartilage in joints, causing the breakdown of healthy cartilage tissue. Although treatments exist for osteoarthritis, such as treatments that aim to alleviate symptoms and invasive joint replacements, there is a need for less invasive treatments that do more than just treat symptoms. To develop such treatments, a better understanding of the mechanisms underlying osteoarthritis is necessary. Cartilage tissue derived from stem cells provides a promising option to learn more about these mechanisms. Human induced pluripotent stem cells (hiPSCs) are particularly interesting for generating model systems, as they can be derived from adult human cells and are capable of differentiating to a wide range of cell types. However, understanding of how these hiPSCs differentiate to chondrocytes, the main cell type in cartilage, is still incomplete.

In this thesis, we use dynamic mathematical models to better understand the process of hiPSC differentiation towards chondrocytes. Our models are based on intracellular network structures and describe how intracellular quantities such as gene expression or protein activity change over time. The intracellular networks used are either based on available literature or are inferred using data-driven methods. We have introduced novel approaches for dynamic modelling of biological systems and we have used our computational models to gain insight into the mechanisms of hiPSC differentiation towards chondrocytes. Our models have led to the identification of candidate driver transcription factors and to concrete suggestions for improvements of state-of-the-art protocols. The methods described in this thesis are applicable beyond the case of hiPSC differentiation towards chondrocytes and provide a foundation for future modelling work on time-dependent biological systems.