Herniation of the lumbar disc can cause severe pain radiating down the leg alongside a dermatome. This pain can be caused by compression of the nerve root, but recent evidence has indicated that a... Show moreHerniation of the lumbar disc can cause severe pain radiating down the leg alongside a dermatome. This pain can be caused by compression of the nerve root, but recent evidence has indicated that a local inflammation response may also play a role. This thesis focuses on how macrophages that infiltrate the herniated disc in patients with lumbar disc herniation, influence pain and recovery after discectomy. Our data shows that for most patients, if macrophages are present, they benefit the process of healing by leading to a quicker resorption of the herniated material which results in faster recovery. However, for patients with Modic changes, which indicates a degenerated endplate (structure between disc and vertebrae), the presence of macrophages is less beneficial, for they recover more slowly after surgery. The reason for this discrepency seems to be an altered differentiation profile in macrophages. Macrophages differentiate into different types with different behaviours: the M2 macrophages are known for its anti-inflammatory properties and tissue resorption. Our study found M2 macrophages in lower numbers in patients with degenerated endplates, which can explain their slower recovery. Together the data indicates that macrophage differentiation profiles in lumbar herniated discs are promising treatment targets. Show less
Relevant human in vitro culture models can contribute to a reduction in animal use for respiratory research and generate data that can be better translated to patients. In this thesis various... Show moreRelevant human in vitro culture models can contribute to a reduction in animal use for respiratory research and generate data that can be better translated to patients. In this thesis various improvements of different current human lung in vitro models were explored. Human induced pluripotent stem cells (hiPSC) were used to generate alveolar type 2 (AEC2)-like cells, that were subsequently cultured at the air-liquid interface (ALI) to create a model of alveolar wound healing at the ALI. Furthermore, a method to utilize organoids was developed for expansion of cells from human lungs to obtain sufficient numbers to reliably establish epithelial cultures. This was done for AEC2 isolated from resected lung tissue, as well as for cell populations from broncho-alveolar lavage fluid from adults and tracheal aspirates from preterm new-borns. Finally, the cellular complexity of the in vitro cultures was expanded by introducing polarized macrophages to the airway ALI cultures. Using these cultures, the cross-talk between macrophages and airway was studied in relation to wound repair. Collectively, the methods that have been developed are expected to contribute to contribute to the use of patient- and disease relevant models in respiratory research. Show less
Cardiometabolic diseases including atherosclerotic cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are the leading cause of preventable death worldwide.... Show moreCardiometabolic diseases including atherosclerotic cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are the leading cause of preventable death worldwide. Hypercholesterolemia and inflammation are common major risk factors for atherosclerotic CVD as well as NAFLD. The studies described in this thesis aimed to get insight in strategies how to further improve cholesterol metabolism and inflammation, by exploring the therapeutic potential of brown fat activation and transcription factors involved in both processes. The results described in this thesis have increased our insight into regulation of cholesterol metabolism and inflammation by brown fat and nuclear receptors, respectively, and provided promising leads for innovative treatment of cardiometabolic diseases including brown fat activation, Δ24-dehydrocholesterol reductase inhibition, and farnesoid X receptor activation. Show less
