To improve the predictive capability of pre-clinical models and reduce the use of animal models in drug discovery and disease modelling, advanced in vitro models are being developed. These... Show moreTo improve the predictive capability of pre-clinical models and reduce the use of animal models in drug discovery and disease modelling, advanced in vitro models are being developed. These microphysiological systems (MPS) or “Organs-on-Chip” (OoC) are being developed to include all aspects of the human physiology to improve the in vitro cellular response. OoCs combined with differentiated human induced pluripotent stem cells (hiPSC) allow the use of cells with patient specific genotypes and aid the development of personalized and precision medicine.In this thesis, the development of tractable models of the vasculature is described. These models allow for the combination of hiPSC-derived vascular and tissue specific cells with haemodynamics to recapitulate essential stimuli of blood vessels. Show less
All tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The... Show moreAll tissues are surrounded by a mixture of noncellular matrix components, that not only provide physical and mechanical support to cells, but also mediate biochemical signaling between cells. The extracellular matrix (ECM) of endothelial cells, also known as the perivascular matrix, forms an organ specific vascular niche that orchestrates mechano-, growth factor, and angiocrine signaling required for tissue homeostasis and organ repair. This concise review describes how this perivascular ECM functions as a signaling platform and how this knowledge can impact the field of regenerative medicine, for example, when designing artificial matrices or using decellularized scaffolds from organs. Stem Cells Translational Medicine 2019;8:375-382 Show less
The glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this... Show moreThe glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this thesis we studied structural and compositional changes of the endothelial glycocalyx upon diabetes in mice and in vitro. In glomerular capillaries, the endothelial glycocalyx contributes to the filtration barrier in the glomeruli. In diabetes the glycocalyx is damaged but can be restored via several pharmacological compounds that subsequently results in a shift from inflammatory towards anti-inflammatory macrophage function (chapter 2-3). In our model this appeared not to a result of changes in nitric oxide availability, affirming the potential overruling role for glomerular macrophages in glycocalyx degradation in diabetic nephropathy (chapter 4). Enzymatic cleavage of heparan sulfates reduced the total amount of luminal glycosaminoglycan content, but increased inflammatory heparan sulfate epitopes in vitro and in zebrafish (chapter 5). In chapter 6 we demonstrate that endothelial-specific loss of hyaluronan, another glycocalyx constituent, results in loss of endothelial barrier function. Overall, this thesis provides evidence that inhibition of glycocalyx degrading enzymes is a potent treatment option in diabetic nephropathy and other vascular diseases. Show less
The endothelial glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in inflammation coagulation and... Show moreThe endothelial glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in inflammation coagulation and permeability in the vasculature. In this thesis we studied the structure and composition of the endothelial glycocalyx. We developed a model to induce an anti-inflammatory endothelial glycocalyx in vitro, using physiolgoical shear stress. Furthermore, we studied the role of this glycocalyx in the glomerular capillaries. Here we show that the endothelial glycocalyx contributes to the filtration barrier in the glomeruli. Consequently this implies that damage of this glycocalyx might be a first step in the development of vasculature-born renal failure, like in Type 2 diabetes. The other way around, we also studied the effect of renal failure on the systemic glycocalyx. Using a non-invasive method, we estimated glycocalyx thickness in the sublingual vasculature of patients with end stage renal disease and patients who received a kidney transplant. Interestingly, the endothelial glycocalyx was highly perturbed during end stage renal disease, but comparable to healthy controls after a kindye transplantation. Altogether the endothelial glycocalyx might be a central mediator in the development of both renal and cardiovascular disease. Show less
