In het proefschrift staat de respons van endotheelcellen (celpopulatie aan de binnenzijde van het hart en de bloedvaten) op verschillende hemodynamische condities centraal. In het bijzonder de... Show moreIn het proefschrift staat de respons van endotheelcellen (celpopulatie aan de binnenzijde van het hart en de bloedvaten) op verschillende hemodynamische condities centraal. In het bijzonder de bijdrage van bloedstroom ge_nduceerde endotheelcel differentiatie aan embryonale hartklep en -septum (tussenschot) ontwikkeling nader onderzocht. In de endotheelcellen is de rol van primaire cilia (haar-achtige sensors aan het celoppervlak) in de interactie tussen specifieke moleculaire signaleringcascades die betrokken zijn bij de aanleg van hartkleppen bestudeerd. Een abnormale signalering door endotheelcellen in het hart kan bijdragen aan het ontstaan van hartklep- en septum afwijkingen. Deze aangeboren hartafwijkingen hebben een belangrijk plek in de kliniek en kunnen levensbedreigend zijn. Show less
Chondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM). Chondrocyte__matrix interactions compensate the lack of cell__cell contact and are modulated by... Show moreChondrocytes interact with their neighbours through their cartilaginous extracellular matrix (ECM). Chondrocyte__matrix interactions compensate the lack of cell__cell contact and are modulated by proteoglycans and other molecules. The epiphyseal growth plate is a highly organized tissue responsible for long bone elongation. The growth plate is regulated by gradients of morphogens that are established by proteoglycans. Morphogens diffuse across the ECM, creating short- and long-range signalling that lead to the formation of a polarized tissue. Mutations affecting genes that modulate cell__matrix interactions are linked to several human disorders. Homozygous mutations of EXT1/EXT2 result in reduced synthesis and shortened heparan sulphate chains on both cell surface and matrix proteoglycans. This disrupts the diffusion gradients of morphogens and signal transduction in the epiphyseal growth plate, contributing to loss of cell polarity and osteochondroma formation. Osteochondromas are cartilage-capped bony projections arising from the metaphyses of endochondral bones adjacent to the growth plate. The osteochondroma cap is formed by cells with homozygous mutation of EXT1/EXT2 and committed stem cells/wild type chondrocytes. Osteochondroma serves as a niche (a permissive environment), which facilitates the committed stem cells/wild-type chondrocytes to acquire secondary genetic changes to form a secondary peripheral chondrosarcoma. In such a scenario, the microenvironment is the site of the initiating processes that ultimately lead to cancer. Show less
Blood-flow-induced shear stress plays an important role in cardiovascular development and disease. How endothelial cells sense shear stress remains to be elucidated. We postulated that the primary... Show moreBlood-flow-induced shear stress plays an important role in cardiovascular development and disease. How endothelial cells sense shear stress remains to be elucidated. We postulated that the primary cilium is a component of the endothelial shear sensor. This luminal cell protrusion contains microtubules and is connected to the microtubular cytoskeleton. We identified cilia on endothelial cells of the embryonic heart in areas of low or oscillatory shear stress. This shear-related distribution is reminiscent of the distribution of atherosclerotic lesions in the adult arterial system, as lesions develop at sites of low or oscillating shear (athero-prone flow). Ciliated endothelial cells are exclusively present at these atherosclerotic predilection sites in adult mice. Athero-prone (oscillatory) but not athero-protective (steady or pulsatile) flow induces ciliation of cultured endothelial cells. Moreover, the endothelial shear response is dependent on the microtubular cytoskeleton and primary cilia sensitise the endothelium for shear. Taken together, these data demonstrate that primary cilia are induced by athero-prone flow and that ciliated cells are more sensitive to shear stress. We conclude that the endothelial biosensor for shear stress is the microtubular cytoskeleton and that the attached primary cilium functions as a signal amplifier in areas subjected to athero-prone flow. Show less
