The research described in this thesis shows that hypercholesterolemia, a well-established risk factor for atherosclerosis, can impact skin lipid pool and barrier function already at young age. In... Show moreThe research described in this thesis shows that hypercholesterolemia, a well-established risk factor for atherosclerosis, can impact skin lipid pool and barrier function already at young age. In the field of atherosclerosis, we showed that the small peptide Lyp-1 can be used as a targeting molecule in liposomal formulations to deliver liver X receptor agonist to plaque resident foam cells/lipid-rich macrophages. Elucidation of the mechanisms underlying the intercommunication between plasma lipids and skin lipids may also bring valuable opportunities to prevent and treat dermatological pathologies in dyslipidemic patients; perhaps in combination with anti-atherogenic therapies. Thus, by deepening our knowledge we may improve our advice to the patients and ultimately improve their quality of life. Show less
Atopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier... Show moreAtopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier function and various other epidermal changes, as well as immunological changes. A decreased skin barrier function allows environmental factors such as allergens and pathogens to penetrate through the skin and evoke an immunological response, which in turn may negatively affect the skin barrier function. The skin barrier is composed of cornified keratinocytes, extracellular lipids and multiple proteins, including filaggrin. The discovery of mutations in the filaggrin gene as a major risk factor for development of AD has intensified research on this protein and its role in AD development, but its exact role in AD is still not clarified. This thesis describes the development of several reconstructed human skin equivalents (HSEs) which recapitulate various characteristics of AD. They display for example reduced filaggrin expression or alterations in epidermal characteristics due to the presence of AD-related inflammatory cytokines. These HSEs are a powerful tool that in the future might be used for screening purposes and/or development of new therapies for this life disabling skin disease. Show less
Human skin equivalents (HSEs) are generated from isolated skin cells. As the primary function of the skin is to form a barrier, in this thesis the barrier properties of three HSEs were assessed and... Show moreHuman skin equivalents (HSEs) are generated from isolated skin cells. As the primary function of the skin is to form a barrier, in this thesis the barrier properties of three HSEs were assessed and compared with native human skin. The results show that all HSEs have a decreased skin barrier function compared to native human skin. Lipids in the outermost layer of the skin, the stratum corneum (SC), play a key role in this barrier function. The lipids in the HSEs are arranged in lipid lamellae, similarly as in human skin, but form a less crystalline organization. Investigation of the lipid composition reveals that all HSEs have an increased presence of mono-unsaturated fatty acids and reduced total fatty acid content compared to human SC, which most likely is responsible for the reduced density in lipid organization. Another group of lipids, the ceramides, show a comparable composition, although the HSEs have increa sed levels of acylceramides compared to native human SC. As we show that the culture conditions are of crucial importance for the SC lipid properties of HSEs, a future change is to optimize the culture conditions to improve epidermal lipid metabolism in HSEs, resulting in improved SC barrier properties Show less
The research outlined in this thesis was focused on the development of a skin barrier model, which can substitute for stratum corneum in diffusion studies. This so-called stratum corneum substitute... Show moreThe research outlined in this thesis was focused on the development of a skin barrier model, which can substitute for stratum corneum in diffusion studies. This so-called stratum corneum substitute (SCS) was prepared with reconstituted SC lipids (cholesterol, free fatty acids and ceramides) on a porous substrate. The results convincingly show that the SCS, which mimics the composition, organisation and orientation of the intercellular lipids in the SC, can be successfully used to study solute permeation through the skin. Moreover, the SCS offers excellent possibilities to investigate the role of each lipid subclass for proper membrane organisation and barrier function. The barrier properties of the SCS can easily be adjusted by applying different amounts of lipids or by modifying its lipid composition, mimicking that of diseased skin. Such studies are crucial to increase our insight in the impaired barrier function as observed in diseased and dry skin. Show less
