The role of fibroblast PPARβ/δ in skin homeostasis

The skin is the largest organ in the body and is made up of mainly the epidermis and dermis. The skin functions as a natural barrier against external stimuli, dehydration and injury. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is one member of the PPAR family of nuclear receptors, and the predominant subtype found in the epidermis and dermis. Epidermal PPARβ/δ has well-established roles in maintaining skin homeostasis, such as during wound healing. However, in the mammalian system, skin homeostasis depends on a complex crosstalk between the epithelial and mesenchymal compartments, underscoring the importance for a tight regulation of the complex epiethelial-mesenchymal interaction. Although epidermal PPARβ/δ in normal wound healing is well-studied, there has been no progress in clinical therapies for diabetic chronic wounds. This is also ensued with problems such as drug bioavailability and patients’ compliance. In our study, we showed that pharmacological activation of fibroblasts PPARβ/δ activity using microencapsulated ligands can promote the healing of diabetic wounds via the modulation of ROS production. The role of PPARβ/δ in other diseases, such as cancer, has also been controversial due to differences in experimental setups and genetic modifications of the PPARβ/δ gene. While epidermal PPARβ/δ has been widely investigated on in these diseases, the role of fibroblasts PPARβ/δ in skin homeostasis and disease has been neglected. Hence, we generated a novel mouse model with the PPARβ/δ gene deleted specifically in the fibroblasts. These animal exhibited skin abnormalities during development, such as dermal thickening and increased collagen production, recapitulating a morphea-like phenotype. In addition, the dermis manifest as a hotbed for inflammatory events. In our subsequent preliminary studies, we showed that cancer-associated fibroblasts from squamous cell carcinoma exhibit low levels of PPARβ/δ. Our novel mouse model will therefore serve as an appropriate model to study the role of fibroblasts PPARβ/δ in diseases, such as acute inflammation, wound healing and tumorigenesis in the future.DOCTOR OF PHILOSOPHY (SBS