Molecular Dermatology and Stem Cell Research
Investigations in the Molecular Dermatology and Stem Cell Research group focus on elucidating the signals governing epidermal renewal from stem cells to differentiated keratinocytes, and how these signals malfunction in specific skin diseases. This research is of a translational nature, and has the ultimate goal to develop novel and specific therapeutic applications based on an improved understanding of the detailed mechanisms the skin uses to renew itself.
Stem cell-driven epidermal renewal
The epidermis is the outermost layer of the skin, and is composed mainly of keratinocytes that assemble into a stratified squamous epithelium. Like epidermal appendages such as hair follicles, sebaceous and sweat glands, the epidermis is renewed throughout the entire life span of an organism. Epidermal renewal begins when a keratinocyte progenitor leaves the stem cell compartment, undergoes a limited number of mitotic divisions, exits the cell cycle and commits to terminal differentiation. At the end of this phase the post-mitotic cells detach from the basement membrane to build up the overlaying stratified epithelium. Although highly coordinated, this sequence of events is endowed with a remarkable versatility, which enables the quiescent keratinocytes in the stem cell and early postmitotic compartment to re-integrate into the cell cycle and become migratory when necessary, for example after wounding. It is this versatility that represents the Achilles heel of epithelial cells, as disruption of these complex mechanisms leads to severe skin diseases such as cancer, psoriasis and also the autoimmune disease Pemphigus vulgaris.
In the laboratory, the main emphasis of recent years was on defining the molecular mechanisms leading to the severe blistering disease Pemphigus vulgaris. In the majority of the patients the etiology of this disease relies on autoantibodies directed against the adhesion molecule desmoglein (Dsg) 3. Dsg3 is part of the desmosome, a multiprotein complex which confers strong intercellular adhesiveness in particular in the germinative layer of the epidermis and skin appendages that contain stem cells and proliferative keratinocytes. Our laboratory has contributed to a novel understanding of the pathophysiology of Pemphigus vulgaris that relies on antibody triggered deregulation of signaling cascades required for the coordinated and controlled renewal of the epidermal sheet. This allows us for the first time to study the molecular mechanisms of stem cell activation including epigenetic changes in human skin by using Pemphigus vulgaris patients as a model system. One of the molecules found to be centrally involved in this process is the armadillo protein plakoglobin through both, structural and signaling activities.
Plakoglobin: an orphan rescued
Although the lack of a developmental phenotype in plakoglobin knock-out mice seemed to exclude a signaling role of plakoglobin, the results from various laboratories including ours today confirms an important signaling role of plakoglobin in epidermal renewal.
Our ongoing studies support that plakoglobin is a central transcriptional effector in the Wnt signaling pathway, which is of importance during development, tissue regeneration and in particular in stem cell regulation. By performing a genome-wide promoter screen we challenge the current understanding of Wnt signaling; it revealed that plakoglobin targeted promoters significantly overlap with those of the classical effector in the Wnt pathway, ß-catenin. This points towards the possibility that the function of these two armadillo proteins is interdependent and the knock-out phenotype of one molecule alone cannot reveal its entire function.
The exact role of plakoglobin in the stem cell compartment and epithelial tissue homeostasis is currently not understood. It is our aim to address this question in normal tissue renewal as well as in hyperproliferative diseases including cancer.