The skin, comprising the epidermis with its appendages (hair follicles, sebaceous and sweat glands) and the dermis, serves as a protective barrier against environmental insults and loss of essential body fluids. The epithelium has a remarkable ability to regenerate throughout life, which depends on self-renewal of epidermal stem cells and differentiation of their progeny. Stem cell fate decisions are determined by cell intrinsic mechanisms but also by the microenvironment. Our mission is to dissect how fibroblasts of the underlying dermis regulate these fate decisions. Importantly, skin dermis arises from two fibroblast lineages which develop from a common progenitor during embryogenesis and have unique functions in skin development and homeostasis, suggesting that they may also play distinct roles in skin pathologies.
Dissecting Fibroblast Heterogeneity in Skin Cancer
When skin tumours arise from neoplastic epidermal cells, they elicit profound and distinct changes in the dermis. Our lab is investigating how signature oncogenic mutations in epithelial cells reprogram fibroblasts to cancer-associated fibroblasts (CAFs) and result in characteristic stromal responses, and if distinct fibroblast subsets have unique functions in skin cancer (basal and squamous cell carcinoma, melanoma) development and progression. By combining 3D in vitro models, in vivo lineage tracing, flow cytometry, single cell RNA sequencing, and mass cytometry (CyTOF) imaging of both murine and human skin tumours we aim at dissecting the abundance and spatial localization of fibroblast subtypes that arise in skin cancer, their function at different stages, and the signalling pathways involved in order to identify novel targets for anti-cancer therapy.
Modulating Dermal Signalling in Skin Regeneration and Fibrotic Skin Disorders
As skin ages, the so called papillary fibroblasts that build the upper dermis and are essential for the development of hair follicles and the arrector pili muscle, diminish in number, and the second lineage comprising reticular fibroblasts which synthesize the bulk of the fibrillary extracellular matrix, preadipocytes and adipocytes of the hypodermis is predominant. Besides, the gene signature of fibroblasts, and thus their properties change. This not only leads to a thinning of the dermis as we age, but also alters the way skin regenerates upon injury. While embryonic and neonatal skin heals without scarring and is capable of forming de novo hair follicles within the wound bed, in adult tissue wound healing will always lead to a scar. This is likely due to the fact that the first phase of dermal wound healing is dominated by reticular fibroblasts, while papillary fibroblasts, which are essential for hair follicle formation, migrate into the wound bed only once re-epithelialisation is completed.
Our lab is addressing if modulating dermal signalling or changing the abundance of specific fibroblast subtypes can redirect regeneration upon injury to a more scar less phenotype.
Like the first phase of wound healing, skin fibrosis is dominated by fibroblasts of the reticular lineage. Therefore, we are also interested in unravelling the role of distinct fibroblast subsets and which signalling pathways are deregulated in fibroblast-mediated skin pathologies such as scleroderma and keloids, which lack an effective clinical treatment regimen.
If you would like to know more about our lab and projects, visit us @ www.lichtenbergerlab.org