Functional deconstruction of distinct fibro-blast subsets in skin physiology and disease
Skin fibroblasts arise from two distinct lineages during embryogenesis, which have unique functions in skin development and homeostasis. In mouse skin, one lineage gives rise to the upper, papillary dermis, including fibroblasts of the dermal papilla, dermal sheath and arrector pili muscle, required for hair follicle (HF) formation. The other lineage forms the lower dermis, including the reticular fibroblasts that synthesize the bulk of the fibrillar extra-cellular matrix (ECM), and the preadipocytes and adipocytes of the hypodermis. Several lines of evidence suggest that also human skin comprises at least two fibroblast lineages with distinct functions.
The papillary and reticular fibroblast lineages also play different roles in skin regeneration. While reticular fibroblasts representing the majority of fibroblasts in adult tissue are important for the first phase of wound healing, the papillary lineage is not repopulated until re-epithelialization and contributes exclusively to the upper dermis, which explains the absence of hair follicles in newly closed wounds and scarring. As skin ages, the papillary fibroblasts diminish in number leading to a progressive thinning of the skin, and besides the gene signature of fibroblasts changes, and thus their properties.
When skin tumors arise from neoplastic epidermal cells, they elicit profound and distinct changes in the dermis. Our studies are shedding light on the important issue of 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.
In addition, our lab is also investigating if modulating dermal signaling can redirect regeneration upon injury to a more scarless phenotype. Furthermore, we aim to address the role of the distinct fibroblast subsets in fibroblast-mediated skin pathologies such as scleroderma and keloids, which lack an effective clinical treatment regimen.
Techniques
We use a broad range of methods including state-of-the-art cell and molecular biology methods, 3D in vitro culture systems (human skin equivalents, organoid cultures), next generation sequencing, single-cell transcriptomics, flow and mass cytometry (CyTOF), in vivo lineage tracing techniques and cutting-edge imaging technologies, and conditional knock-out mice or murine skin disease models to unravel the role of distinct fibroblast subsets in skin physiology and pathology.