WATT LAB PROJECTS
For Researchers
The major research interest of the wattlab is in how the differentiated state of adult tissues is maintained. We primarily study this using mammalian skin as a model system.
Current projects are concerned with self-renewal and lineage selection by human and mouse epidermal stem cells; the role of stem cells in epidermal and oral tumour formation; and the assembly and function of the epidermal cornified envelope.
We are particularly interested in the interplay between intrinsic and extrinsic factors in the regulation of the cell fate decisions.
WATT LAB PROJECTS
Cell Fate Decisions & the Skin Microenvironment
The epidermis, the outermost layer of the skin, is a stratified epithelium which is maintained and constantly renewed by stem cells residing in its innermost layer. When differentiation begins, the stem cells migrate up towards the surface and build biochemical structures that form the external barrier that protects us from the outside environment.
The balance between the proliferation and differentiation of the epidermal stem cells is thus essential for the maintenance of healthy skin. We are broadly interested in how stem cells and their differentiation programmes are regulated by interactions with the microenvironment and what molecular mechanism influence the equilibrium of proliferation and differentiation. We investigate this in a number of ways.
Papillary Dermis →
Matthew Blakeley
Extracellular matrix
In skin, epidermal stem cells attach to a basement membrane, a thin structure between dermis and epidermis. Mutations in the extracellular matrix (ECM) components of the basement membrane or cell adhesion regulators can cause severe diseases such as Kindler syndrome and epidermolysis bullosa. In addition, the interaction between cancer cells and microenvironment is a key factor affecting disease progression.
We are studying how studying how epithelial stem cells and tumour initiating cells interact with their microenvironment and how this modulates cell differentiation. We have recently characterized a new receptor called embigin that is highly expressed in sebaceous gland cells, regulating the adhesion to their microenvironment. We found that embigin is a direct cell surface receptor for fibronectin, a large molecule abundant in the extracellular matrix of progenitor cell niche.
Lipids and Non-Coding RNA
Lipids are extremely important for the function of the epidermis as their chemical and physical properties prevent the loss of water from inside the body. We sought to investigate if any lipid species produced in epidermal stem cells could help regulate their fate. Using a combination of siRNA screens and lipidomics, we were able to identify lipids that can trigger the differentiation process.
A growing body of research is defining an increasingly prominent role for long non-coding RNAs in the regulation of cell biology through a variety of modalities. We are currently investigating how a class of highly expressed, poorly conserved long non-coding RNAs participate in epidermal stem cell fate decision and characterising the molecular mechanism behind their activity.
Topography
Topography is a physical niche factor in the stem cell microenvironment. It is usually caused by changes in the surface where stem cells attach. We are interested in finding out if this affects the growth and specialization of epidermal stem cells and which mechanisms are involved in this process.
Dedifferentiation
Dedifferentiation is the process by which differentiated cells acquire the properties of stem cells. In adult mammals it usually occurs during tissue regeneration following injury. In multi-layered epithelia such as the epidermis, terminal differentiation has typically been considered to be irreversible. This concept has recently been overturned but further research is needed to understand the mechanisms underlying this cell transition. During mouse skin wound healing the differentiated Gata6+ cells of the sebaceous duct migrate into the interfollicular epidermis and dedifferentiate, acquiring stem cell properties.
We aim to characterise the molecular basis underlying epidermal dedifferentiation following wounding by integrating single-cell mRNA-Seq analysis of Gata6-lineage positive cells during distinct stages of the dedifferentiation process in vivo. Cellular plasticity contributes to the regenerative capacity of tissues; thus, our studies will provide new insights into how changes in cell state contribute to the physiology of tissue damage. It will suggest new interventions in disease and cancer, as it points to an underlying physiologic form of cell plasticity.
WATT LAB PROJECTS
Fibroblasts
Fibroblasts are cells that play an essential role in maintaining the structural integrity of most tissues. They synthesize structural proteins such as collagen and elastin that make up the ECM of connective tissue. Previous and ongoing research in the Watt Lab has demonstrated functional heterogeneity within the dermal fibroblast population and has characterised their contribution to skin development and repair at different body sites and during various stages of development. Furthermore, fibroblast heterogeneity can be influenced by the tissue microenvironment and in diseased states. These different fibroblast subpopulations have distinct functions in the skin yet remain less well characterized.
We focus on the different subpopulations of fibroblasts in human skin, specifically in the context of therapeutic applications for wound repair, tissue regeneration and diseases characterized by excessive scar tissue (fibrosis). We are developing a fibroblast cell therapy for wound healing, resolving scar formation and as a potential treatment for various skin diseases. We also aim to gain mechanistic understanding of cell-matrix interactions in the dermis.
Deep Dermis →
Matthew Blakeley
WATT LAB PROJECTS
Ageing
How and why do we age? Is aging considered a disease? How can we prolong skin aging? We investigate the interplay between transcription and DNA methylation on chronological skin aging. Through computational and cell molecular techniques we are unravelling the causes of sun-protected skin aging in healthy females.
We are also interested in how stem cells lose their proliferative capacity with age, with a focus on how skin topography influences aging as an extrinsic factor.
Skin ageing →
Vasiliki Salameti
WATT LAB PROJECTS
Human Cell Atlas
We are currently working on the Human Cell Atlas – an international collaborative effort to map all cell types within the human body – to generate a comprehensive Skin Cell Atlas. Single cell genomics has revealed that many skin cell types can be subdivided into discrete subpopulations however the spatial relationships of these cell populations and how they differ qualitatively and across anatomical sites and in cutaneous malignancy remain poorly understood.
To address these questions, we have combined single cell genomics with spatial transcriptomic approaches (spatial transcriptomics and in situ sequencing) to decipher these relationships in both healthy skin and skin cancer.
Sequencing of face skin biopsy →
Clarisse Ganier
WATT LAB PROJECTS
Oral Squamous Cell Carcinoma
Mouse oral keratinocytes →
Priyanka Bhosale
Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. Most cases are diagnosed in locally advanced stages along with the presence of lymph node metastasis. Despite advances in treatment, the 5-year survival rate for OSCC remains below 50-60%. In order to improve OSCC treatment and prognosis there is a pressing need to understand the impact of cellular and genetic heterogeneity on the biology of this tumour type. OSCCs are highly heterogenous, and this heterogeneity is attributed to various molecular and genetic events along with tumour microenvironment factors that drive carcinogenesis. Currently, we are studying how cancer stem cells create their own microenvironment and how this can be modulated by targeted therapies.
We are investigating the impact of individual mutations on OSCC development using a 4NQO- (4nitroquinoline1oxide) - based oral carcinogenesis mouse model which resembles tobacco related human OSCCs. By deleting the gene of interest from the basal epithelial stem cells we study the tumour development trajectory and track the phenotypic and microenvironmental changes during this process.
We specifically focus on the deregulation of balance between epithelial stem cell proliferation and differentiation along with changes in the cell morphology, ECM changes and difference in immune infiltration within tumour due to specific gene mutation. To further validate the observed phenotypes, we use patient derived OSCC lines and clinical samples wherever applicable.
Cancerous tumour →
Kalle Sipilä
WATT LAB PROJECTS
Bardet Biedl Syndrome
Bardet-Biedl Syndrome (BBS) is an autosomal recessive disorder which results in defective primary cilia, a sensory organelle with key roles in chemosensation and mechanosensation and houses key components of growth factor signalling pathways. Defects in the primary cilium can affect many different organs throughout the body, including causing chronic kidney disease (CKD).
BBS patients with mutations in the BBS10 gene have the most significantly increased risk of developing severe CKD. The aetiology of this increased occurrence of CKD is unclear, and renal defects in patients are heterogeneous.
We use iPSCs derived from patients and differentiate them in vitro into 3D kidney organoids, which result in the formation of renal structures within the organoid, and 2D monolayers which display epithelial characteristics to uncover where BBS10 mutations may result in renal defects emerging.