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WATT LAB PROJECTS

For Public

The main research interest of the Watt Lab is understanding how stem cells maintain and renew adult tissues. We primarily investigate this using human and animal epidermis as a model. 

The Epidermis

The skin is the largest organ of the human body, with a total area of around 20 square feet covering an adult body. It is made up of three layers, the epidermis, dermis, and the hypodermis, each of which has a vastly different anatomy and function. 

 

We are interested in the outermost layer, or the epidermis, which plays a number of important functions:

  • Prevents loss of water, keeping your skin hydrated and healthy.

  • Protects your body from harm, including UV radiation from the sun, pathogens (i.e. bacteria and viruses), physical damage, and chemicals. 

  • Providing your skin colour

  • Making new skin cells to maintain this important barrier. 

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Various cells within the epidermis help to carry out these functions. Keratinocytes make up around 90% of the cells in the skin, they produce the protein keratin which is the main component of the epidermis, providing strength and flexibility. Other cells include melanocytes which produce melanin, the pigment responsible for skin colour and protection from UV radiation, and Langerhans cells which are a type of immune cell that “eat” pathogens. 

 

Like the skin itself, the epidermis is made up of 5 layers which contain these cells. From the bottommost to topmost layers these are:

LAYER

Stratum basale (single layer of cells)

Stratum Spinosum (8-10 layers of cells)

Stratum granulosum (3-5 layers of cells)

Stratum lucidum (2-3 layers of cells)

Stratum corneum (20-30 layers of cells)

FUNCTION

Most contains the stem cells required for regenerating the other layers of the epidermis. This layer is separated from the dermis below by a barrier called the basement membrane. This layer also contains melanocytes.

Also known as the “prickle cell layer” as it is mostly consisting of keratinocytes with spiny projections that reach out and anchor tightly to other cells. This makes your skin strong and flexible. This layer also contains the Langerhans cells. 

Keratinocytes migrating up from the stratum spinosum mature and produce an abundance of keratin which is found in granules inside the cells. 

Thin, layer of flattened keratinocytes which adhere together, making a tough, durable material. 

The visible layer of your epidermis and is made up of dead keratinocytes which will eventually shed off as your skin is renewed. 

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Human skin →

Christina Philippeos

Epidermal Stem Cells of the Skin 

Stem cells are the building blocks of the human body, with the ability to renew themselves (proliferation) and specialise into other cell types (differentiation). Epidermal stem cells are found in the bottom most layer of the skin, they are responsible for the regular renewal of the cells in the epidermis and for healing wounds. When differentiation begins, the stem cells migrate up towards the surface of the epidermis. 

WATT LAB PROJECTS

The Stem Cell Microenvironment 

The balance between the proliferation and differentiation of the epidermal stem cells is essential for the maintenance of healthy skin. We are broadly interested in how stem cell proliferation and differentiation is regulated by interactions with the specific local environment surrounding them (microenvironment).

 

A cell’s microenvironment can influence its properties through various physical, mechanical, and chemical mechanisms. We investigate these in a number of ways.  

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Papillary Dermis →

Matthew Blakeley

Extracellular matrix 

The extracellular matrix is an intricate network of proteins and molecules that surround and support a cell. We are investigating how epidermal stem cells interact with the extracellular matrix. 

Lipids

Lipids are a broad range of organic compounds including fats, oils, and hormones. They 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 have investigated which lipids produced by epidermal stem cells could help regulation their differentiation. 

Non-Coding RNA

RNA is structurally similar to DNA but consists of just one strand of “code” containing genetic information. Coding RNA carries instructions from DNA to make proteins. Non-coding RNA is not turned into protein but has other functions such regulating the expression of genes. We are currently investigating how a class of non-coding RNAs are involved in epidermal stem cell fate decision. 

Topography 

Topography refers to the physical landscape of 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, such as keratinocytes, become stem cells again. In adult mammals this usually occurs during tissue repair following injury. It we previously believed that differentiation of cells in the epidermis was irreversible. This concept has recently been overturned but further research is needed to understand the mechanisms involved. We aim to discover the molecular changes underlying epidermal dedifferentiation following a wound. 

WATT LAB PROJECTS

Fibroblasts 

Fibroblasts are a type of cell that are essential for maintain the structural integrity of many tissues in the body. They produce proteins that make up the ECM, such as collagen which provides structure and strength to your tissues or elastin which makes tissues extendable and elastic. Fibroblasts are also critical in supporting normal wound healing through the production of new ECM proteins to support other cells and contract the wound. Research in the Watt Lab has demonstrated that different populations of fibroblasts found in the middle layer of the skin, the dermis, show distinct functional properties. These functional differences are influences by their specific environment and during disease. 

 

By understanding how the functions of fibroblasts differ and using the best fibroblasts for the job, we are developing a cell therapy for wound healing, reducing scar formation and as a potential treatment for various skin conditions like acne scarring.

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Deep Dermis →

Matthew Blakeley

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WATT LAB PROJECTS

Ageing

How and why do we age? Is aging considered a disease? How can we prolong skin aging? 

We are unravelling how DNA and gene expression changes cause of sun-protected skin aging in healthy female. We are also interested in how stem cells lose their ability to renew with age.

Skin ageing →

Vasiliki Salameti

WATT LAB PROJECTS

Human Cell Atlas

The Human Cell Atlas is an international collaborative effort to map all cell types within the human body.

 

Many skin cell types can be subdivided into different populations but how they differ across parts of the body and in skin cancer is not well understand. We are working with the Human Cell Atlas to map these differences on a genetic level.  

WATT LAB PROJECTS

Oral Squamous Cell Carcinoma 

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. Despite advances in treatment, the 5-year survival rate for OSCC remains below 50-60%. In order to improve OSCC treatment and prognosis we need to understand how the same types of cells can genetically and physically differ from one another in the tumour. This difference is known as heterogeneity. Cells in OSCCs are highly heterogenous, and this is thought to be due to factors in the tumour microenvironment.  

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We are trying to understand how the microenvironment changes as tumours progress, with a specific focus on the how balance of proliferation and differentiation in cancer causing stem cells becomes irregular.

 

We also look at changes in the extracellular matrix and the movement of immune cells into tumours. To do this, we use mice with mutations in stem cells that cause oral cancer resembling human OSCC cause by tobacco use. We also use cells from patients with OSCC wherever possible. 

Cancerous tumour →

Kalle Sipilä

WATT LAB PROJECTS

Bardet Biedl Syndrome

Bardet-Biedl Syndrome (BBS) is a rare genetic disorder which affects many parts of the body, including vision loss, obesity, intellectual disability, and chronic kidney disease (CKD). This is caused by an underlying defect in the primary cilia of cells, small finger-like projects which protrude from the surface of the cell and detect chemical and mechanical changes in the environment. 

BSS patients with mutations in the BBS10 gene have the most significantly increased risk of developing severe CKD but how this develops is unclear and it offer differs between patients. To investigate this, we take adult cells from patients the BBS10 mutation and turn them back into stem cells. 

This allows us to differentiate them into kidney cells, making 3 dimensional mini kidneys in a dish. These mini organs do not exactly resemble a full kidney but share many of the same features and functions which means we can use them to study what goes wrong in the kidney in people with BBS. 

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