Download Epidermal Stem Cells

BIOLOGY OF DISEASES
• Skin diseases
Topics
• Epidermal Stem Cells
• Skin cancer
• Basal cell carcinoma
• Squamous cell carcinoma
• Melanoma
• Psoriasis
Epidermal Stem Cells
• Epidermal stem cells are a subpopulation of keratinocytes
• Epidermal stem cells give rise to interfollicular epidermis, hair
follicles and sebaceous glands
• Sweat glands are derived from the epidermis during embryonic
development but is is not known whether epidermal stem cells
contribute to this differentiation pathway during postnatal life.
Properties of Stem Cells
• Not terminally differentiated
• Can divide without limit (at least for the lifetime)
• When a stem cell divides, each daughter cell has a choice: remain as a
stem cell or embark on a course that commits to differentiation
• Self-maintenance of stem cell population
• Often pluripotent differentiation potential
Transit amplifying cells
Model of epidermal cell lineages
Maintenance of stem cell compartment
• Divisional asymmetry
• Population asymmetry
• Epidermal stem cells form clusters
• Locations:
upper hair follicle (bulge) and patches of basal keratinocytes
at the tips of dermal papillae (between rete ridges)
• Stem cell niche
Stem cell niche
Stem Cell Research
• Problem: no definite cell surface marker to distinguish pure
populations of epidermal stem cells (compare to haematopoietic stem
cells).
• Indirect methods utilised
Clone forming ability of individual
keratinocytes
• Only stem cells have unlimited potential for cell divisions.
• When keratinocytes are cultured in low density only stem cells give
rise to large colonies
• Transfection and viral transduction can be used to manipulate cells in
culture
Stem cells are slowly cycling in vivo
Stem cell fate can be studied in vivo using
transgenic mice
Biomedical applications for epidermal stem
cells
• Wound healing
• Gene therapy
• Implications in carcinogenesis
Skin Cancer
• Mouse 2-stage skin carcinogenesis => tumour growth can be promoted
even 1 year after exposure to carcinogen.
• Mutated differentiated cells are shed off from the surface of the skin
but mutated stem cells and their stem cell daughters remain in the skin
and can acquire further mutational hits
2-stage skin carcinogenesis
• Mutations are caused by applying a mutagen ( for example DMBA)
to shaved back skin
• Tumour growth is promoted by repeated applications of TPA over
several weeks
• Multiple benign papillomas, some of them convert to malignant
carcinomas.
• When applied to transgenic or knock-out mice, 2-stage model gives
information on roles of individual proteins in carcinogenesis
Skin cancer
• Basal Cell Carcinoma and Squamous Cell Carcinoma are of
keratinocyte origin
• Melanoma originates from melanocytes
Ultraviolet light is carcinogenic
Sunburn
UV light is mutagen
DNA-Repair mechanisms protect cells from
mutagens
• Excision repair mechanism can cut out thymine dimers
• Xeroderma Pigmentosum, a rare inherited disease. Affected individual
lack excision repair and are extremely prone to skin cancer.
Basal Cell Carcinoma
Basal Cell Carcinoma
• Basal cell carcinoma is hardly ever invasive and can be completely
cured by surgery
Basal Cell Carcinoma
Inherited BCC Naevus
Actinic Keratoses
Squamous Cell Carcinoma
Squamous Cell Carcinoma
Malignant melanoma
Sunburn and melanoma
Melanocytes
Melanoma - staging is important prognostic
tool
Familial melanoma - mutations in p16 INK
tumour suppressor gene
Invasion and metastasis
• Cytoskeleton
• Adhesion
• Cell-cell
• Cell-matrix
• Signalling proteins
• Rho family
• Tumour microenvironment
• Matrix Metalloproteinases
ECM Turnover - MMPs
• Matrix metalloproteinases are enzymes that cleave components of
ECM
• Over 20 different enzymes with differenrt specificities.
• Common theme: expressed as an inactive proenzyme
• Also other substrates than ECM proteins
• TIMPs = tissue inhibitors of MMPs
Experimental Therapies for Melanoma
• Immunotherapy - Tumour vaccines
• Some promising results
• Inhibitors of MMPs
• Against invasion and angiogenesis
• Early results in human trials (many different tumour types) disappointing
Psoriasis - a disease of immune cells and
keratinocytes
Psoriasis has a genetic component
Chicken or Egg