#13331 - Stem Cells - Organisation of the Body

Stem cells

-stem cells are undifferentiated and are capable of self renewal and division without limit

-two types of division- symmetric division- forms two daughter cells that both remain as stem cells- asymmetric division one of the 2 daughter cells becomes a transit amplifying cells-committed to a specific fate

-whether the stem cells divides symmetrically/ asymmetrically depends on the positioning of the spindle fibres- if they are placed vertically the membrane protein ‘numb/par’ is distributed evenly whereas if spindle fibres are aligned horizontally- the membrane protein is asymmetrically distributed

-the number of different cell types the transit amplifying cells can differentiate into determines the potency of the stem cell

-totipotent stem cells can differentiate into all types of cells including extraembryonic structures (placenta)

-pluripotent cells can differentiate into all the cells in the embryo- multipotent cells differentiate into one of the germ layers- multiple lineages of cells found in the embryo whereas unipotent stem cell can only differentiate into one type of cell

Detecting the presence of stem cells- label them with a radioactive nucleotides- BRDU- the highest concentration of these radioactive nucleotides are found in stem cells as these are label retaining cells as they have a low rate of turnover

The role of stem cells in development

Embryonic stem cells

-totipotent stem cells- can from entire blastocyst

-cleavage, 2-4 cell stage

-pluripotent- can form embryo but not surrounding tissue- forms the three germ layers

-8 cell stage

-Somites via cell induction produce myocytes- Example of induction- inductive processes occurs in muscle development in a developing embryo- the myotome which differentiates into muscle cells is induced by surrounding cells of the neural tube, epidermis and the lateral plate mesoderm- the neural tube releases signalling molecules- neurotrophin 3, Wingless family 1,3- this results the transcription factor Myf5 to be produced in hypaxial muscles and Pax3,Myod be produced in epaxial muscles.

-neural crest cells- can differentiate into Schwann cells, melanocytes- failure of migration of the neural crest cells leads to the Pie-Bald defect, sympathetic ganglia, parasympathetic ganglia

Fate mapping is used to show what different cells the neural crest cells differentiate into. Moving stem cells into different locations determines potency/ using a culture dish the potency can be tested to see what structures derive

-limb development- stem cells ‘chondroblasts/osteoblasts proliferate and terminally differentiate- mutations in the FGF3 receptor it leads to Achondroplasia

Adult stem cells

-important to maintain cell populations for long periods of time

-committed stem cell- give rise to smaller subpopulations of cells

-multipotent- give rise to many cell types

-unipotenti- give rise to one type of cells

-important for the continued production of epithelium, blood, muscle, liver and brain

Renewal in epithelium: skin

-skin is stratified squamous epithelium layer

-basal cells contains proliferating stem cells- few true stem cells and many transit amplifying cells. True stem cells don’t divide very often as this limits the potential for mutations during DNA replication- reduces the chance of cancer and also has the potential for very rapid repopulation when required.

-cells move through layers of skin to replace cells sloughed off at the surface

-cells move through states of gene expression towards terminal differentiation

-cells express a seires of different keratin proteins during differentiation

. To remain as an epidermal stem cell, the cell has to be attached to the extra cellular matrix of the basal lamina and this ensures the size of the stem cell population doesn’t increase without limit because if the cells become crowded out they lose their stem cell character and they differentiate. This was shown when basal keratinocytes are held in suspension instead of being allowed to settle and attach to the bottom. This resulted in the inhibition of division in basal keratinocytes and led to their differentiation.

The epidermal stem cells can be used to repair extensive burns- stem cells from the basal layer can be removed from the basal layer and cultured to obtain a large number of keratinocytes which is used to repopulate the damaged body surface

Gut

-stem cells found in the crypts of the small intestine- constant renewal of tissue in the lining of the small intestine which constantly sheds a layer of its epithelium due to abrasive forces of the food as it moves along the gut

-lining of the small intesting renews faster than any other tissue- turnover about 1 week

-dividing stem cells lie in the crypts and the cells then travel upwards- there are four types of differentiated cells- enterocytes, goblet cells, enteroendocrine cell and paneth cell

-proliferation is regulating by cell to cell signalling- Wnt signalling- once the stem cells leave the crypt they lose their exposure to Wnt signalling and causes an inhibition in cell division- leads to terminal differentiation

-transgenic mouse whose gut epithelial cell secreted a diffusible inhibitor of Wnt signalling- the inhibition of Wnt signalling resulted in no proliferating cells and the lining of the small intestine was composed of fully differentiated absorptive cells

-Wnt signalling switches on Notch signlling which results in the stem cells becoming committed to one of four cell fates- some cells there is an expression of Notch ligand whereas in other cells notch receptors- notch ligands form secretory cells, cells with activated notch receptors become absorptive cells

-both cells continue to divide until they are pushed out of the crypt into base of the villi where they undergo terminal differentiation- enterocytes, goblet cells, enteroendocrine cells move up the villi- paneth cells move to the bottom of the crypts

-the absorptive, goblet and enteroendocrinecell travel upwards from stem cell region and paneth cells migrate downwards

Blood cells

-Haematopoietic stem cell, bone marrow differentiates into multipotent stem cells and lymphoid progenitor cell

-Lymphoid progenitor cell: differentiates into Natural killer cells, T lymphocytes, B lymphocytes

-Myeloid progenitor cell: Neutrophil, Basophil, Eosinphil, Monocyte/macrophage, RBC

-Leukocytes: Granulocytes (Neutrophils, Eosinphils, Basophils), Monomuclear cells (monocytes, lymphocytes

-bone marrow transfer resupplies all haematopoietic tissue

-to specifically collect stem cells- use cell surface antibodies and collect and transfuse back into irradiated mouse

The...