#13352 - Stem Cells - Organisation of the Body

What are stem cells? Discuss how these cells play a role in normal development and turnover of tissues. How might stem cells be used to treat disease?

Stem cells are undifferentiated cells that are capable of limitless division. There are two types division which these cells can undergo; symmetric division forms two daughter cells that both remain as stem cells whereas in asymmetric division one of the two daughter cells becomes a transit amplifying cell which is committed to a specific fate and becomes terminally differentiated to a specific type of cell. The number of different cell types the transit amplifying cells can differentiate into determines the potency of the stem cell. Totipotent stem cells are able to differentiate into all types of cells including the extra embryonic structures such as the placenta. In comparison, pluripotent cells can differentiate into all the cells found in the embryo but can’t differentiate to form the placenta. Multipotent stem cells can differentiate into multiple lineages of cells found in the embryo whereas a unipotent stem cell can only differentiate into one type of stem cells. Stem cells can be classified into categories depending on where they are found. Embryonic stem cells arise from the inner cell mass during in vitro culture of blastocyts removed from a fertilised egg and these cells are totipotent. The other main type of stem cells is adult stem cells which are either multipotent or unipotent and are found in the body after development. These stem cells play a key role in replacing differentiated cells that cannot themselves divide such as the epithelium, blood, muscle, liver and brain. The continual renewal of these cells is essential in the development and turnover of tissues.

In many tissues there are multipotent stem cells and when under homeostatic conditions they remain quiescent but when they receive a particular signal they enter the cell cycle where they often divide asymmetrically. One of the two daughter cells form progenitor cells that undergo further cellular proliferation, progressive differentiation and this leads to the expansion of committed progenitor cell populations. The other daughter cell remains as a stem cell.

Epidermal stem cells

One example of adult stem cells are the epidermal stem cells which are found in the basal layer of the epidermis. The main function of the epidermis, which is a stratified squamous keratinised epithelium, is to resist mechanical stresses and to protect the underlying tissues from bacteria, UV light and excessive wetting. In the basal layer of the epidermis there are few true stem cells which undergo asymmetric division to form transit amplifying cells. The transit amplifying cells continue to proliferate but once they become committed to differentiation the cell leaves the cell cycle and migrates through the basal, prickle and granular layers of the epidermis where they progressively differentiate. As these cells travel through these layers they move through states of gene expression and express a series of different keratin proteins. Once they reach the stratum corneum, the outermost layer of the epidermis, the keratinocytes loose their nucleus and organelles and form keratinised squames which are made up of remanants of keratinocytes such as desmosomes, tonofilaments and cornified cell membranes. These squames are eventually are sloughed off at the surface due to abrasion. The continuous migration of these transit amplifying cells allows the skin to replace the cells sloughed off at the surface and this whole process takes on average about 30 days. The epidermal stem cells can be used to repair skin after extensive burns. The stem cells from the basal layer can be removed and cultured to obtain a large number of keratinocytes which can be used to repopulate the damaged body surface.

Like in the basal layer the epidermis, stem cells are also found at the base of the hair follicle which allows for the regrowth of hair. 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 lining of the small intestine

Another key area where stem cells are found is in the crypts of the small intestine. The small intestine is folded many times to form structures known as the villi, which projects into the lumen and crypts, which descend into the underlying connective tissue. The presence of stem cells allows for constant renewal of tissue in the lining of the small intestine which constantly sheds of its layer of epithelium due to the abrasive forces of the food as it moves along the gut. The dividing cells that are found in the crypts are multipotent as they generate four different types of cells: enterocytes, goblet cells, paneth cells and enteroendocrine cells. The main function of enterocytes is absorbing nutrients and secreting hydrolytic enzymes. These cells are characterised by their densely packed microvilli on their apical surfaces which increases their surface area. Goblet cells secrete mucus whilst the paneth cells form part of the defense system that synthesise and secrete proteins of the defensin family that kill bacteria. The final type of cell is the enteroendocrine cells that secrete serotonin in response to nutrients. The serotonin binds to nearby sensory neurones and signals to the brain which results in less hunger.

The stem cells in the crypts of the small intestine are continuously proliferating and the key signal that keeps these cells in their proliferative state is Wnt. Once the stem cells leave the crypt they lose their exposure to Wnt signalling molecules and this causes an inhibition in cell division and causes the cells to become terminally differentiated. The importance of Wnt was shown using 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 non dividing absorptive cells. The absence of secretory cells such as goblet cells, enteroendocrine and paneth cells also led to the conclusion that the presence of Wnt determines if the stem cell becomes an absorptive or secretory cell. The distinction between absorptive and secretory cells is caused by the Wnt signalling switching on notch signalling which results in the stem cells becoming committed to one of the four cell fates. In some cells the Wnt signalling molecule leads to the expression of a notch ligand whereas in other cells the presence of Wnt leads to the formation of a notch receptors. The cells that express notch ligands become commited to form secretory cells and the ligands they form activate receptors in neighbouring cells. The cells who have activated notch receptors become commited to form absorptive cells. Both types of cells continue to divide until they are pushed out of the crypt into the base of the villi where they undergo terminal differentiation. The enterocytes, goblet and enteroendocrine cells migrate out of the crypts and up the villi whereas paneth cells migrate to the bottom of the crypts. The separation of the different types is controlled by the type of proteins...