Development and Maintenance of the Cell type and Structure

When cells differentiate they do so through a series of changes in their potential to produce different types of cell.

Cells in the early human embryo are not committed to be any particular type of cell and can differentiate to produce a complete human.

This is termed totipotent and is very unusual in human cells and is usually lost beyond the eight-cell stage or morula

Cells then become stem cells that have the ability to produce a wide range of different cell types within a particular type of tissue, this is called pluripotent. They may be able to produce a number of different types of connective tissues, or a range of epithelia or lymphoid cells but cannot produce cells of other lineages

Cells may then become blast cells that are capable of division and may produce a limited range of related cell types but cannot produce cells of other tissue types.

Finally cells may become mature end cells which cannot divide and may have a very short lifespan.

Mitosis

MitosisMitosis

Totipotent embryonic cellUnlimited mitosis

Pluripotent stem cell(unlimited division)

Blast cell(limited division)

Mature end cell(non-mitotic)

Characteristics of Cell growth in Cultures

When mammalian cells are grown in culture they show a number of characteristics which are different to bacterial cells.

• They are anchorage dependant and will only grow if attached to a substrate.

• They show contact inhibition• They show limited growth potential

Contact Inhibition

• Cells are unable to grow over the top of other cells in culture. They will spread across the surface and once a Confluent Monolayer is formed they cease dividing. So cells need to be regularly subcultured into new dishes to keep them dividing.

• The trigger for this seems to be the development of gap junctions between the cells. Cells which are unable to form gap junctions (eg some tumour cells) can form piles of cells more like the colonies of bacterial growth.

Hayflick Limit

• It was also found that most mature mammalian cells had a limited ability to divide.

• Cells could divide between 10 and 50 times before becoming senescent and ceasing to grow. It was also found that generally cells from older animals had less growth potential than cells from younger animals.

Telomeres

The reason for this limit to growth is the presence at the end of the chromosomes of a telomere. Telomeres are repetitive pieces of DNA whose sole function seems to be to cleanly terminate the DNA of the chromosome and prevent the formation of “sticky ends” which could result in chromosome fusion.

During DNA replication there is a region at the end of the DNA helix which cannot be replicated by the usual mechanism and is lost.

• Since it is the telomeres that are at the end of the chromosome it is the telomeres which are lost.

• When the telomeres have been exhausted the cell can no longer safely divide and becomes senescent.

• Thus the number of replicates of the telomere determines how many divisions a cell can perform.

Chromosome

Chromosome

Chromosome

Chromosome

Senescence

Mitosis

Mitosis

Mitosis

• Some cells have the ability to replace telomeres.• This requires the use of a specific enzyme called a

telomerase.• Telomerases are active in germ cells and stem

cells.• Telomerases are also re-activated in the

conversion of normal cells into cancer cells (malignant transformation)

Chromosome

Chromosome

Mitosis

Telomerase

Chromosome

Chromosome

The gradual change from a dividing and flexible cell to a fixed and non-mitotic cell has been compared to the way water runs from a mountain. Water falling on the top of a mountain can run off in several different directions but once committed to one side or the other it cannot then change and run off the other side. It’s fate becomes determined.

This is sometimes called the epigenetic landscape.

Some tissues retain cells that are capable of division and proliferation throughout life whilst others lose the ability to divide in early life and the adult tissues are incapable of division.

Three types are usually distinguished and the type of tissue controls how well cells repair and how likely they are to develop malignancies.

  Mitotic ability

Examples Healing Malignancies

Labile Cells

Short G0. Always in mitotic cycle.

Basal cells of skin, haemopoietic cells, crypt cells of gut, seminiferous germ cells.

Heal by regeneration provided some stem cells remain.

Common sites for malignancies.

Stable Cells

Long G0. Cells only divide when stimulated

Parenchyma of liver & kidney. Fibroblasts

Regenerate if some reserve cells left unharmed and connective tissues are intact. Scarring occurs if the connective tissue is lost and/or no undamaged reserve cells remain

Less common sites but still occur

Permanent Cells

Cannot divide

Neurones of CNS, Cardiac and skeletal muscle cells

Scar formation Rarely become malignant in adults.

So ischaemic damage to permanent tissues (eg myocardium or neuronal tissue) results in loss of tissue and replacement with scar tissue.

Research is now investigating whether stem cells introduced into such damaged tissue might lead to regeneration of tissue rather than just healing by scarring.

The use of stem cells may also prove useful in treating tissues where the cells degenerate in other ways (eg Parkinson’s disease or Alzheimer’s dementia).

Since no DNA is lost during the differentiation of tissues why is it that tissues do not regress and become stem cells again when required?

The cell seems to be able to selectively switch off DNA more or less permanently. This results in different cells having different genes active at any one time. Some genes (“housekeeping” or constitutive genes) are needed in all cells and these include genes for glycolysis, cell membrane synthesis & repair and protein production.

Other genes are tissue specific and need only be active in a few cells of the body. It is these facultative genes that become permanently inactivated in most adult cells.

There are probably several mechanisms involved in this switching off, which include condensation of the DNA around histones forming heterochromatin and methylation of the bases in DNA.

Once this type of switching off occurs then it is probably irreversible in normal metabolism. Reversal may be possible in certain circumstances (hence the cloning of adult animals) but in most cases is permanent eg the heterochromatic X chromosome in women.

Less permanent switching off is also possible and this is part of normal cell regulation of metabolism and involves different methods of switching genes on and off eg using gene promoters, repressors etc which will be covered in more detail in Molecular Biology courses.

How do cells ‘decide’ which genes to inactivate?

The position of a cell within the body, the humoral control chemicals and the cell from which the cell arises all play a role in this differentiation

Cell position seems a crucial factor with the links being via

• cell receptors linking on to receptors on other cells (calcium dependant adhesion receptors, Cadherins),

• cell receptors linking on to cell adhesion molecules (CAM)

• cell receptors linking on to connective tissue (integrins).

• gap junctions

These interactions indicate exactly where the cell is located and therefore which type of cell it should differentiate into.

If appropriate signals are absent then the cell will fail to divide and may commit suicide (apoptosis or programmed cell death).

The induced suicide of unwanted cells is a major feature of embryo development and accounts for the disappearance of many temporary structures (eg gill slits, tissue between digits, tail in tadpole).

Once a cell is committed to being one specific phenotype then the range of its active/inactive genes is probably controlled by a homeotic type of control. A single master control gene then regulating which genes are activated, which are repressed and which are permanently switched off

The fact that each cell type has a characteristic set of labels and active genes allows modern biomedical science to identify cell types not just by their morphology but also by their metabolism.

Thus lymphocytes which were originally only classified as “small” or “large” can now by using monoclonal antibodies be identified into many subgroups (T cells & B cells, T helper cells, T suppressor cells, Killer cells, …………)

It also allows the origin of cancer cells to be determined.

Many tumours are difficult to identify because they have lost the morphological characteristics of the original tissue but they often still retain some of the original antigens and proteins of the parent tissue and so can be diagnosed from these labels