Biología de la Diferenciacion celular

1. Development and Maintenance
of the Cell type and Structure

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

3. 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

4. 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.

5. Mitosis
Mitosis
Mitosis
Totipotent
embryonic cell
Unlimited
mitosis
Pluripotent stem cell
(unlimited division)
Blast cell
(limited
division)
Mature end cell
(non-mitotic)

6. 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

7. 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.

8. 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.

9. 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.

10. • 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.

11. Chromosome
Chromosome
Chromosome
Chromosome
Senescence
Mitosis
Mitosis
Mitosis

12. • 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)

13. Chromosome
Chromosome
Mitosis
Telomerase
Chromosome
Chromosome

14. 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.

15. 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.

16. 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.

17. 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).

18. 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?

19. 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.

20. 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.

21. 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.

22. How do cells ‘decide’ which
genes to inactivate?

23. 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

24. 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

25. 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).

26. 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).

27. 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

28. 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, …………)

29. 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