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Lecture 1+2 - Haematopoiesis
Haematopoiesis is the production of mature blood cells.
Haematopoiesis is to safely supply the appropriate number of mature cells, to adapt to changed physiological requirements,
and to respond rapidly and effectively to change or needs.
All different blood cells arise from a single precursor cell type (the haematopoietic stem cell).
This stem cell that has the capability to form any of the different mature cell types -
however which ones are produced will depend on the needs of the body at that time.
(ie: there must be a control process that determines which cells are produced.)
Types of Blood Cells:
Red cells (Erythrocytes) - Involved in oxygen carriage.
Platelets - Involved in initial formation of a plug that prevents bleeding after injury.
White cells: Lymphocytes, Granulocytes and Monocytes.
Lymphocytes: Mainly involved in antibody production or the killing of virus infected human cells.
Granulocytes (Include Eosinophils, Neutrophils and Basophils) directly kill invading organisms.
Monocytes: directly kill organisms or sick cells and which helps stimulate lymphocytes.
Red Blood Cells - Oxygen Carriage.
Red Blood Cells carry oxygen in the body.
There are 20-30 trillion in the body.
They have a lifespan up to 120 days.
They are produced at the rate of 180 million per hour.
Red cells may be needed in large numbers very suddenly (such as when bleeding), blood transfusion is a recent invention.
Red blood cells may need to be temporarily increased (eg: at latitude with lower O2).
Red blood cell production may need to be increased throughout life to compensate for disease (eg: In sickle cell disease red cells may survive 15 days or less).
White Blood Cells - Fight Infection.
WBC's fight infection in the body.
They survive around 5-10 days on average but can be much less. During infection the
neutrophil directly detects and ingests bacteria - after a consuming a small number (around 100) it is exhausted and is removed from circulation. In these circumstances they may need to be replaced after hours or minutes.
The number of WBC's needs to be controlled.
Why control of WBCs is needed:
If the number of white cells falls to very low levels then the body cannot protect itself against bacteria (even those that are normally present on skin, gut or mouth).
Whilst, If there are too many then they may behave abnormally - for example too many neutrophils can be present attacking the normal skin.
Platelets - Promote Clotting.
Platelets are small cell fragments that promote clotting.
They survive minutes to days.
We produce 400,000,000,000 per day.
They are needed in good number and may be rapidly used up after major injury -
sometimes they are never needed and survive for around 2 weeks before being removed from the body naturally.
Why control of Platelets in needed:
If there are too many platelets, then the blood becomes "too sticky" and platelets may block blood vessels causing death of tissues - this mainly affects small capillaries.
If there are too few platelets, then bleeding after trauma can become very severe, but we can also see small haemorrhagic spots (petichae) where small capillaries leak and are not sealed by platelets.
In major surgery so many platelets may be used that a transfusion of platelets is required,
but generally the body is able to increase platelet number sufficiently to cope.
The system must therefore:
Get the numbers of mature cells right.
Respond to long-term changes in need.
Respond to very sudden change. Good Definition of Haematopoiesis:
To safely supply the appropriate number of mature cells, to adapt to changed physiological requirements, and to respond rapidly and effectively to change or need.
Producing Stem Cells
The haematopietic stem cell is the starting point of haematopoiesis.
The key feature of the stem cell system is "plasticity" the multipotent stem cell can produce any of the different mature cell types.
The multipotent stem cell therefore provides the ability to direct cell production to any particular lineage according to need - this is the first step in providing the flexibility required to meet the body needs.
Properties of the Multipotent Haematological Stem Cell:
SELF RENEWAL (making an identical copy of itself) - The stem cell system ensures we always have cells able to make blood.
LINEAGE CHOICE (making mature cells of the right type) - The stem cell system ensures we are able to produce the type of cells we need.
When a stem cell divides it makes two daughter cells.
However, there is a choice, either Self-Renewal or Differentiation:
SELF RENEWAL - Where an identical copy is made, and the stem cell poo is maintained. This is vital to maintain, increase or reduce stem cell number.
DIFFERENTIATION - Where the daughter cell begins to form a mature blood cell and can no longer self-renew. This is vital to maintain, increase or reduce stem cell number.
Each stem cell division makes two new cells and the fate of those cells is central to what happens. It is really important that the stem cell system is controlled.
Self-renewal is vital to ensure we do not "run out of stem cells" as we get older but must be tightly controlled to ensure we do not end up with too many or too few stem cells
Differentiation is also vital since that is what makes mature cells - again the right number of cells must enter differentiation to make mature blood cells The Self Renewal Choice What happens if stem cell division has different fates:
If each division produces one identical daughter cell (self-renewal) then number of stem cells is maintained.
Fewer self-renewal at lower rates, or higher rates has a massive impact even over a limited number of divisions. This mechanism allows stem cell number to be adapted to need but emphasises the importance of control.
The differentiation choice is also important for flexibility, where the stem cell becomes committed to a particular lineage.
Controlling which lineage, it takes allows the selective expansion of one or more mature cell types.
Stem Cells and Cancer
• As stem cells are self-replicating cells each can already make identical copies of itself and if the process goes wrong then the risk of cancer is high.
• When cells lose the capacity to mature then primitive forms accumulate causing things such as acute leukaemia.
• Most blood cancers arise from stem cells simply because the process of selfrenewal (making identical copies), this is a central feature of cancer.
• If a stem cell is mutated in a way that loses control of self-renewal, then there will be cancer.
How Stem Cells avoid Cancer
The lower the number of stem cells the lower the risk of a mutation that might cause cancer.
Keep the numbers small - The more of them the more vulnerability to damage.
Keep the number of divisions few - Damage is more likely during proliferation.
Control them tightly through the Stem Cell niche. •
So once haematopoietic stem cells become committed to development. Its committed daughter cells then make up to 19 cycles of division before a mature cell is made.
This gives up to 500,000 mature cells from each stem cell, however the stem cell itself needs to divide only once so relatively few stem cells and stem cell divisions are needed to support the body's needs.
The stem cell niche is also an important control - stem cells find it difficult to survive outside of this particular environment - so if a cell does lose control of self-replication it will still find it difficult to survive as it overcrowds its niche.
The stem cell depends greatly on the cells and proteins around it - this is known as the "stem cell niche".
The elements of the niche can control the stem cell function and stem cells cannot survive well outside this niche - this prevents an excessive expansion of numbers.
Stem Cells Summary
Stem cell can self-renew and form identical copies of themselves - this allows stem cell number to be maintained through life.
Stem cells can also "commit" to develop into mature cells according to the bodies needs. These lineages committed cells can no longer self-renew, but can greatly expand their number.
The system is flexible: stem cell number can be increased or reduced if required by increasing the number of self-renewal divisions.
The ability to self-renew is dangerous if it goes wrong. The process therefore is tightly controlled.
The Proliferating and Differentiating Pool
The committed precursor cells are not simply the "in-between cells" that link stem cells to mature cells - their behaviour is vital to the control of haematopoiesis.
The number of cells potentially produced here is huge - a single stem cell entering the committed precursor pool can make up to around 20 divisions each yielding two daughter cells.
This produces a lot of mature cells: 2, 4, 8, 16, 32, 64, 128 etc as divisions continue and each stem cell can therefore produce as many as 500,000 mature cells. This is the stage where number is controlled.
Initially cells are highly proliferative, but as the process develops they acquire more functional characteristics and no longer proliferate.
When we look at blood cells in bone marrow we see the appearances change from initial highly proliferative appearances to later cells that resemble mature cells and act very similarly to mature cells with fewer numbers of division.
The Importance of Death
The cells of the committed progenitor pool still have a "choice" - to carry on dividing and maturing or to die.
This is vital to allow the body to respond to need.
Death is a really important mechanism to control the numbers.
With any single cell having a 40% chance of death the actual number of mature cells produced is much lower than could be produced - this may seem wasteful but in fact it is essential to haematopoiesis.
If we prevent cell death, then the number of cells produced is greatly increased.
This shows in a diagram how a single stem cell makes many mature cells of red cell,
white cell or platelet types, but also many dead cells.
Varying the cell death allows either greater numbers or fewer mature cells to be formed.
By varying death in a particular lineage, fine control over red cells, white cells or platelets can be achieved.
This is the flexibility of the system that allows it to meet the needs of the body.
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