Haematopoiesis (1&2)

Question 1

What is Haematopoiesis?

Answer 1

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

Question 2

The red blood cell:

Answer 2

• Carry oxygen in the body – lungs, absorbed through membrane and then released into tissues
• 20-30 trillion in the body
• Lifespan up to 120 days – diseases can make them last 3 days
• Produce: 180 million per hour to maintain the numbers

Question 3

Why do you need red blood cells?

Answer 3

1. Blood transfusions
2. Temporarily increased in high latitudes
3. May increase throughout life to compensate for diseases

Question 4

The white blood cell:

Answer 4

• Fight infection in the body
• 5-10 days lifespan
• A sausage shaped nucleus to allow it to pass through thin membranes
• Make 10 billion per day
• Too few is a problem – infection (neutrophils)
• Too many is a problem – damage (when someone is prescribed an injection to increase their neutrophil count and they forget to cross off their intake, taking more, neutrophils will get into the skin and cause it to eat it away)
• But we may need large numbers very suddenly (infection) – many bacteria can divide every 20 mins, numbers increase exponentially, neutrophils will be the first line of defence

Question 5

Platelets:

Answer 5

• Small cell fragments that promote clotting
• From a megakaryocyte
• Survive minutes to days
• Produce 400 billion a day
• Too many is a problem – blocking vessels
• Too few is a problem – bleeding in the legs due to the back pressure in legs
• But we may need large numbers very suddenly (surgery)

Question 6

The system must therefore:

Answer 6

• Get the numbers of mature cells right
• Respond to long-term changes in need
• Respond to very sudden change

Question 7

SELF RENEWAL:

Answer 7

• making an identical copy of itself

- The stem cell system ensures we are able to produce the type of cells we need

Question 8

LINEAGE CHOICE:

Answer 8

• making mature cells of the right type

- this is differentiation

Question 9

Stem cell process:

Answer 9

Every time a stem cell divides it must produce one identical copy (self-renewal) to itself and one can be different (lineage), if not then the stem cell dies out

Question 10

Chemotherapy:

Answer 10

you may want to increase rates of self-renewal stem cells

Question 11

Plasticity:

Answer 11

you need more cells in the proliferation stage- different lineages

Question 12

STEM CELLS AND CANCER:

Answer 12

• When cells lose the capacity to mature then primitive forms accumulate (acute leukaemia)

As stem cells are self-replicating cells each can already make identical copies of itself, if the process goes wrong then the risk of cancer is high.

Question 13

Avoiding cancer 1 (Principles of stem cells):

Answer 13

1. Keep the numbers small:
   The more of them the more vulnerability to damage – when the stem cell has a designated job it then divides many times as it has committed
2. Keep the number of divisions few:
   Damage is more likely during proliferation

Question 14

Solution:

Answer 14

• Once haematopoietic stem cell becomes 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, this reduces DNA damage

Question 15

Avoiding cancer 2 (Principles of stem cells):

Answer 15

Control them tightly: The “stem cell niche” which gives them local hormones, adhesive proteins (sticky) which gives signals that the cell is happy

• 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.
• If a stem cell try to leave this site it will die as it’s no longer part of the niche

Question 16

The proliferating and differentiating pool:

Answer 16

• Initially cells are highly proliferative, but as the process develops they acquire more functional characteristics and no longer proliferate.
• More granules are made which makes it less proliferative

Question 17

The importance of death:

Answer 17

1. The rates of cell death in the proliferating pool can be up to 40%. This can have a very significant effect on the final number of cells produced.
2. This means you can produce more or less cells in a department of the body - more specific

Question 18

If we prevent cell death, then the number of cells produced is greatly increased:

Answer 18

• Death of early cells has a more major effect on cell number than later cells, but will take longer to affect eventual cell number

Question 19

ERYTHROPOIETIN (Facts):

Answer 19

A cytokine increasing red cell production (a haemorrhage, thalassemia, high altitudes)

Question 20

What is EPO for?

Answer 20

• To ensure that the red cell number is sufficient to deliver oxygen to tissues
• The body doesn’t have a set number of red blood cells (no two people have the same number), however must be efficient to deliver oxygen – measures oxygen not RBC

Question 21

What must EPO achieve?

Answer 21

The correct number of red cells must be produced – an excess number is dangerous

Question 22

How does EPO do it?

Answer 22

Acting mainly on later red cell precursors it enhances the survival of erythroid precursors and increases maturation rate to expand the proliferating pool

Question 23

How is EPO controlled?

Answer 23

1. when oxygen levels are low it is sensed by the kidney
2. This triggers EPO to be released
3. Responds to great blood loss of a blood cell need

Question 24

Granulocyte colony stimulation factor (G-CSF) Facts:

Answer 24

Increasing neutrophil production

Question 25

What is G-CSF for?

Answer 25

To ensure that the neutrophil number is sufficient to fight infection

Question 26

What must G-CSF achieve?

Answer 26

It must provide a baseline number of neutrophils to protect the body, but also respond very rapidly during infection with no upper limit (not like haemoglobin).

Question 27

How does G-CSF do it?

Answer 27

Acting mainly on late granulocyte precursors it enhances the survival of the precursors and increases maturation rate and granule formation to massively increase output and function

Question 28

How is G-CSF controlled?

Answer 28

1. When inflammation or infection is detected in the body, endothelial cells release G-CSF
2. The G-CSF the produces neutrophils in large numbers according to how great the stimulus is

Question 29

Thrombopoietin TPO Facts:

Answer 29

Increased platelet production

Question 30

What is TPO for?

Answer 30

To ensure that there are always enough platelets to prevent haemorrhage
The older you get, more cholesterol and therefore more likely to have a haemorrhage

Question 31

What does TPO achieve?

Answer 31

The correct number of platelets must be produced – an excess number is dangerous, but so is too few it can result in bruising

Question 32

How does TPO do it?

Answer 32

Acting mainly on megakaryocytes it enhances the survival of megakaryocyte precursors within the proliferating pool to increase number and rate of maturation

Question 33

How is TPO controlled?

Answer 33

1. TPO is produced in response to inflammation
2. This causes a high number of cytokines to be produced
3. TPO then binds to platelets to destroy it
4. Very confusing - but if low numbers of platelets then more TPO produced and if a high number of platelets then TPO destroys it?

Question 34

Control of the system is through a network of cytokines:

Answer 34

• The stimulus and control of the cytokine depends on what it is meant to achieve
• In almost all cases the control is achieved by altering cell death in the proliferating pool but some affect stem cells
• Additionally, the cytokines can affect mature cell function.