Haemopoesis Flashcards
How are new blood cells produced?
All cells of the blood originate from multipotent stem cells
in the bone marrow - haemopoietic stem cells (HSCs)
• All blood cells come from self-renewing haematopoietic
stem cells (HSCs) - All stem cells perform asynchronist division; two essential features:
1. Ability to differentiate into a variety of mature cell types
2. Capacity for self-renewal
• In healthy adults the HSC normally reside in small numbers
in the bone marrow
• HSC are very rare around 1 in every 20 million nucleated
cell in the bone marrow is a HSC
How does a haematopoietic stem cell know what to divide into?
Depending on what cues the HSC receives will determine what the cell will divide into.
Extrinsic cytokines/ IL bind to receptor and initiate a signalling cascade.
Leads to up/ down regulation of genes, transcription (intracellular signallers are transcription factors) and translation.
Where does haemopoesis occur in adults?
Major sites of adult inntramedullary haemopoiesis:
• The sterum, proximal ends of femur and pelvis
• Minor sites include the ribs, vertebrae, skull and sacrum
Where does haemopoesis occur in the embryo and foetus?
0-2 months yolk sac (embryonic stage):
1. Produces primitive erythroid cells (EryP) and macrophages that are not
derived from a haemopoetic stem cells
- Haemopoeisis is necessary for cellular respiration, due to
constant production of ATP for oxygen to transport e-
2. Definitive erythropoiesis begins with formation of self-renewing
haemopoietic stem cells (HSCs) in aorta-gonad-mesonephros (AGM)
- within the dorsal aorta here you can detect CD34+ HSCs
- can make a wider range of haematopoietic cells, inc lymphocytes
- Haemoglobin is Gower1, Gower 2 and Portland
2-7 months liver and spleen:
- Yolk sac and AGM cease their role; the liver is the primary site of blood
cell production.
- Haemoglobin F replaces the embryonic haemoglobin variants
5-9 months bone marrow:
- Granulocytic and megakaryocytic production shifts to bone marrow
first, followed by erythropoiesis.
By birth all bones are capable of haemopoesis
What growth factors and signalling molecules are involved in haemopoesis and erythropoesis?
From a multipotent progenitor (more mature HSC):
- if acted upon by IL-7, the external factor, PU1 will be switched.
This is an essential transcription factor for the master
lymphoid pathway and common lymphoid progenitors will be produced
- if acted upon by GATA 1 and 2, common myeloid progenitors will
be produced. Similarly when acted upon by TPO, essential for
erythropoesis and platelet production.
- if EPO then acts upon the megakaryocyte erythroid progenitors RBCs
rather than platelets are formed.
How is haemopoesis regulated?
Control can be extrinsic or intrinsic
• Extrinsic: cell-to-cell interactions, extracellular matrix, environmental
regulators such as cytokines
- Not including TPO (liver) and EPO (kidney), all other cytokines
are produced in bone marrow stromal cells (adipocytes, fibroblasts,
osteoblasts, endothelial cells and macrophages)
- Cytokines regulate the process of haemopoiesis, namely the
haemopoietic growth factors (glycoprotein hormones) and
interleukins.
- These have multiple roles and are multi-redundant, so other
species can do the same things
- Regulate the proliferation and differentiation of haemopoietic
progenitor cells
- Plastic in nature - influenced by outside events
- Terminal deficiency means cells cannot go the other way
• Intrinsic: genetic events, transcription factors, stage specific cell
cycle regulation
What changes in haemopoesis occur in disease states?
During disease the fatty bone marrow is capable of reversion
to haemopoiesis and in many cases there is also expansion of
haemopoiesis down the long bones.
The liver and spleen are also capable of resuming their foetal haemopoietic activity known as extramedullary haemopoiesis.
What is erythropoiesis?
Erythrocytes – red blood cells represent the most common
cell type in adult blood
Make 1 x 10^12 new erythrocytes each day, 2.3 million RBC/second
Life span 120 days - diseases that shorten this lead to anaemia, so can indicate specific disease process
Balance between RBC production and destruction depends on
• Hormonal controls
• Adequate supplies of iron, amino acids, and B vitamins
EPO commits common erythroid megakaryocyte progenitors (of the myeloid linage) to becoming RBCs
Erythroblasts/normoblasts are the first morphological cell visible, followed by nucleated RBCs, then reticulocytes.
- reticulocytes circulating for 2-3 days and are the closest thing we
can measure to interpret bone marrow activity
- reticulocytes still contains some ribosomal RNA, mature for 1-2 days in
the peripheral blood when RNA is lost completely. But the nucleus has
been expelled so there is no nuclear DNA
- they have also lost ribosomes to leave space for carrying O2.
However, they can’t can make any more proteins so die if any damage
occurs. Also they have no mitochondria (no krebbs cycle for anaerobic
respiration), so produce energy through the glycolysis pathway
(produces 2 ATP, used solely for transportation)
- the reticulocyte count indicates rate of RBC formation
What is erythropoietin?
Erythropoietin (Epo) is the essential erythroid-specific growth factor
Produced by peritubular interstitial cell’s in the outer vortex of the kidneys in response to O2 supply.
In the bone marrow:
EPO EPO Stem cells -—> early -—> late -—> CFU-E —-> normoblasts
BFU-E BFU-E |
|
RBCs
What happens if erythropoietic homeostasis is unbalanced?
- Stimulus - e.g. hypoxia due to:
- decreased RBC count
- decreased Hb
- decreased O2 availability
- Kidney releases EPO
- EPO stimulates red bone marrow
- Enhances erythropoiesis increases RBC count
- O2-carrying ability of blood increases
What is thrombopoesis?
An adequate supply of platelets is essential to repair the minute
vascular damage that occurs with daily life, and to initiate
thrombus formation in the event of overt vascular injury.
Megakaryocytes are formed from CFU-Meg by a unique process
called endomitotic replication
- Developing megakaryocytes generally undergo nuclear maturation (ploidization) prior to cytoplasmic development.
- Megakaryocytes at any ploidy level >8N can undergo cytoplasmic maturation and platelet production.
- Platelets are first released between the endothelial cells of the marrow sinuses as proplatelets.
- Proplatelets break into mature platelets and are released into the peripheral blood
Endomitotic replication is where DNA replication and
cytoplasmic expansion occurs but not cell division. Therefore
cells can be polyploid up to 64n DNA content
Thrombopoietin (TPO) is essential for platelet production
How do megakaryocyte develop and produce platelets?
Megakaryocytes are formed from CFU-Meg by a unique process
called endomitotic replication.
There are two phases; phase 1 - megakaryocyte maturation, phase 2 - platelet generation
Megakaryocytes begin as progenitor cells BFU-mk and CFU-mk these have a ploidy of 2-4n). These generally undergo nuclear maturation (ploidization) to give morphologically recognisable megakaryocytes; stage I = 8n, stage II = 16n, stage III = 32n, stage IV = 64n.
Throughout each stage the megakaryocytes undergo endomitosis (DNA replication without cell division)and cytoplasm enlargement (cytoskeletal proteins and platelet granules)
Mature cells, adhered to endothelium, eject nucleus and extends long branching processes (proplatelets) between the endothelial cells of the marrow sinuses into blood vessels. Organelles and granules are transported to proplatelets
Proplatelets break into mature platelets and are released into the peripheral blood, these contain granuoles required for clotting (ATP, serotonin, thrombosis, etc.)
Each megakaryocyte can produce 1000 -3000 platelets
