Origin of Blood Cells

Question 1

Define and describe haematopoiesis.

Answer 1

It is the formation of blood cells.

STEM CELLS produce PROGENITORS which produce IMMATURE PRECURSORS which produce MATURE CELLS. That is the most basic of red blood cell differentiation.
Throughout the process of making specialised cells from stem cells, growth factors are added throughout.

Question 2

Give three examples of precursors and the mature cells that they produce.

Answer 2

• β-LYMPHOCYTES make PLASMA CELLS
• MONOCYTES make MACROPHAGES
• MEGAKARYOCYTES make PLATELETS (megakaryocytes are large polyploid cells which platelets bud off of)

Question 3

What are the different sites of haematopoiesis throughout a human’s lifetime?

Answer 3

IN THE EARLY FOETUS: in the yolk
IN THE FOETUS: in the liver
IN AN INFANT: throughout the bone marrow
IN AN ADULT:
- in the central skeleton
- in the vertebrae
- in the ribs and sternum
- in the skull
- in the sacrum
- in the pelvis
- in the proximal ends of the humerus and the femur

Question 4

Describe the bone marrow.

Answer 4

The bone marrow is a spongey, jelly-like tissue. It has many blood vessels which bring nutrients and take away new blood cells. It is a metabolically active, innervated organ.
There are two types of bone marrow:
- RED MARROW: where active haematopoiesis takes place
- YELLOW MARROW: where it is filled with fat cells

Question 5

EDIT: What is the difference between a bone marrow trephine biopsy and a bone marrow aspiration?

Answer 5

BONE MARROW TREPHINE BIOPSY:
- bone marrow is removed in pieces
EDIT: “A bone marrow trephine means that they remove a 1 or 2cm core of bone marrow in one piece”
- used to examine the bone marrow architecture

BONE MARROW ASPIRATION:

• bone marrow cells are sucked out in a syringe
• used to examine cellular morphology

Question 6

What are the most common cells seen in the bone marrow?

Answer 6

The most common cells are neutrophil precursors called myelocytes and myeloblasts.

Question 7

EDIT: Describe the formation of neutrophils (myelopoiesis).

Answer 7

1) MYELOBLAST
2) promyelocyte
3) MYELOCYTE
4) metamyelocyte
5) BAND
6) SEGMENTED NEUTROPHIL
(Caps ones are more important)

Question 8

Describe the formation of red blood cells (erythropoiesis).

Answer 8

1) PROERYTHROBLAST
2) BASOPHILIC ERYTHROBLAST
3) POLYCHROMATIC ERYTHROBLAST
4) PYKNOTIC ERYTHROBLAST
5) RETICULOCYTE
6) MATURE RED BLOOD CELL

As we go along, the nucleu shrinks and condenses.

Question 9

Describe platelet formation.

Answer 9

1) MEGAKARYOBLAST (to the next step, there is only DNA replication, no cell division)
2) MEGAKARYOCYTE
3) BLOOD PLATELETS

Question 10

Briefly, describe the formation of lymphocytes (lymphopoiesis).

Answer 10

1) STEM CELL
2) forms a COMMON LYMPHOID PROGENITOR
3) forms either a T-LYMPHOCYTE or a B-LYMPHOCYTE

Question 11

Where does T-Cell formation occur?

Answer 11

T-Cell formation occurs in the thymus.
The early progenitor migrates to the thymus and T-Cell receptor gene arrangement occurs. Positive and negative selection also occur.

Question 12

Where does B-Cell formation occur?

Answer 12

B-Cell formation occurs in the bone marrow.
Immunoglobin gene arrangement occurs. There is the expression of surface IgM. The immature B-Cell migrates to the secondary lymphoid organs for maturation and antigen selection.

Question 13

Describe how progenitors are undifferentiated yet still committed.

Answer 13

They’re undifferentiated in the sense that you cannot tell the difference between them morphologically because they don’t show the characteristics of mature cells.
However, they are considered committed in the sense that they’re already committed as to what they will become when they generate mature cells.

Question 14

Why are progenitors called Colony Forming Units (CFUs)?

Answer 14

Progenitors grow to form colonies of mature cells. There can be from 32 to hundreds or thousands of cells in a colony. Thus, progenitors are called “Colony Forming Units” or “CFUs”.

Question 15

List some examples of some CFUs.

Answer 15

• CFU-G: (neutrophilic) granulocyte progenitor
• CFU-GM: granulocyte/monocyte progenitor
• CFU-E: erythroid progenitor
• CFU-Mk: megakaryocyte progenitor
• CFU-bas: basophil progenitor
• CFU-eo: eosinophil progenitor

Early erythroid progenitors (CFU-E) grow to make large colonies that look like they have burst apart. Thus, the name BFU-E (burst forming unit-erythroid) was given.

Question 16

What are CSFs?

Answer 16

Factors which were discovered to stimulate colony growth were named Colony Stimulating Factors or CSFs

Question 17

List some examples of CSFs.

Answer 17

• G-CSF: granulocyte-CSF
• M-CSF: monocyte-CSF
• GM-CSF: granulocyte/monocyte-CSF

Question 18

Briefly, describe the steps towards a bone marrow transplant and what is required of the donor.

Answer 18

1) must completely ablate haemopoiesis with radiation and drugs
2) infuse the compatible donor bone marrow cells
3) haemopoiesis can be completely restored (via the donor cells)

The donor must be HLA (Human Leukocyte Antigen) matched (either from a sibling or unrelated donor), or the transplantation can occur via autologous BMT (when you reinfuse the patient with their own bone marrow).

Question 19

What are some situations in which bone marrow transplant can be used?

Answer 19

• leukaemia, lymphoma, myeloma
• intensified chemotherapy for solid tumours
• genetic diseases (eg. thalassaemia, SCID)

Question 20

List some of the risks and benefits of undergoing a bone marrow transplant.

Answer 20

RISKS:

• significant mortality while waiting for engraftment (up to 30 days)
• infection could occur due to neutropenia (low neutrophil amount)
• bleeding could occur due to thrombocytopenia (low platelet count)
• Graft versus Host disease (long-term risk in which the graft starts attacking the body)

BENEFITS:
- for many diseases, this is the only curative treatment

Question 21

Describe how haematopoietic stem cells can be described as pluripotent and self-maintaining.

Answer 21

They are considered pluripotent because they can give rise to cells of every blood lineage.
They are also considered self-maintaining in the sense that a stem cell can divide to produce more stem cells.

Question 22

How did we prove that haematopoietic stem cells are pluripotent?

Answer 22

This was proved via mice.
Stem cells were marked by retrovirus insertion. They were then transplanted into irradiated mice with a small number of stem cells. The same marked stem cells gave rise to neutrophils, lymphocytes, etc.

Question 23

Describe Chronic Myeloid Leukaemia (CML).

Answer 23

Chronic Myeloid Leukaemia (CML) is caused by a chromosome translocation in a stem cell.
CML mostly affects neutrophil lineage, but the Philadelphia chromosome is also found in T-lymphocytes and other lineages.

Question 24

What cells present the CD34 antigen, and why?

Answer 24

Stem cells and early progenitors carry the cell surface antigen CD34. It’s used to purify stem and progenitor cells.

Question 25

Describe haematopoietic growth factors.

Answer 25

They are polypeptide growth factors (cytokines). They bind to the cell surface transmembrane receptors. They stimulate the growth and survival of progenitors.

Question 26

Describe the specificity of haematopoietic growth factors.

Answer 26

• some stimulate early progenitors (eg. IL-3, stem cell factors (SCF))
• some stimulate late progenitors (eg. M-CSF (monocyte-CSF))
• some are specific to one lineage (eg. erythropoietin)
• some stimulate several different lineages

Question 27

Describe erythropoietin (including its clinical application).

Answer 27

It’s produced in the kidney in response to hypoxia. It increases RBC production by increasing the survival of erythroid progenitors (CFU-E). It’s specific to one lineage (erythroid) and acts on late progenitors.

CLINICAL APPLICATIONS:

• treating anaemia of kidney failure
• an alternative to blood transfusions in Jehovah’s Witnesses

Question 28

Describe G-CSF (granulocyte colony stimulating factor) (including its clinical applications).

Answer 28

It’s produced by many cell types in response to inflammation.

It acts on mature neutrophils in the periphery.

• acts as a chemoattractant
• promotes neutrophil maturation
• promotes neutrophil activation

It stimulates neutrophil production in the bone marrow.

• stimulates neutrophil progenitors (CFU-G)
• helps stimulate progenitors of other lineages, but only in combination with other growth factors

CLINICAL APPLICATIONS:
- stimulates neutrophil recovery after bone marrow transplantation
- stimulates neutrophil recovery after chemotherapy
- treatment of hereditary (and other cases of) neutropenia
(because G-CSF also helps to stimulate other cell lineages, it will also (for example) stimulate platelet recovery after bone marrow transplantation)

Question 29

How does G-CSF treatment contribute to Peripheral Blood Stem Cell Transplantation (PBSCT) and how is PBSCT used?

Answer 29

G-CSF treatment causes stem cells to be released from the bone marrow into the circulation. This is seen by the appearance of CD34 on cells in the circulation. We can collect the stem cells by leukapheresis.

PBSCT is used as an alternative to bone marrow for transplantation. It’s less traumatic for the donor, as it is so painless that it does not require a general anaesthetic.

Question 30

NEW: What is reticulocyte?

Answer 30

Immature RBC that just left the bone marrow. Still has some RNA, ribosomes. Quickly loses these to make a mature RBC.