Origin of Blood Cells Flashcards
Define and describe haematopoiesis.
Formation of mature blood cells derived from haemopoietic stem cells which undergo highly regulated division and differentiation
STEM CELLS produce PROGENITORS which produce IMMATURE PRECURSORS which produce MATURE EFFECTOR 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.
- Occurs to to maintain balance between self renewal, migration, cell death, terminal differentiation. Highly regulated to maintain circulating cell numbers within
relatively constant level
Give three examples of precursors and the mature cells that they produce.
- β-LYMPHOCYTES make PLASMA CELLS
- MONOCYTES make MACROPHAGES
- MEGAKARYOCYTES make PLATELETS (megakaryocytes are large polyploid cells which platelets bud off of)
PRECURSORS are the first morphologically identifiable cells within hematopoiesis.
- Limited self-renewal action
EXAMPLES:
- Erythroblast
- Myeloblast
- Monoblast
- Lymphoblast
- Megakaryoblast
What are the different sites of haematopoiesis throughout a human’s lifetime?
IN THE EARLY FOETUS in first trimester: in the yolk sac
IN THE FOETUS in second trimester: in the liver and spleen
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
May re-expand to foetal sites in times of severe demand; e.g. thalassemia
Describe the bone marrow.
Haemopoiesis occurs in BM environment. Bone marrow is a spongey, jelly-like tissue within bone. It has many blood vessels which bring nutrients and take away new blood cells.
There are two types of bone marrow:
- RED MARROW: where active haematopoiesis takes place
- YELLOW MARROW: where it is filled with fat cells
Produces
~2x10^11 red blood cells
~5x10^10 neutrophils
Plus smaller numbers of other cell types
Requires enormous levels of cell replication
The most common cells seen in bone marrow are neutrophil precursors called myelocytes and myeloblasts.
Basophil precursor - Basophilic myeloblast
Eosinophil precursor - Eosinophilic myeloblast
What is the difference between a bone marrow trephine biopsy and a bone marrow aspiration?
BONE MARROW TREPHINE BIOPSY:
- bone marrow is removed in pieces
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
- see mature cells plus many immature precursor cells
Describe the formation of neutrophils (myelopoiesis/granulopoiesis).
- Multipotent haemopoietic stem cell – CD34+
- Myeloid stem cell
- Progenitor – CFU-GM
- Progenitor – CFU-G
PRECURSORS 1-5
1) MYELOBLAST
2) promyelocyte
3) MYELOCYTE
4) metamyelocyte
5) BAND
6) SEGMENTED NEUTROPHIL
- Can also be used to form eosinophils
- The same process except the precursors(3-5) are eosinophilic
Describe the formation of red blood cells (erythropoiesis).
- Multipotent haemopoietic stem cell – CD34+
- Myeloid stem cell
- Progenitor – BFU-ME
- Progenitor – CFU-E
PRECURSORS
1) PROERYTHROBLAST
2) BASOPHILIC ERYTHROBLAST
3) POLYCHROMATIC ERYTHROBLAST
4) PYKNOTIC ERYTHROBLAST
5) RETICULOCYTE
6) MATURE RED BLOOD CELL
Basophilic erythroblast recognised due to blue cytoplasm
Polychromatophilic erythroblast recognised due to blue and pink cytoplasm
Orthochromatic erythroblast recognised due to pink cytoplasm
As we go along, the nucleus shrinks and condenses.
where blast cells are ‘germ’ or ‘seed’ cells
Describe platelet formation (thrombopoiesis)
- Multipotent haemopoietic stem cell – CD34+
- Myeloid stem cell
- Progenitor – CFU-ME
- Progenitor – CFU-M
PRECURSORS
1) MEGAKARYOBLAST (to the next step, there is only DNA replication, no cell division)
2) PRO MEGAKARYOCYTE THEN MEGAKARYOCYTES - large polyploid cells
3) BLOOD PLATELETS formed from cytoplasmic fragments
Platelet formation stem cells are haemocytoblasts.
Briefly, describe the formation of lymphocytes (lymphopoiesis).
1) LYMPHOID STEM CELL
2) forms a COMMON LYMPHOID PROGENITOR (Pre-B cells; Pre- T cells –> B-lymphoblast; T-lymphoblast)
3) forms either a T-LYMPHOCYTE or a B-LYMPHOCYTE. B-lymphocytes can form plasma cells.
Antigen independent phase
- Initial lymphopoiesis in bone. Marrow and maturation occurring in lymph nodes and thymus
Antigen dependant phase
- 2nd cycle of differentiation and proliferation in response to antigen exposure
Where do T-cell and B-cell formation occur?
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.
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.
Describe how progenitors are undifferentiated yet still committed.
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.
Why are progenitors called Colony Forming Units (CFUs)?
Give examples.
COLONY ASSAY PROCESS
Single cell suspension of bone marrow which is then incubated for 7-14 days in semi-solid medium (agar, methylcellulose) with growth factors
Progenitors grow and differentiate 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”. Used to study the proliferation and differentiation pattern of haematopoietic progenitors.
Progenitor cells can be detected through special in vitro assays where colonies are formed
EXAMPLES
- 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.
What are CSFs?
Give examples.
Factors that were discovered to stimulate colony growth were named Colony Stimulating Factors or CSFs
EXAMPLES
- G-CSF: granulocyte-CSF
- M-CSF: monocyte-CSF
- GM-CSF: granulocyte/monocyte-CSF
Briefly, describe the steps towards a bone marrow transplant and what is required of the donor.
What are some situations in which bone marrow transplant can be used?
List some of the risks and benefits of undergoing a bone marrow transplant.
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).
SITUATIONS
- leukaemia, lymphoma, myeloma
- intensified chemotherapy for solid tumours
- genetic diseases (eg. thalassaemia, SCID)
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) - haemotopoietic stem cells are the only bone marrow stem cells that provide long term engraftment - not precursors or progenitors
BENEFITS:
- for many diseases, this is the only curative treatment
Describe how haematopoietic stem cells can be described as pluripotent and self-maintaining.
How were haematopoietic stem cells proven to be pluripotent?
They are considered pluripotent because they can give rise to cells of every blood lineage. Resemble small lymphocytes, unlimited renewal and dysfunctions can lead to aplastic anaemia/certain types of leukaemia.
They are also considered self-maintaining in the sense that a stem cell can divide to produce more stem cells.
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.
Multipotent stem cells are also derived from pluripotent stem cells and are also capable of cell renewal and differentiation. Progenitor cells are derived from multipotent stem cells - have limited self-renewal/differentiation properties. Progenitors express differentiation surface antigens e.g CD71 on erythroid PC.
