W10 Origin of blood cells Flashcards
Steps to mature blood cells
Stem cells > progenitors > precursors > mature blood cells
Each day the adult bone marrow produces
~2x1011 red blood cells
~5x1010 neutrophils
Plus smaller numbers of other cell types
Requires enormous levels of cell replication
Sites of haematopoiesis in infant
Throughout bone marrow
Sites of haematopoiesis in adult
Central skeleton vertebrae ribs and sternum skull sacrum pelvis proximal ends of humerus and femur
Bone marrow
Spongy jelly like tissue
Inside the bone
Many blood vessels
- bring nutrients and take away new blood cells
Red marrow
Active haematopoiesis
Yellow marrow
Filled with fat cells
Bone marrow trephine
Trephine biopsy used to examine bone marrow architecture
Bone marrow aspirate
Used to examine cellular morphology
See mature cells plus many immature precursor cells
Commonest cells are neutrophil precursors, called myelocytes and myeloblasts
Blast cell
Blast- “seed” or “germ” cell
Basophil precursor
Basophilic myeloblast
Eosinophil precursor
Eosinophilic myeloblast
Erythropoiesis
Process which produces RBC
Proerythroblast > basophilic eryhtroblast > polychromatic erythroblast > pyknotic eryhtroblast > reticulocyte > mature RBC
Platelet formation
Megakaryoblast undergoes DNA replication but no cell division
Megakaryocyte formed which is a large polyploid cell
Cytoplasmic fragments then forming blood platelets
Lymphopoiesis
Stem cell converted into Common lymphoid progenitor
Then into T + B lymhocytes
T-cell formation in thymus
Early progenitor migrates to thymus
T-cell receptor gene rearrangement
Positive & negative selection
B-cell formation in bone marrow
Immunoglobulin gene rearrangement
expression of surface IgM
Immature B-cell migrates to 2prime lymphoid organs for maturation and antigen selection
Undifferentiated progenitors
You cannot tell the difference between them morphologically because they do not show the characteristics of mature cells
Committed progenitors
They are already committed as to what they will become when they generate mature cells
Colony assays process
Singe cell suspension of bone marrow which is then incubated for 7-14 days in semi-solid medium (agar, methylcellulose) w/growth factors
Colony assays
Progenitors grow to form colonies of mature cells
From 32 to hundreds or thousands of cells in a colony
Thus progenitors are called “Colony Forming Units” -CFU
Used to study the proliferation and differentiation pattern of hematopoietic progenitors
Colony assays types
CFU-G (neutrophilic) granulocyte progenitor CFU-GM granulocyte/monocyte progenitor CFU-E erythroid progenitor CFU-Mk CFU-bas CFU-eo
Burst forming unit - erythroid
Early erythroid progenitors grow to make large colonies that look like they have burst apart
Thus the name BFU-E (burst forming unit- erythroid)
CSF
Factors which were discovered to stimulate colony growth were named colony stimulating factors (CSF) e.g.
G-CSF granulocyte-CSF
M-CSF monocyte-CSF
GM-CSF
Bone marrow transplantation
completely ablate haemopoiesis with radiation and drugs
infuse compatible donor bone marrow cells
haemopoiesis can be completely restored
BMT donor
Donor must be HLA matched
sibling or unrelated donor
Or autologous BMT (cells or tissues obtained from the same individual)
reinfuse patients own bone marrow
BMT engraftment
Only haematopoietic stem cells can give long term engraftment
NOT progenitors
NOT precursors
BMT applications
Leukaemia, lymphoma, myeloma
Intensified chemotherapy for solid tumours
Genetic diseases e.g. thalassaemia, SCID etc
BMT risks
significant mortality while waiting for engraftment
infection due to neutropenia (low neutrophil count)
bleeding due to thrombocytopenia (low platelets)
Graft versus Host Disease (GVHD)
BMT benefits
For many diseases, this is the only curative treatment
Pluripotent
Can give rise to cells of every blood lineage
Self maintaining
A stem cell can divide to produce more stem cells
Mice (stem cells)
mark stem cells by retrovirus insertion
transplant irradiated mice with small number of stem cells
same marked stem cell gives rise to neutrophils, lymphocytes etc
CML
Human
Chronic myeloid leukaemia (CML) is caused by a chromosome translocation in a stem cell
disease mostly affects neutrophil lineage
but Philadelphia chromosome also found in T-lymphocytes and other lineages.
CD34
Stem cells and early progenitors carry the cell surface antigen CD34
Later progenitors = CD34 +ve
Immature precursors = CD34 -ve
Use to purify stem and progenitor cells
HAEMATOPOIETIC GROWTH FACTORS
Polypeptide growth factors (cytokines)
Bind to cell surface transmembrane receptors
Stimulate growth and survival of progenitors
HAEMATOPOIETIC GROWTH FACTORS - specific/stim
some stimulate early progenitors,
e.g. Il-3, stem cell factor (SCF)
others stimulate late progenitors
e.g. M-CSF (monocyte-CSF)
some are specific to one lineage
e.g. erythropoietin
others stimulate several different lineages
Erythropoietin
Produced in the kidney
In response to hypoxia
Increases red blood cell production by increasing survival of erythroid progenitors (CFU-E)
Specific to one lineage (erythroid)
Acts on late progenitors
Clinical applications of recombinant erythropoietin
Treating anaemia of kidney failure
Alternative to blood transfusion in Jehovah’s Witnesses
G-CSF
Produced by many cell types
In response to inflammation
Granulocyte colony stimulating factor
G-CSF - acts on mature neutrophils in the periphery
chemoattractant
promotes neutrophil maturation
promotes neutrophil activation
G-CSF - 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
G-CSF - clinical applications
stimulate neutrophil recovery after bone marrow transplantation
stimulate neutrophil recovery after chemotherapy
treatment of hereditary neutropenia and other causes of neutropenia
because G-CSF also helps to stimulate other lineages, it will also (for example) stimulate platelet recovery after bone marrow transplantation
Peripheral blood stem cell transplantation
G-CSF treatment causes stem cells to be released from the bone marrow into the circulation
Seen by appearance of CD34 + cells in the circulation
Collect by leukapheresis
Peripheral blood stem cell transplantation - advantages
Used an alternative to bone marrow for transplantation
Less traumatic for donor, no general anaesthetic
