Bone marrow Flashcards
Where is bone marrow
In the space between the cortex of bones
Traversed by bone trabeculae and blood vessels
Ribs, skull, vertebrae, and pelvic girdle, etc
Bone marrow function
Site of origin, maturation, and development of all peripheral blood cells
Lymphocytes are formed here, so it is classified as a primary lymphoid tissue
Hematopoiesis for:
- White blood cells (granulocytes, monocytes, lymphocytes)
- Red blood cells
- Platelets
- Granulopoiesis (neutrophil, eosinophil, basophil, mast cell), monocytopoiesis (monocytes, macrophages, DCs), lymphopoiesis (T cells, B cells, NK cells)
- Erythropoiesis
- Thrombopoiesis
Sites of hematopoiesis with age
Fetus: 0-2 months in yolk sac, 2-7 months in liver and spleen, 5-7 months in bone marrow
Infants: bone marrow, practically all bones
Adults: vertebrae, ribs, sternum, skull, sacrum, pelvis, and end of femurs
3 basic components of the bone marrow
Stem cells
Bone marrow microenvironment
Hematopoietic growth factors
Stem cells
Arise from yolk sac
Self renewable
Multilineage differentiation potential
Bone marrow microenvironment
- ECM
- Stromal cells
- ECM: attachment of progenitor cells or stem cells
- Stromal cells: physical support for hematopoietic cells, produce hematopoietic growth factors and express adhesion molecules that influence differentiation, ex: macrophages, fibroblasts, endothelial, etc
Stem cells express cell surface adhesion molecules to attach with specific structure in the ECM
Hematopoietic growth factors produced by stromal cells are presented to immobilized stem cells
Hematopoietic growth factors
Glycoproteins that act at low concentrations
Produced by many cells: stromal cells, monocytes, lymphocytes
May effect more than one lineage, or could be specific for 1
Active on stem cells and/or functional differentiated cells
Show synergistic or additive action with other growth factors
May have multiple actions
How to extract bone marrow
Take it from the iliac crest
Need two needles: one to break through the cortical bone and aspirate, and a second larger hollow Boar needed to extract the tissue
Erythropoiesis
Key factors: erythropoietin, GM-CSF, IL-3, IL-11
Maturation characteristics: nuclear condensation with ultimate extrusion of the nucleus, change of cytoplasm from deep basophilic, organelle rich substance, to a cytoplasm that consists almost entirely of hemoglobin
Rate: 3-4x10^9 cell/kh/day
Live 120 days
At the beginning the precursors have a lot of mRNA - will stain one colour
Later on they have a lot of hemoglobin and that will stain with eosin 1 - shift in colour from deep blue to purplish pink
Erythropoiesis morphological changes
Cytoplasm changes from blue to orange (decrease in RNA, increase in hemoglobin)
Nucleus becomes smaller (chromatin pattern more compact than expelled out of the cells)
5 stages of erythropoiesis
- Proerythroblast
- Basophilic erythroblast
- Polychromatic erythroblasts
- Orthochromatic erythroblasts
- Nuclear expulsion
Erythroid island
Macrophages store iron to give to the RBC precursors They also phagocytose the extruded nuclei
So they have to be in the islands
Erythropoietin
Erythropoietin made in the kidney
If there is less O2 flowing into the kidney it will activate cells and they will produce it
Find its way to marrow and stimulates precursors to enhance production of red cells
The reticulocytes will get pushed out to try to compensate for sudden anemia
Will take 5 days, so wont see results of increasing production until then
Thrombopoiesis
Key factors: thrombopoietin, GM-CSF, IL-3/6, EPO
Maturation characteristics: increase size and DNA content, nuclear division without cell division, increase nuclear lobulations, development of demarcation membranes and cytoplasmic granules, platelet release
Platelets survive 10 days
Thrombopoiesis stages
5
Promegakaryoblast Megakaryoblast Promegakaryocyre Granular megakaryocyte Platelet producing megakaryocyte
Thrombocytopenia in liver failure
Liver produces thrombopoietin
Patients with liver failure often have decreased platelet count (thrombocytopenia) and are at risk for bleeding
Liver makes the coagulation factor
Granulopoiesis
Key regulatory factors: GM-CSF, G-CSF, IL-3
Maturation characteristics: nuclear segmentation, acquisition of primary and then secondary granules
Negative feedback inhibition by mature forms
Eosinophil and basophil maturation are similar
2 maturation characteristics for granulopoiesis
Nuclear segmentation
Acquisition of primary and then secondary granules
“Left shift”
If you have a really bad infection then more immature granulocytes will be released to help
So left shift refers to having more precursors in the blood
6 stages of granulopoiesis
- Myeloblast: production of primary granules
- Promyelocyte: largest cell, numerous primary granules, paranuclear hoff (lots of protein synthesis)
- Myelocyte: last stage with proliferative potential, secondary granule formation
- Metamyelocyte: nuclear indentation, more secondary than primary granules
- Band: horse shoe nucleus (when segmentation is more than half)
- Segmented neutrophils
Monocytopoiesis
progenitor, key factor, maturation characteristics, stages (3)
Same progenitor cell as for segmented neutrophil
Key factors: M-CSF
Maturation characteristics: gradual nuclear folding, acquisition of cytoplasmic granules
Stages: monoblast, promonocyte, mature monocyte
Acute myeloid leukemia
Stem cells and progenitor cells have self renewal and maturation property (maturation shuts off self renewal)
Mutations that preserve self renewing but interfere with maturation lead to continuous proliferation of immature daughter cells
These eventually take over the bone marrow and lead to acute myeloid leukemia
Symptoms: anemia, depressed immunity, bleeding
Lymphopoiesis
T, B and NK cells arise from same stem cell
Key factors: IL2/3/4/7
Stages of maturation defined by surface antigen rather than morphologic
B cells mature from their progenitors within the bone marrow
T cell progenitors first mature into thymocytes (in bone marrow), then migrate to thymus where they mature into T cells
Light chain versus heavy chain rearrangement
Light: only V and J regions
Heavy: V, D and J regions
Genes involved in recombination
RAG-1 and 2
Recombinase activated gene
3 outcomes of B cell maturation
- Apoptosis (no functional Ig)
- Mature B cell (does not bind to self antigens)
- Receptor editing (binds to self antigens)
Burkitt lymphoma
Form of non-Hodgkin’s lymphoma in which cancer starts B-cells
Fastest growing tumor
Caused by a translocation between chromosome 8 (gene to go into cell cycle) and 14 (heavy chain enhancer that is always on)
Follicular lymphoma
Too many B cells
Translocation between chromosome 14 (enhancer region) and 18 (has Bcl-2)
Unopposed production of anti-apoptotic gene
What regions are on chromosome 8 14 18 that are important in either Burkitt's lymphoma or follicular lymphoma
8: promotes cell going in to cell cycle
14: heavy chain enhancer region
18: anti-apoptosis
Burkitt: 8:14 translocation
Follicular: 14:18 translocation
