kevin (L5) Flashcards
haematopoiesis
Haematopoiesis
- highly organised differentiation process
- ordered expression of different sets of genes
Controlled by factors in the environment of the developing blood cell – the bone marrow in adults
haematopoietic stem cell
Mature blood cells in healthy individuals mostly have short lifetimes (exception: lymphocytes) and are constantly regenerated in the bone marrow.
we make 5 x 1011 blood cells daily
This is accelerated when there is haematological stress
e. g. infection, need more leukocytes
e. g. high altitude, need more red cells.
haematopoiesis in embryo (per week)
Haematopoiesis begins at a very early stage in embryonic development, at about 3 weeks in the human.
At that time the cells in the embryo separate into 2 sets, one generating the embryo proper & all the tissues of the adult, the other forming the YOLK SAC (aka vitelline sac) which is the site where blood cells and blood vessels are first formed.
yolk sac
DIAGRAMS IN L5-S6
5 week foetus
The yolk sac joined to the embryo by a stalk.
Contains mesoderm derived cells
“haemangioblasts”
Differentiate to form (nucleated) red blood cells and endothelial cells which generate a capillary system (“plexus”) within the yolk sac.
what starts forming at 5 weeks
Heart is fully formed - liver started forming too
Mesoderms cells make up the stork - have a set of stem cells that from red blood cells which have nuclei (for first month)
Generate a capillary system in yolk sac
Heart pumps blood through the yolk sac
At the same time the heart and aorta start to form: these join up with the capillary plexus and the erythrocytes start to circulate.
where does the late stage occur?
At a later stage of embryogenesis haematopoiesis occurs mainly in the liver and at birth shifts to the bone marrow (BM).
Described as definitive unlike the early primitive haematopoiesis occurring in the yolk sac.
Now, the entire range of blood cells found in the adult are produced.
Bone Marrow
The BM is in effect a highly specialised tissue comprising a range of cells
- some of which (haematopoietic cells) form blood cells
- others (stromal cells) provide support functions for the haematopoietic cells, providing the specialised environment needed for haematopoiesis to occur.
- Yet other cells (osteoblasts and osteoclasts) are concerned with producing the bone itself.
what happens during an immune response?
(Bear in mind that cells of the immune system undergo further proliferation and differentiation in the periphery – especially in secondary lymphoid tissue – during immune responses: one of the purposes of haematopoiesis is to generate cells which are capable of responding to pathogens.)
where does haematopoiesis occur?
haematopoiesis occurs in bones bones are: - a source of skeletal rigidity - reservoir of Ca2+ and PO4 3- - haematopoietic organs
Adults made mostly in the bone marrow of the vertebrae (the bones that make up the spine), ribs, pelvis, skull, sternum (the breastbone), and parts of the humerus (the upper arm bone) and femur (the thigh bone).
major sites of blood
Major sites of the blood come from the vertebrae, ribcage, sternum, pelvis, parts of the femur, and parts of the ilium bones
bones
(Bone marrow is made in epiphyseal of the femur)
Bone is a specialised form of connective tissue (mesodermal/mesenchymal origin) with an extracellular matrix (ECM) which is rigid
Rigid outer layer of dense compact (aka cortical) bone, 70% hydroxyapatite (hydrated calcium phosphate)
Inner core of much less dense spongy bone (aka cancellous, trabecular).
Diaphysis is largely made of fat - as soon as the fat grows and over proliferates in medullary cavity, the stem cell stop dividing
Endosteum → exists in both the diaphysis and the epiphysis
There is a niche for the homeopathic stem cells on the endosteum that is in lining of the bone cavity
osteon
The osteon is the unit structure of compact bone made up of concentric mineralised lamellae around a central (Haversian) canal.
Unit of bone is osteon - made up of canaliculi
Holes in bone are blood vessels
Permeated through the outer coat, the periosteum, and they invaginate into the spongy bone area
We have vertical tracts - called haversian canal
We have horizontal tracts - called volkmann’s canal
DIAGRAM IN L5 S14
structure of bones cnotrolled by?
Structures are controlled by osteoblasts and osteoclasts
They are adding cells
When the cells are there they excrete a mineral salt (calcium appetite)
This makes the solidity and strength of the bones
bone marrow
The bone marrow (BM) is within the medullary cavity & spongy bone.
It is intensely cellular because that is where blood cells are produced.
Two kinds, red and yellow
- red in flat bones and at the epiphyses of long bones
- yellow in the shafts of long bones.
(Yellow marrow contains lots of fat, especially in older
individuals, & that is why roast BM is so yummy.)
histology of red bone marrow
trabecular bone
granulocytes
megakarocytes
erythroid island
Platelets formed from megakaryocyte cells
These are massive cells that excrude their membrane through the blood vessels and get washed away to form the platelets
Platelets can be activated to form a clot
Diff cell types are so packed together in bone - difficult to differentiate them
There is a niche around the edge
DIAGRAM IN L5 S17
discovery of hematopoietic stem cell
The understanding of the haematopoietic role of bone marrow (BM) started to develop in the 1960s with research on the effects of radiation in animals.
The main cause of death after exposure to ionising radiation is haematological failure.
Transfusion of blood or most lymphoid tissues does not save the animal
Transfusion of BM does.
serial transplants
Repeated serial transplants can be done.
So the HSC is capable of self renewal
- but not for ever: eventually the transplant does not work, indicating that the stem cell is not immortal
- Probably true of all adult stem cells
- cf “Hayflick limit”
- “end replication problem” & telomeres
use of hematopoietic stem cell
all blood cell types could be derived from single BM cells.
haematopoietic stem cells (HSCs) are the multipotent parental cell type for ALL blood cells and probably also endothelium.
experiments demonstrating multipotency
The experiments demonstrating multipotency depended on irradiating the BM cells used to reconstitute the mice with SMALL doses of radiation, not enough to kill the cells but enough to cause minor chromosome alterations (“chromosomal markers”) in rare cells
results of experiment
In some individual transplanted mice there could be found cells of all leukocyte types bearing the same marker
In other mice, ALL myeloid but NOT lymphoid cells had the same marker
And in yet others ALL lymphoid but NOT myeloid cells had the same marker
conclusion of experiment
This implied that there were also stem cells of more restricted potency
capable of producing EITHER myeloid OR lymphoid cells
these are now known as common lymphoid progenitor or common myeloid progenitor cells
CLP & CMP.
These can be thought of as transit amplifying cells.
HSC used as marker
Each marker is unique;
all descendants of a marked cell (a CLONE) have the same maker.
Hence if particular cells in a mouse all heave the same marker they are all descended from the same stem cell.
so what can the HSC turn into
HSC:
- Common Lymphoid Progenitor –> lymphocytes
- Common Myeloid Progenitor –> granulocytes / erythrocytes / thrombocytes
- transit amplifying cells –> end cells (differentiated)
