Hematopoiesis Flashcards
what produces hematopoietic stem cells (HSCs) and endothelial cells?
common embryonic stem cells called hemangioblasts
where do embryonic hematopoietic stem cells (HSCs) originate?
in the yolk sac and aorta-gonad-mesenephros (AGM) region of the embryo
what species is the exception when it comes to blood cell types in utero?
cats - they produce a wider spectrum of blood cell types
describe the appearance of embryonic cells
they are huge and nucleated
when does bone marrow organization begin?
during the second trimester
describe bone development in 4 steps
- *
1. cartilage is calcified
2. chondroclasts degrade mineralized cartilage
3. vessels invade marrow space that is created
4. osteoblasts form bony trabeculae - *
what two things form a connective tissue meshwork?
- vascular sinuses
2. extravascular mesenchymal stromal cells
when do hematopoietic cells from liver form circulating blood cells?
once hematopoietic microenvironment forms
what is extravascular space?
space between the vascular sinuses in bone marrow
what does extravascular space create?
a hematopoietic microenvironment
what does the extravascular space contain?
- stromal elements (cells and extracellular matrix)
- osteoclasts, plasma cells, mesenchymal stem cells, mast cells (rare)
- accessory cells for hematopoiesis
- hematopoietic cells
what cells are produced in the vascular space in birds?
erythrocytes and thrombocytes
where are all blood cells created in mammals? where do blood cells then go?
in extravascular space. they then have to migrate through the endothelium and into sinus, then circulatory system once its developed
where are quiescent hemaopoietic stem cells (HSCs) concentrated?
near endosteal and trabecular bone (osteoblasts)
where are more active HSCs and hematopoietic cells found?
near vascular sinuses
where are erythroid cells found?
around macrophages
where are megakaryocytic cells found?
near sinusoidal endothelial cells
where are granulocytic cells found?
near stromal cells located away from vascular sinuses
what cells are found in bone marrow stroma (connective tissue)?
- endothelial cells
- stromal cells
- adipocytes
- autonomic nerves
- extracellular matrix
what is the function of bone marrow endothelial cells?
they synthesize hematopoietic growth factors
what do bone marrow endothelial cells regulate?
** they regulate transendothelial movement of cells to and from the extracellular space**
what do bone marrow endothelial cells and stromal cells produce?
extracellular matrix components
describe some characteristics of bone marrow stromal cells
- fibroblastic-type or vascular smooth muslce like cells
- extensive branched cytoplasmic processes that provide structural support for the bone marrow
what is the function of bone marrow stromal cells?
** they synthesize collagen fibers and other extracellular matrix components **
what is the function of adventitial stromal cells in bone marrow?
they support the endothelium of the venous sinuses
** how do bone marrow stromal cells support hematopoiesis? **
** through cell-to-cell contacts and synthesis of growth factors **
what do bone marrow adipocytes develop from?
stromal cells
** what is the main function of bone marrow adipocytes? **
they accumulate increased lipid when the numbers of hematopoietic cells in the marrow decrease (reversible)
what is the main function of nerves in bone marrow?
largely vasomotor in function
** what may nerves in bone marrow promote ? **
** HSC mobilization **
what might nerves in bone marrow do (we are not sure)?
regulate hematopoietic growth factor synthesis by other cells
what is the function of collagen fibers in the extracellular matrix?
provide scaffolding
what does the extracellular matrix consist of?
collagen fibers
basal laminae of the sinuses
adhesion molecules
proteoglycans
which accessory cells are involved in regulating hematopoiesis that reside in the extravascular space of bone marrow?
- macrophages
- T-lymphocytes, B-lymphocytes, and NK cells
- osteoblasts
which accessory cell is most important for erythropoiesis?
macrophages
what is the function of the various lymphocytes and NK cells in the extravascular space of bone marrow?
some produce positive growth factors
other subsets produce factors that inhibit proliferation of hematopoietic cells
what are osteoblasts important for in the extravascular space of bone marrow?
stem cell maintenance
** what are HSCs positive for?**
** the CD34 surface antigen **
what is the appearance of HSCs and HPCs? (hematopoietic stem cells and hematopoietic progenitor cells)
they are lymphocyte-like in appearance
** what is CD an abbreviation for ? **
** clusters of differentiation antigens **
what is the function of hematopoietic stem cells?
- proliferation and sustained self-replication
**what do hematopoietic stem cells (HPCs) have the capacity to do? **
** to differentiate into all blood cell types and some tissue cell types (like macrophages, dendritic cells, osteoclasts, mast cells) **
briefly describe the cell cycle (G1, S, G2, M, Go)
G1 = protein synthesis and preparation of DNA replication S = DNA synthesis G2 = protein synthesis and preparation for mitosis M = mitosis Go = resting phase
what is the function of hematopoietic progenitor cells (HPCs)?
proliferation, they replicate more rapidly than HSCs
describe the replication of hematopoietic progenitor cells
limited self-replication - not sustained without replenishment from HSCs
describe the differentiation of hematopoietic stem cells
more restricted lineage potential than HSCs
describe the amounts of HPCs relative to HSCs
- hamatopoietic progenitor cells are much more common in neonates than adults. HPCs represent about 1% of bone marrow cells in adults *
what do HSCs produce?
- common lymphoid progenitor cells (CLP)
- common myeloid progenitor cells (CMP)
what do CLPs (common lymphoid progenitors) give rise to?
B lymphocytes, T lymphocytes and NK cells
what do CMPs (common myeloid progenitors) give rise to?
non lymphoid blood cells, macrophages, dendritic cells, osteoclasts and mast cells
what are colony forming units (CFUs)?
progenitor cells that are recognized in bone marrow cultures by the types of colonies they form
what are some examples of colony forming units (CFUs)?
- common myeloid progenitor
- GM progenitor
- erythroid progenitors
what types of cells do mesenchymal stem cells produce?
- stromal cells and adipocytes
- endothelial cells
- fibroblasts and myoblasts
- osteoblasts and chrondrocytes
what can additional stem cells in marrow grow?
- hepatocytes and cholangiocytes
- **neural cells **
- epithelial cells of skin and GI tract
define homing of HSCs and HPCs
the process by which circulating HSCs and HPCs bind to luminal surfaces of endothelial cells in the bone marrow
what is the process of homing of HSCs and HPCs
- migrate through endothelial cells
- migrate through extravascular space and bind to appropriate microenvironment location
- proliferate, self-replicate and differentiate
what is the most important adhesion molecule?
beta-1-integrin
what do adhesion molecules do?
they bind to glycoproteins including VCAM-1 in ECM
**what type of adhesion molecules do hematopoietic cells express on their surface? **
** it varies depending on the hematopoietic cell**
what does the binding of hematopoietic cells to ECM glycoproteins play a role in?
**activating signal pathways for cell growth, survival and differentiation or modulating responses to growth factors **
describe the appearance of proteoglycans
they have a protein core with negatively charged repeating charbohydrate glycosaminoglycans (GAGs) such as chondroitin sulfate
what is the function of proteoglycans?
they bind growth factors and strengthen the bonding of hematopoietic cells through binding with receptors on hematopoietic cells
what are hematopoeitic growth factors?
they are glycoproteins that promote the proliferation, maturation and survival of hematopoietic cells
** where are hematopoietic growth factors produced? **
** locally in the marrow (paracrine and autocrine) and/or by cells in peripheral tissues (endocrine) **
what do cytokines include?
colony stimulating factors (CSFs), interleukins, and poietins
what must hematopoietic cells have?
**an appropriate surface receptor to respond to a specific hematopoeitic growth factor **
what does binding and activation of hematopoietic growth factor receptors do? (4 things)
- generation of transcription factors
- synthesis of molecules that inhibit apoptosis
- formation of cell cycle regulators (cyclins)
- **synthesis of additional HGF and HGF receptors **
what is an identifying characteristic in the cell types or stages stimulated by hematopoietic growth factors (HGFs)?
**there is considerable redundancy and overlap in the cell types or stages stimulated by HGFs **
what are some examples of early-acting factors within HGFs?
- stem cell factor
- flt3 ligand (FL)
- thrmbopoietin (TPO)
what do early-acting factors require the presence of?
other cytokines including IL3, IL6, IL11 and G-CSF
what are some examples of intermediate-acting HGF factors?
IL3 (multi-CSF), GM-CSF, and IL-4
what are some examples of late acting HGFs?
G-CSF, M-CSF, EPO, TPO, and IL5
define indirect stimulation
TNF and IL1 stimulate stromal and accessory cells to release various HGFs
what can CMP give rise to? what can that then differentiate into?
CMP can give rise to MkEP which can differentiate into MkP (megakaryocyte progenitors) and EPs (erythroid progenitors)
what is the production of EP (erythroid progenitors) stimulated by?
SCF, IL-3, GM-CSF, and TPO in presence of EPO
where do erythroid cells develop?
around macrophages
what do macrophages help create?
microenvironment
in what ways do macrophages help create a microenvironment?
- early intermediate-acting growth factors
- erythropoietin
- inflammatory cytokines which can inhibit erythropoiesis
what is the function of erythroid islands?
** they phagocytize expelled nuclei and damaged or aged erythrocytes **
what do erythroid islands store from phagocytized erythrocytes?
iron
what nutrients are needed for erythropoiesis?
amino acids
essential fatty acids
metals
vitamins
name some examples of metals needed as nutrients for erythropoiesis
iron - for heme synthesis
copper - hephaestin, ceruplasmin
cobalt - component of B12
name some examples of vitamins needed for erythropoiesis
vitamin B6 - heme synthesis
tetrahydrofolic acid - DNA, RNA synthesis
vitamin B12 - folate metabolism
in what step of the maturational divisions is marrow released?
during the development of reticulocytes
when are reticulocytes formed?
when metarubicytes expel their nuclei, usually while still bound to macrophages
how many reticulocytes can be formed by one rubiblast?
one rubiblast produces about 16 reticulocytes in about 4 days
where does reticulocyte maturation occur?
in marrow, blood, and spleen
what type of reticulocytes do dogs have in blood?
aggregate reticulocytes
what type of reticuolcytes do cats have in blood?
many punctate reticulocytes, sometimes no aggregate reticulocytes
what type of reticuolcytes do cattle and goats have in blood?
none
what type of reticuolcytes do sheep have in blood?
small numbers of punctate reticulocytes
what type of reticuolcytes do horses have in blood?
none, even in response to anemia
what are howell-jolly bodies
small pieces of nuclei that may be left behind in teh cell after nuclear extrusion
how do H-J bodies (howell-jolly) form?
either karyorrhexis (fragmentation) of the metaurbricyte nucleus or during abnormal mitosis
which organ removes H-J bodies?
the spleen
what is erythropoietin growth factor?
the principal growth factor that promotes the viability, proliferation and differentiation of EPs expressing specific cell surface EPO receptors
when do EPO receptors peak?
at CFU-E stage and decline
what is the main mechanism of erythropoietin?
inhibition of apoptosis
what is the effect of high concentrations of erythropoietin?
shorten marrow transit time and promote early release of large “stress” reticulocytes
what are the sites of EPO synthesis?
renal interstitial cells
extrarenal production - liver, bone marrow macrophages and erythroid cells
what increases the number of cells producing EPO?
hypoxia
what causes inhibitionof erythropoiesis?
- lack of HGFs
- inhibitors
what are some examples of growth factors?
IL-3, GM-CSF, G-CSF
they act on CMP, GMP and GP
what is the effect of G-CSF? which cells does it effect?
increased cell division, decrease marrow transit time
GPs to myeloblasts
what cells produce growth factors?
T-lymphocytes and mononuclear phagocytes
fibroblasts and endothelial cells
how is granulopoiesis inhibited? (3 ways)
- mature neutrophils in marrow release inhibitory substances like serine proteases
- neutrophil clearance of circulating G-CSF by binding to receptors
- mature neutrophils in peripheral tissues can remove bacterial stimulus for granulopoiesis
how are eosinophils produced (3 ways)?
- marrow storage pool like neutrophils
- IL-3 and GM-CSF for early progenitors
- **IL-5 from Th2 lymphocytes for terminal maturation **
how are basophils produced? (4 ways)
- GMP produces bipotential basophil/mast cell progenitor
- basophil progenitor for basophils
- granules at myelocyte stage
- ** specific factor not recognized - growth factors similar to those for eosinophils**
how are mast cells produced (3 ways)?
- mast cell progenitor (MaP)
- mast cells develop in tissues
- SCF is especially important for mast cell formation, multiple cytokines involved
what are examples of growth factors used for the production of monocytes?
IL-3, GM-CSF, M-CSF, and IL-34
what is an unique characteristic about monocytopoiesis?
short generation time and little marrow reserve
what may monocytes become?
macrophages or inflammatory dendritic cells in tissues, depending on the amounts of various cytokines present
what does CDP form?
pre-classical dendritic cells and plasmacytoid dendritic cells
where are CDP products released?
into the blood and enter the tissues
what stimulates production of CDP?
various cytokines
what are osteoclasts?
multinucleated cells which degrade bone
what do osteoclasts develop from?
monocyte progenitors
what are SCF and flt3 ligand?
early lymphoid progenitor cells in marrow
where are most B-cells produced in mammals? birds?
in mammals - mostly marrow.
dogs, pigs, ruminants - peyer’s patches
in birds - bursa of fabricius
where are T-cells produced?
in the thymus
progenitors in the marrow
final development in thymus
what is the most important growth factor needed for B-lymphocyte production?
Il-7
what inhibits B-lymphocyte production
certain cytokines including interferons
where do activated B-lymphocytes migrate to?
cortex of lymph nodes and follicles in peyer’s patches and spleen
what may B-lymphocytes developinto?
mature plasma cells
what growth factors promote development of T-lymphocyte production?
Flt3L and IL-7
where do T-lymphocytes accumulate?
in paracortical areas of lymph nodes
periarteriolar lymphoid sheaths of spleen
interfollicular areas of peyer’s patches
where are NK cells primarily produced? are growth factors required?
in bone marrow
yes
where do subsets of NK cells develop?
thymus, lymph nodes, liver and spleen
do non-mammals have megakaryocytes?
no; the only giant cell in the marrow is the osteoclast
where is the megakaryocyte niche located?
just outside the vascular sinuses
what stimulates thrombopoiesis
proliferation and expansion of megakaryocyte progenitor cells
what are the 2 main functions of thrombopoietin?
- promotes differentiation of progenitor cells into megakaryocytes
- stimulates increased endomitosis, results in increased ploidy and size
where is the major site of thrombopoietin production?
endothelial cells of liver
where are TPO (thrmbopoietin) receptors located and what do they do?
located on platelets and megakaryocytes, they bind and remove TPO, providing negative feedback
what stimulates thrombopoietin (TPO) synthesis by liver during inflammation?
IL-6
