Haemopoiesis

Haemopoiesis
■ Site of haemopoiesis
■ Haemopoietic stem and progenitor cells
■ Bone marrow stroma
■ The regulation of haemopoiesis
■ Haemopoietic growth factors
This chapter is concerned with the general aspects of blood cell
formation (haemopoiesis).
The processes that regulate haemopoiesis and the early stages of
formation of red cells (erythropoiesis), granulocytes and monocytes
(myelopoiesis) and platelets (thrombopoiesis) are also discussed.
Site of haemopoiesis 1
In the first few weeks of gestation, the yolk sac is a transient site of
haemopoiesis. However, definitive haemopoiesis derives from a
population of stem cells first observed on the AGM
(aorta‐gonads‐mesonephros) region.
These common precursors of endothelial and haemopoietic cells
(haemangioblasts) are believed to seed the liver, spleen and bone
marrow.
From 6 weeks until 6–7 months of fetal life, the liver and spleen are the
major haemopoietic organs and continue to produce blood cells until
about 2 weeks after birth.
Site of haemopoiesis 2
The placenta also contributes to fetal haemopoiesis.
The bone marrow is the most important site from 6–7 months of fetal
life.
During normal childhood and adult life the marrow is the only source of
new blood cells.
The developing cells are situated outside the bone marrow sinuses;
mature cells are released into the sinus spaces, the marrow
microcirculation and so into the general circulation.
Site of haemopoiesis 3
In infancy all the bone marrow is haemopoietic but during childhood
there is progressive fatty replacement of marrow throughout the long
bones so that in adult life haemopoietic marrow is confined to the
central skeleton and proximal ends of the femurs and humeri.
Even in these haemopoietic areas, approximately 50% of the marrow
consists of fat.
The remaining fatty marrow is capable of reversion to haemopoiesis
and in many diseases there is also expansion of haemopoiesis down
the long bones.Moreover, the liver and spleen can resume their fetal
haemopoietic role (‘extramedullary haemopoiesis’).
Haemopoietic stem and progenitor cells 1
Haemopoiesis starts with a pluripotential stem cell that can by
asymmetric cell division self‐renew but also give rise to the separate
cell lineages.
These cells are able to repopulate a bone marrow from which all stem
cells have been eliminated by lethal irradiation or chemotherapy.
This haemopoietic stem cell (HSC) is rare, perhaps 1 in every 20 million
nucleated cells in bone marrow.
Haemopoietic stem and progenitor cells 2
The stem cell has the capability for self‐renewal so that marrow
cellularity remains constant in a normal healthy steady state.
There is considerable amplification in the system: one stem cell is
capable of producing about 106 mature blood cells after 20 cell
divisions.
In humans HSCs are capable of about 50 cell divisions.
Under normal conditions most are dormant.
Haemopoietic stem and progenitor cells 3
With aging, the number of stem cells falls and the relative proportion
giving rise to lymphoid rather than myeloid progenitors also falls.
Stem cells also accumulate genetic mutations with age, and these may
be present in tumours arising from these stem cells.
The precursor cells are capable of responding to haemopoietic growth
factors with increased production of one or other cell line when the
need arises.
Normal bone marrow trephine biopsy (posterior iliac crest).
Haematoxylin and eosin stain; approximately 50% of the
intertrabecular tissue is haemopoietic tissue and 50% is fat.
Baso, basophil; BFU, burst‐forming unit; CFU, colony‐forming unit; E, erythroid; Eo, eosinophil; GEMM, granulocyte,
erythroid, monocyte and megakaryocyte; GM, granulocyte, monocyte; Meg, megakaryocyte; NK, natural killer.
Bone marrow stroma 1
The bone marrow forms a suitable environment for stem cell survival,
self‐renewal and formation of differentiated progenitor cells.
The stromal cells include mesenchymal stem cells, adipocytes,
fibroblasts, osteoblasts, endothelial cells and macrophages and they
secrete extracellular molecules such as collagen, glycoproteins and
glycosaminoglycans to form an extracellular matrix.
In addition, stromal cells secrete several growth factors necessary for
stem cell survival.
Bone marrow stroma 2
Stem cells are able to traffic around the body and are found in
peripheral blood in low numbers.
In order to exit the bone marrow, cells must cross the blood vessel
endothelium and this process of mobilization is enhanced by
administration of growth factors such as granulocyte colony‐stimulating
factor (G‐CSF).
The regulation of haemopoiesis
Haemopoiesis starts with stem cell division in which one cell replaces
the stem cell (self‐renewal) and the other is committed to
differentiation.
Which cell lineage is selected for differentiation may depend both on
chance and on the external signals received by progenitor cells.
Haemopoietic growth factors 1
The haemopoietic growth factors are glycoprotein hormones that
regulate the proliferation and differentiation of haemopoietic
progenitor cells and the function of mature blood cells.
The growth factors may cause cell proliferation but can also stimulate
differentiation, maturation, prevent apoptosis and affect the function
of mature cells.
Haemopoietic growth factors 2
Stromal cells are the major source of growth factors except for
erythropoietin, 90% of which is synthesized in the kidney, and
thrombopoietin, made largely in the liver.
An important feature of growth factor action is that two or more
factors may synergize in stimulating a particular cell to proliferate or
differentiate.
Moreover, the action of one growth factor on a cell may stimulate
production of another growth factor or growth factor receptor.
Growth factors may stimulate proliferation of early bone marrow cells, direct differentiation to one or other
cell type, stimulate cell maturation, suppress apoptosis or affect the function of mature non‐dividing cells, as
illustrated here for granulocyte colony‐stimulating factor (G‐CSF) for an early myeloid progenitor and a
neutrophil.
Haemopoietic growth factors 3
These factors maintain a pool of haemopoietic stem and progenitor
cells on which later‐acting factors, erythropoietin, G‐CSF, macrophage
colony‐stimulating factor (M‐CSF), IL‐5 and thrombopoietin, act to
increase production of one or other cell lineage in response to the
body’s need.
Granulocyte and monocyte formation, for example, can be stimulated
by infection or inflammation through release of IL‐1 and tumour
necrosis factor (TNF).
In contrast, cytokines, such as transforming growth factor‐β (TGF‐β)
and γ‐interferon (IFN‐γ), can exert a negative effect on haemopoiesis
and may have a role in the development of aplastic anaemia.
CSF, colony‐stimulating factor;
FLT3‐L, FLT3 ligand; G‐CSF,
granulocyte colonystimulating factor;
GM‐CSF, granulocyte–macrophage
colony‐stimulating factor; IL,
interleukin; M‐CSF, macrophage
colony‐stimulating factor; SCF, stem
cell factor; TNF, tumour necrosis
factor; VEGF, vascular endothelial
growth factor.
* These also act synergistically with
early acting factors on pluripotential
progenitors.