Haematopoiesis

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Diagram showing the development of different blood cells from haematopoietic stem cell to
mature cells

Haematopoiesis (/hɪˌmætoʊpɔɪˈiːsɪs, ˈhiːmətoʊ-, ˌhɛmə-/,[1] from Greek αἷμα,
"blood" and ποιεῖν "to make"; also hematopoiesis in American English;
sometimes also h(a)emopoiesis) is the formation of blood cellular components.
All cellular blood components are derived from haematopoietic stem cells.[2] In a
healthy adult person, approximately 1011–1012 new blood cells are produced daily
in order to maintain steady state levels in the peripheral circulation.[3][4]

Contents

 1Process
o 1.1Haematopoietic stem cells (HSCs)
o 1.2Cell types
o 1.3Terminology
 2Location
o 2.1Extramedullary
 3Maturation
o 3.1Cell fate determination
o 3.2Growth factors
o 3.3Transcription factors
 o 3.4Myeloid-based model
 4Other animals
 5See also
 6References
 7Further reading
 8External links

Process[edit]
Haematopoietic stem cells (HSCs)[edit]
Main article: Hematopoietic stem cell
Haematopoietic stem cells (HSCs) reside in the medulla of the bone (bone
marrow) and have the unique ability to give rise to all of the different mature
blood cell types and tissues.[2] HSCs are self-renewing cells: when they
differentiate, at least some of their daughter cells remain as HSCs, so the pool of
stem cells is not depleted. This phenomenon is called asymmetric division.[5] The
other daughters of HSCs (myeloid and lymphoid progenitor cells) can follow any
of the other differentiation pathways that lead to the production of one or more
specific types of blood cell, but cannot renew themselves. The pool of
progenitors is heterogeneous and can be divided into two groups; long-term self-
renewing HSC and only transiently self-renewing HSC, also called short-terms.
[6]
 This is one of the main vital processes in the body.
Cell types[edit]
All blood cells are divided into three lineages.[7]

 Red blood cells, also called erythrocytes, are the

oxygen-carrying cells. Erythrocytes are functional and
are released into the blood. The number of
reticulocytes, immature red blood cells, gives an
estimate of the rate of erythropoiesis.
 Lymphocytes are the cornerstone of the adaptive
immune system. They are derived from common
lymphoid progenitors. The lymphoid lineage is
composed of T-cells, B-cells and natural killer cells.
This is lymphopoiesis.
 Cells of the myeloid lineage, which
include granulocytes, megakaryocytes and macrophag
es, are derived from common myeloid progenitors, and
are involved in such diverse roles as innate
immunity and blood clotting. This is myelopoiesis.
Granulopoiesis (or granulocytopoiesis) is haematopoiesis of granulocytes, except
of mast cells which are granulocytes but with an extramedullar maturation.[8]
Megakaryocytopoiesis is haematopoiesis of megakaryocytes.
Terminology[edit]
Between 1948 and 1950, the Committee for Clarification of the Nomenclature of
Cells and Diseases of the Blood and Blood-forming Organs issued reports on the
nomenclature of blood cells.[9][10] An overview of the terminology is shown below,
from earliest to final stage of development:

 [root]blast
 pro[root]cyte
 [root]cyte
 meta[root]cyte
 mature cell name
The root for erythrocyte colony-forming units (CFU-E) is "rubri", for granulocyte-
monocyte colony-forming units (CFU-GM) is "granulo" or "myelo" and "mono", for
lympocyte colony-forming units (CFU-L) is "lympho" and for megakaryocyte
colony-forming units (CFU-Meg) is "megakaryo". According to this terminology,
the stages of red blood cell formation would be: rubriblast, prorubricyte, rubricyte,
metarubricyte, and erythrocyte. However, the following nomenclature seems to
be, at present, the most prevalent:

Commi "lympho "megakaryo

"rubri" "granulo" or "myelo" "mono"
ttee " "

Lineag Lymphoi
Myeloid Myeloid Myeloid Myeloid
e d

CFU-
CFU- GEMM CFU-
CFU-GEMM→CFU-
CFU CFU-L GEMM→ →CFU- GEMM→C
GM→CFU-G
CFU-E GM→C FU-Meg
FU-M

lymphocy erythropoi monocyt thrombocyto

Process granulocytopoiesis
topoiesis esis opoiesis poiesis
[root]b Lymphob Proerythro Monobla Megakaryobl
Myeloblast
last last blast st ast

Polychro
pro[roo Prolymph matophilic Promono Promegakary
Promyelocyte
t]cyte ocyte erythrocyt cyte ocyte
e

[root]c Normobla Eosino/neutro/basophilic Megakaryoc

–
yte st myelocyte yte

Eosinophilic/neutrophilic/ba
meta[r Early
Large ly Reticuloc sophilic metamyelocyte,
oot]cyt monocyt -
mphocyte yte Eosinophilic/neutrophilic/ba
e e
sophilic band cell

mature
Small ly Erythrocyt granulocytes (Eosino/neutro Monocyt thrombocyte
cell
mphocyte e /basophil) e s (Platelets)
name

Osteoclasts also arise from hemopoietic cells of the monocyte/neutrophil lineage,

specifically CFU-GM.

Location[edit]
Main article: Haematopoietic system

Sites of haematopoesis (human) in pre- and postnatal periods

In developing embryos, blood formation occurs in aggregates of blood cells in the
yolk sac, called blood islands. As development progresses, blood formation
occurs in the spleen, liver and lymph nodes. When bone marrow develops, it
eventually assumes the task of forming most of the blood cells for the entire
organism.[2] However, maturation, activation, and some proliferation of lymphoid
cells occurs in the spleen, thymus, and lymph nodes. In children, haematopoiesis
occurs in the marrow of the long bones such as the femur and tibia. In adults, it
occurs mainly in the pelvis, cranium, vertebrae, and sternum.[11]
Extramedullary[edit]
In some cases, the liver, thymus, and spleen may resume their haematopoietic
function, if necessary. This is called extramedullary haematopoiesis. It may
cause these organs to increase in size substantially. During fetal development,
since bones and thus the bone marrow develop later, the liver functions as the
main haematopoetic organ. Therefore, the liver is enlarged during development.
[12]

Maturation[edit]

More detailed and comprehensive diagram that shows the development of different blood
cells in humans.

 The morphological characteristics of the hematopoietic

cells are shown as seen in a Wright’s stain, May-Giemsa
stain or May-Grünwald-Giemsa stain. Alternative names of
certain cells are indicated between parentheses.
  Certain cells may have more than one characteristic
appearance. In these cases, more than one representation
of the same cell has been included.
 Together, the monocyte and the lymphocytes comprise the
agranulocytes, as opposed to the granulocytes (basophil,
neurtophil and eosinophil) that are produced during
granulopoiesis.
 B., N. and E. stand for Basophilic, Neutrophilic and
Eosinophilic, respectively – as in Basophilic promyelocyte.
For lymphocytes, the T and B are actual designations.

1. The polychromatic erythrocyte (reticulocyte) at the right

shows its characteristic appearance when stained with
methylene blue or Azure B.
2. The erythrocyte at the right is a more accurate
representation of its appearance in reality when viewed
through a microscope.
3. Other cells that arise from the monocyte: osteoclast,
microglia (central nervous system), Langerhans cell
(epidermis), Kupffer cell (liver).
4. For clarity, the T and B lymphocyte are split to better
indicate that the plasma cell arises from the B-cell.
Note that there is no difference in the appearance of B-
and T-cells unless specific staining is applied.

As a stem cell matures it undergoes changes in gene expression that limit the

cell types that it can become and moves it closer to a specific cell type (cellular
differentiation). These changes can often be tracked by monitoring the presence
of proteins on the surface of the cell. Each successive change moves the cell
closer to the final cell type and further limits its potential to become a different cell
type.
Cell fate determination[edit]
Two models for hematopoiesis have been proposed: determinism and stochastic
theory.[13] For the stem cells and other undifferentiated blood cells in the bone
marrow, the determination is generally explained by the determinism theory of
haematopoiesis, saying that colony stimulating factors and other factors of the
haematopoietic microenvironment determine the cells to follow a certain path of
cell differentiation.[2] This is the classical way of describing haematopoiesis.
In stochastic theory, undifferentiated blood cells differentiate to specific cell types
by randomness. This theory has been supported by experiments showing that
within a population of mouse haematopoietic progenitor cells, underlying
stochastic variability in the distribution of Sca-1, a stem cell factor, subdivides the
population into groups exhibiting variable rates of cellular differentiation. For
example, under the influence of erythropoietin (an erythrocyte-differentiation
factor), a subpopulation of cells (as defined by the levels of Sca-1) differentiated
into erythrocytes at a sevenfold higher rate than the rest of the population.
[14]
 Furthermore, it was shown that if allowed to grow, this subpopulation re-
established the original subpopulation of cells, supporting the theory that this is a
stochastic, reversible process. Another level at which stochasticity may be
important is in the process of apoptosis and self-renewal. In this case, the
haematopoietic microenvironment prevails upon some of the cells to survive and
some, on the other hand, to perform apoptosis and die.[2] By regulating this
balance between different cell types, the bone marrow can alter the quantity of
different cells to ultimately be produced.[15]
Growth factors[edit]

Diagram including some of the important cytokines that determine which type of blood cell
will be created.[16] SCF= Stem cell factor Tpo= Thrombopoietin IL= Interleukin GM-
CSF= Granulocyte Macrophage-colony stimulating factor Epo= Erythropoietin M-
CSF= Macrophage-colony stimulating factor G-CSF= Granulocyte-colony stimulating
factor SDF-1= Stromal cell-derived factor-1 FLT-3 ligand= FMS-like tyrosine kinase 3 ligand
TNF-a = Tumour necrosis factor-alpha TGFβ = Transforming growth factor beta [17]

Red and white blood cell production is regulated with great precision in healthy
humans, and the production of leukocytes is rapidly increased during infection.
The proliferation and self-renewal of these cells depend on growth factors. One
of the key players in self-renewal and development of haematopoietic cells
is stem cell factor (SCF),[18] which binds to the c-kit receptor on the HSC. Absence
of SCF is lethal. There are other important glycoprotein growth factors which
regulate the proliferation and maturation, such as interleukins IL-2, IL-3, IL-6, IL-
7. Other factors, termed colony-stimulating factors (CSFs), specifically stimulate
the production of committed cells. Three CSFs are granulocyte-macrophage
CSF (GM-CSF), granulocyte CSF (G-CSF) and macrophage CSF (M-CSF).
[19]
 These stimulate granulocyte formation and are active on either progenitor
cells or end product cells.
Erythropoietin is required for a myeloid progenitor cell to become an erythrocyte.
[16]
 On the other hand, thrombopoietin makes myeloid progenitor cells differentiate
to megakaryocytes (thrombocyte-forming cells).[16] The diagram to the right
provides examples of cytokines and the differentiated blood cells they give rise
to.[20]
Transcription factors[edit]
Growth factors initiate signal transduction pathways, which lead to activation
of transcription factors. Growth factors elicit different outcomes depending on the
combination of factors and the cell's stage of differentiation. For example, long-
term expression of PU.1 results in myeloid commitment, and short-term induction
of PU.1 activity leads to the formation of immature eosinophils.[21] Recently, it was
reported that transcription factors such as NF-κB can be regulated
by microRNAs (e.g., miR-125b) in haematopoiesis.[22]
The first key player of differentiation from HSC to a multipotent progenitor (MPP)
is transcription factor CCAAT-enhancer binding protein α (C/EBPα). Mutations in
C/EBPα are associated with acute myeloid leukaemia.[23] From this point, cells
can either differentiate along the Erythroid-megakaryocyte lineage or lymphoid
and myeloid lineage, which have common progenitor, called lymphoid-primed
multipotent progenitor. There are two main transcription factors. PU.1 for
Erythroid-megakaryocyte lineage and GATA-1, which leads to a lymphoid-primed
multipotent progenitor.[citation needed]
Other transcription factors include Ikaros[24] (B cell development),
and Gfi1[25] (promotes Th2 development and inhibits Th1)
or IRF8[26] (basophils and mast cells). Significantly, certain factors elicit different
responses at different stages in the haematopoiesis. For example, CEBPα in
neutrophil development or PU.1 in monocytes and dendritic cell development. It
is important to note that processes are not unidirectional: differentiated cells may
regain attributes of progenitor cells.
An example is PAX5 factor, which is important in B cell development and
associated with lymphomas.[27] Surprisingly, pax5 conditional knock out mice
allowed peripheral mature B cells to de-differentiate to early bone marrow
progenitors. These findings show that transcription factors act as caretakers of
differentiation level and not only as initiators.[28]
Mutations in transcription factors are tightly connected to blood cancers, as acute
myeloid leukaemia (AML) or acute lymphoblastic leukemia (ALL). For example,
Ikaros is known to be regulator of numerous biological events. Mice with no
Ikaros lack B cells, Natural killer and T cells.[29] Ikaros has six zinc
fingers domains, four are conserved DNA-binding domain and two are
for dimerization.[30] Very important finding is, that different zinc fingers are
involved in binding to different place in DNA and this is the reason for pleiotropic
effect of Ikaros and different involvement in cancer, but mainly are mutations
associated with BCR-Abl patients and it is bad prognostic marker.[31]
Myeloid-based model[edit]
For a decade now, the evidence is growing that HSC maturation follows a
myeloid-based model instead of the 'classical' schoolbook dichotomy model. In
the latter model, the HSC first generates a common myeloid-erythroid progenitor
(CMEP) and a common lymphoid progenitor (CLP). The CLP produces only T or
B cells. The myeloid-based model postulates that HSCs first diverge into the
CMEP and a common myelo-lymphoid progenitor (CMLP), which generates T
and B cell progenitors through a bipotential myeloid-T progenitor and a myeloid-B
progenitor stage. The main difference is that in this new model, all erythroid, T
and B lineage branches retain the potential to generate myeloid cells (even after
the segregation of T and B cell lineages). The model proposes the idea of
erythroid, T and B cells as specialized types of a prototypic myeloid HSC.[32]

Other animals[edit]
In some vertebrates, haematopoiesis can occur wherever there is a
loose stroma of connective tissue and slow blood supply, such as
the gut, spleen or kidney.[33]

See also[edit]
 Clonal hematopoiesis
 Erythropoiesis-stimulating agents
 Haematon
 Haematopoietic stimulants:
o Granulocyte colony-stimulating factor
o Granulocyte macrophage colony-stimulating factor
 Leukocyte extravasation
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Further reading[edit]
  Godin, Isabelle & Cumano, Ana, eds.
(2006). Hematopoietic stem cell development.
Springer. ISBN 978-0-306-47872-7.

External links[edit]
Scholia has a topic profile
for Haematopoiesis.

 Hematopoietic cell lineage in KEGG

 Hematopoiesis and bone marrow histology
show

Immunology: lymphocytic adaptive immune system and complement

show

Organs of the lymphatic system

show

Myeloid physiology
show

Cell signaling: cytokines
Categories: 
 Hematopoiesis
 Histology
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 This page was last edited on 13 December 2019, at 02:23 (UTC).
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