Hemopoiesis

http://en.wikipedia.org/wiki/Haematopoiesis

 Haematopoiesis (from Ancient Greek: ,

"blood"; "to make") (or
hematopoiesis in American English;
sometimes also haemopoiesis or
hemopoiesis) is the formation of blood
cellular components. All cellular blood
components are derived from
haematopoietic stem cells. In a healthy adult
person, approximately 10111012 new blood
cells are produced daily in order to maintain
steady state levels in the peripheral
circulation.[1][2]
http://en.wikipedia.org/wiki/Haematopoiesis

Nagasawa Nature Reviews Immunology 6, 107116 (February 2006) | doi:10.1038/nri1780

All blood cells are divided into three lineages

Erythroidcells are the oxygen carryingred blood cells.
Bothreticulocytesanderythrocytesare functional and
are released into the blood. In fact, a reticulocyte
count estimates the rate oferythropoiesis.
Lymphocytesare the cornerstone of the adaptive
immune system. They are derived from common
lymphoid progenitors. The lymphoid lineage is
primarily composed ofT-cellsandB-cells(types of
white blood cells). This is lymphopoiesis.
Myelocytes, which includegranulocytes,
megakaryocytesandmacrophagesand are derived
from common myeloid progenitors, are involved in
such diverse roles asinnate immunity,
adaptive immunity, andblood clotting. This is
myelopoiesis.
Granulopoiesis(or granulocytopoiesis) is
haematopoiesis ofgranulocytes.
Megakaryocytopoiesisis haematopoiesis of
megakaryocytes.
http://en.wikipedia.org/wiki/Haematopoiesis

Multipotency and self-renewal

As stem cells, HSC are defined by their ability to replenish
all blood cell types (Multipotency) and their ability to selfrenew.
It is known that a small number of HSCs can expand to
generate a very large number of daughter HSCs.
This phenomenon is used inbone marrow transplantation,
when a small number of HSCs reconstitute the
hematopoietic system. This process indicates that,
subsequent to bone marrow transplantation, symmetrical
cell divisions into two daughter HSCs must occur.
Stem cell self-renewal is thought to occur in the
stem cell nichein the bone marrow, and it is reasonable to
assume that key signals present in this niche will be
important in self-renewal.
There is much interest in the environmental and molecular
requirements for HSC self-renewal, as understanding the
ability of HSC to replenish themselves will eventually allow
the generation of expanded populations of HSCin
vitrothat can be used therapeutically.

There are various kinds of colony-forming units:

Colony-forming unitlymphocyte(CFU-L)
Colony-forming uniterythrocyte(CFU-E)
Colony-forming unit granulo-monocyte(CFU-GM)
Colony-forming unitmegakaryocyte(CFU-Me)
Colony-forming unitBasophil(CFU-B)
Colony-forming unitEosinophil(CFU-Eo)

The above CFUs are based on the lineage. Another CFU,

thecolony-forming unitspleen(CFUS) was the basis of anin
vivoclonal colony formation, which depends on the ability of
infused bone marrow cells to give rise to clones of maturing
hematopoietic cells in the spleens of irradiated mice after 8 to
12 days. It was used extensively in early studies, but is now
considered to measure more mature progenitor orTransit
Amplifying Cellsrather than stem cells.

 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.
HSCs are self-renewing cells: when they proliferate, at least
some of their daughter cells remain as HSCs, so the pool of
stem cells does not become depleted.
The other daughters of HSCs (myeloid and lymphoid
progenitor cells), however can commit to any of the alternative
differentiation pathways that lead to the production of one or
more specific types of blood cells, but cannot self-renew. This
is one of the vital processes in the body.
http://en.wikipedia.org/wiki/Haematopoiesis and Hematopoietic_stem_cell

 HSCs are also found inumbilical cordblood and, in small

numbers, inperipheral blood. Stem and progenitor cells can
be taken from the pelvis, at the iliac crest, using a needle
and syringe. The cells can be removed a liquid (to perform
a smear to look at the cell morphology) or they can be
removed via a core biopsy (to maintain the architecture or
relationship of the cells to each other and to the bone).
In order to harvest stem cells from the circulating
peripheral, blood donors are injected with a cytokine, such
as granulocyte-colony stimulating factor (G-CSF), that
induce cells to leave the bone marrow and circulate in the
blood vessels.
In mammalian embryology, the first definitive HSCs are
detected in the AGM (Aorta-gonad-mesonephros), and then
massively expanded in the Fetal Liver prior to colonising
the bone marrow before birth.[2]

http://en.wikipedia.org/wiki/Haematopoiesis and Hematopoietic_stem_cell

http://en.wikipedia.org/wiki/Haematopoiesis

 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
thespleen,liverandlymph nodes.
Whenbone marrowdevelops, it eventually assumes the
task of forming most of the blood cells for the entire
organism.
Maturation, activation, and some proliferation of
lymphoid cells occurs in secondary lymphoid organs
(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.
In some cases, the liver, thymus, and spleen may
resume their haematopoietic function. This is called
extramedullary haematopoiesis . 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.
blood island

http://en.wikipedia.org/wiki/Haematopoiesis

Cell Morphology

http://www.anatomyatlases.org/MicroscopicAnatomy/Section04/Plat
e0458.shtml

Exercise

http://www.dartmouth.edu/~anatomy/Histo/lab_4/bonemarrow/DMS104/popup.html

Erythropoiesis

Granulopoiesis

Cell Differentiation
Thedeterminismtheory 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.
This is the classical way of describing
haematopoiesis.
The ability of the bone marrow to regulate the
quantity of different cell types to be produced is
more accurately explained by astochastictheory.
Undifferentiated blood cells are determined to
specific cell types by randomness.
The haematopoietic microenvironment prevails
upon some of the cells to survive and some, on
the other hand, to performapoptosisand die.
http://en.wikipedia.org/wiki/Haematopoiesis

Transcription factors
Growth factors initiatesignal transductionpathways,
alteringtranscription factors, that, in turn activate
genes that determine the differentiation of blood
cells.
The early committed progenitors express low levels
of transcription factors that may commit them to
discrete cell lineages.
Which cell lineage is selected for differentiation may
depend both on chance and on the external signals
received by progenitor cells.
Several transcription factors have been isolated that
regulate differentiation along the major cell lineages.
PU.1 commits cells to the myeloid lineage
GATA-1has an essential role in erythropoietic and
megakaryocytic differentiation.
The Ikaros, Aiolos and Helios transcription factors
play a major role in lymphoid development.[5]
http://en.wikipedia.org/wiki/Haematopoiesis

 The proliferation and self-renewal of these cells

depend onstem cell factor(SCF).Glycoprotein growth
factors regulate the proliferation and maturation of
the cells that enter the blood from the marrow, and
cause cells in one or more committed cell lines to
proliferate and mature.
Three more factors that stimulate the production of
committed stem cellsare called
colony-stimulating factors(CSFs) and include
granulocyte-macrophage CSF(GM-CSF),
granulocyte CSF(G-CSF) and macrophage CSF(MCSF). These stimulate muchgranulocyteformation
and are active on eitherprogenitor cellsor end
product cells.
Erythropoietinis required for a myeloid progenitor cell
to become an erythrocyte.[3]
Thrombopoietinmakes myeloid progenitor cells
differentiate tomegakaryocytes(thrombocyte-forming
cells).[3]
http://en.wikipedia.org/wiki/Haematopoiesis

Nagasawa Nature Reviews Immunology 6, 107116 (February 2006) | doi:10.1038/nri1780

SCF=Stem Cell Factor, Tpo=Thrombopoietin, IL=Interleukin, GM-CSF=

Granulocyte Marophage-colony stimulating factor, Epo=Erythropoietin, MCSF=Macrophage-colony stimulating factor, G-CSF=
Granulocyte-colony stimulating factor, SDF-1=Stromal cell-derived factor-1
, FLT-3 ligand=FMS-like tyrosine kinase 3ligand, TNF-a =

Nagasawa Nature Reviews Immunology 6, 107116 (February 2006) | doi:10.1038/nri1780

 In this model, the intermediate precursor cells

between haematopoeitic stem cells (HSCS)
which are located near the osteoblasts 7,8,
endothelial cells113or CXC-chemokine ligand
12hi(CXCL12hi) reticular cells10 and pre-pro-B
cells would move towards CXCL12hireticular cells.
Pre-pro-B cells associate with CXCL12hireticular
cells, whereas pro-B cells move away and instead
adjoin interleukin-7 (IL-7)-expressing cells10.
Subsequently, pre-B cells leave IL-7-expressing
cells10.
B cells expressing cell-surface IgM exit the bone
marrow and enter the blood to reach the spleen,
where they mature into peripheral mature B
cells.
End-stage B cells (plasma cells) again home to
CXCL12hireticular cells in the bone marrow10.

Stem cell heterogeneity

It was originally believed that all HSC were alike in their selfrenewal and differentiation abilities.
Muller-Sieburg group in San Diego illustrated that different
stem cells can show distinct repopulation patterns that are
epigenetically predetermined intrinsic properties of clonal
Thy-1loSCA-1+lin-c-kit+HSC.[3][4][5]
The results of these clonal studies led to the notion of lineage
bias. Using the ratioof lymphoid (L) to myeloid (M) cells in
blood as a quantitative marker, the stem cell compartment can
be split into three categories of HSC.
a)Balanced (Bala) HSC repopulate peripheral white blood cells in
the same ratio of myeloid to lymphoid cells as seen in
unmanipulated mice (on average about 15% myeloid and 85%
lymphoid cells, or 310).
b)Myeloid-biased (My-bi) HSC give rise to too few lymphocytes
resulting in ratios 0<<3,
c) Lymphoid-biased (Ly-bi) HSC generate too few myeloid cells,
which results in lymphoid-to-myeloid ratios of 10<<oo.
All three types are norm three types of HSC, and they do not
represent stages of differentiation. Rather, these are three
classes of HSC, each with an epigenetically fixed differentiation
program

Cluster of differentiation and other

markers
Many of markers belong to thecluster of differentiationseries,
like:CD34,CD38,CD90,CD133,CD105,CD45, and alsoc-kit, the receptor forstem cell factor. The hematopoietic stem cells
are negative for the markers that are used for detection of
lineage commitment, and are, thus, called Lin-; and, during
their purification byFACS, a bunch of up to 14 different mature
blood-lineage marker, e.g.,CD13&CD33for myeloid,CD71for
erythroid,CD19for B cells,CD61for megakaryocytic, etc. for
humans; and,B220(murineCD45) forB cells,Mac-1(CD11b/
CD18) formonocytes,Gr-1forGranulocytes,Ter119for
erythroid cells,Il7Ra,CD3,CD4,CD5,CD8forT cells, etc. (for
mice) antibodies are used as a mixture to deplete the lin+ cells
or late multipotent progenitors (MPP)s.
There are many differences between the human and mice
hematopoietic cell markers for the commonly accepted type of
hematopoietic stem cells.[1].
Mouse HSC:CD34lo/-,SCA-1+,Thy1.1 +/lo,CD38+,C-kit+, lin Human HSC:CD34+,CD59+,Thy1/CD90+,CD38lo/-,Ckit/CD117+, linhttp://en.wikipedia.org/wiki/Haematopoiesis and Hematopoietic_stem_cell

http://cytometry.nencki.gov.pl/?a=S2vlp8PU

http://commons.wikimedia.org/wiki/File:Fluorescence_Assisted_
Cell_Sorting_%28FACS%29_A.jpg

 Various theories exist about how HSCs

diversify
One model (the classical model) proposes
that lymphocytes and myelo-erythroid
lineages branch separately at an early
stage of hematopoiesis,
Another model (the myeloid-based
model) proposes that the myeloid potential
is retained for much longer among cells
that can become lymphocytes.
A revised scheme for developmental pathways of hematopoietic cells: the
myeloid-based model

 The blood cell family consists of a variety of cell

types, all of which are formed from a
hematopoietic stem cell (HSC).
Over the last century, the classification of blood
cell types was largely based on morphological
criteria, leading to the emergence of the classical
dichotomy concept, in which the blood cell family
was subdivided into two major lineagesa myeloerythroid lineage and a lymphoid lineage.
Therefore, it has been stated in most textbooks
that the first branch point from the HSC produces
progenitors for these two lineages.

 Representative models of hematopoiesis. (A) HSC firstly

generates a common myeloiderythroid progenitor (CMEP) and
a common lymphoid progenitor (CLP), which produce myeloid
or erythroid cells and T or B cells, respectively. An alternative
myeloid-based model postulates that the HSC first diverges into
the CMEP and a common myelolymphoid progenitor (CMLP);
(B) In this model, the first branch point generates CMEPs and
CMLPs, and the myeloid potential persists in the T and B cell
branches even after these lineages have diverged.

The concept of the myeloid-based model. (A) In the classical model,

erythroid, myeloid, T and B lineage cells are placed in parallel. (B) The
myeloid-based model proposes that myeloid cells represent a prototype of
blood cells, whereas erythroid, T and B cells represent specialized types.
Prototypic cells, namely myeloid cells, are equipped with the basic
machinery required for host defense cells, e.g. phagocytic activity and
mobility.
In the case of B cells, phagocytic activity is reduced but still maintained
while the antigen-presenting ability is rather strengthened, and finally, an
ability to recognize specific antigen is newly acquired.

 T-cell progenitors retain myeloid potential after terminating B cell

potential. Early T-cell progenitors in the adult thymus that have lost Bcell potential still retain a substantial capacity to generate
macrophages
certain proportion (30%) of thymic macrophages are produced by
myeloidT progenitors, by firstly making bone marrow chimeric mice
carrying bone marrow cells from wild-type mice and from human-CD3
transgenic mice that lack T lineage cells and subsequently assessing
contribution rate of wild-type versus transgenic cells for the production
of thymic macrophages (22).
These findings strongly argues against the existence of CLPs on the
physiological pathway from the HSC to T cells in adult hematopoiesis.

 Schematic illustration of the

early differentiation and
proliferation of thymic T
lineage cells. A single early
thymic progenitor undergoes
>10 cell divisions during the
DN1 and DN2 stages to
generate >1000 DN3 cells. The
shutoff of myeloid potential
occurs during the transition
step from the GFPDN2 stage
to the GFP+DN2 stage and
subsequently the T-cell
lineage-determined
progenitors undergo several
cell divisions before they enter
the DN3 stage to initiate TCR
chain gene rearrangement.

An illustration of why cell-fate maps should not be over-simplified

(using hypothetical cell lineages X, Y, and Z).
(A) An example of the developmental process to produce X cells, Y
cells or Z cells. Suppose that a progenitor having potential for X, Y
and Z lineages (XYZ-progenitor) first migrates to a particular site
(site P); there, it will make X-progenitors and self-renewing XYZprogenitors, followed by production of X cells from the X-progenitors.
Then, the XYZ-progenitor migrates to the next site (site Q), where
they lose their potential to become Y cells to become XZ-progenitors
on one hand and on the other hand segregation to Y-progenitors also
occurs that become Y cells.
Note that the XZ progenitors do not produce X cells in site Q but can
produce X cells in other place. The XZ-progenitor then migrates to
site R and produces Z-progenitors and finally Z cells there.

 A simplified model for the process shown in (A), which

contains information about developmental potential and cell
fate. A map like this is useful not only to understand reality
but also for further investigations into differentiation
mechanisms.
A map of lineage restriction focusing on the way from the
XYZ-progenitor to a Z cell. Particularly in studying the
molecular mechanisms in lineage commitment for the
production of Z cells, the information for the order of lineage
restriction [XYZ XZ Z] is essential.

 A map that describes only the physiological cell fate. This

map might be misleading because the information about
the lineage restriction process shown in (C) is absent.