hemopoiesis.ppt

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

• Haematopoiesis (from Ancient Greek: αἷμα,
"blood"; ποιεῖν "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 1011–1012
new blood cells are produced daily in order to
maintain steady state levels in the peripheral
circulation.[1][2]

Nagasawa Nature Reviews Immunology 6, 107–116 (February 2006) | doi:10.1038/nri1780

All blood cells are divided into three lineages
• Erythroid cells are the oxygen carrying red blood cells.
Both reticulocytes and erythrocytes are functional and are released
into the blood. In fact, a reticulocyte count estimates the rate
of erythropoiesis.
• Lymphocytes are the cornerstone of the adaptive immune system.
They are derived from common lymphoid progenitors. The
lymphoid lineage is primarily composed of T-cells and B-cells (types
of white blood cells). This is lymphopoiesis.
• Myelocytes, which
include granulocytes, megakaryocytes and macrophages and are
derived from common myeloid progenitors, are involved in such
diverse roles as innate immunity, adaptive immunity, and blood
clotting. This is myelopoiesis.
• Granulopoiesis (or granulocytopoiesis) is haematopoiesis
of granulocytes.
• Megakaryocytopoiesis is haematopoiesis of megakaryocytes.

Multipotency and self-renewal
• As stem cells, HSC are defined by their ability to replenish all blood
cell types (Multipotency) and their ability to self-renew.
• It is known that a small number of HSCs can expand to generate a
very large number of daughter HSCs.
• This phenomenon is used in bone 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 niche in
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 HSC in vitro that can be used
therapeutically.

• There are various kinds of colony-forming units:
• Colony-forming unit lymphocyte (CFU-L)
• Colony-forming unit erythrocyte (CFU-E)
• Colony-forming unit granulo-monocyte (CFU-GM)
• Colony-forming unit megakaryocyte (CFU-Me)
• Colony-forming unit Basophil (CFU-B)
• Colony-forming unit Eosinophil (CFU-Eo)
• The above CFUs are based on the lineage. Another CFU, the colony-
forming unit–spleen (CFU–S) was the basis of an in vivo clonal 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 or Transit
Amplifying Cells rather 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 in umbilical cord blood and, in small numbers,
in peripheral 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]

• 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.
• 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

Cell Morphology
• Exercise
• http://www.dartmouth.edu/~anatomy/Histo/lab_4/bonemarrow/DMS104/popup.html
http://www.anatomyatlases.org/MicroscopicAnatomy/Section04/Plate0458.shtml

• The determinism theory of hematopoiesis, saying that
colony stimulating factors and other factors of the
hematopoietic microenvironment determine the cells
to follow a certain path of cell differentiation.
• This is the classical way of describing hematopoiesis.
• The ability of the bone marrow to regulate the quantity
of different cell types to be produced is more
accurately explained by astochastic theory.
• 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 perform apoptosis and die.
Cell Differentiation

Transcription factors
• Growth factors initiate signal transduction pathways,
altering transcription 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-1 has an essential role in erythropoietic and
megakaryocytic differentiation.
• The Ikaros, Aiolos and Helios transcription factors play a
major role in lymphoid development.[5]

• The proliferation and self-renewal of these cells depend
on stem 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 cells are called colony-stimulating factors (CSFs) and
include granulocyte-macrophage CSF (GM-CSF), granulocyte
CSF (G-CSF) and macrophage CSF (M-CSF). These stimulate
much 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.[3]
• Thrombopoietin makes myeloid progenitor cells differentiate
to megakaryocytes (thrombocyte-forming cells).[3]

SCF= Stem Cell Factor, Tpo= Thrombopoietin, IL= Interleukin, GM-CSF= Granulocyte
Marophage-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
TGF-β = Transforming growth factor beta

• 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
International Immunology Volume 22, Issue 2 Pp. 65-70.

• 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
lineages—a myelo-erythroid 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 myeloid–erythroid 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 myelo–lymphoid 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.

• In this model, the intermediate precursor cells
between haematopoeitic stem cells (HSCS) — which
are located near the osteoblasts7, 8, endothelial
cells113 or CXC-chemokine ligand 12hi (CXCL12hi)
reticular cells10 — and pre-pro-B cells would move
towards CXCL12hi reticular cells.
• Pre-pro-B cells associate with CXCL12hi reticular 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
CXCL12hi reticular cells in the bone marrow10.

Stem cell heterogeneity
• It was originally believed that all HSC were alike in their self-renewal 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-1lo SCA-1+ lin- c-kit+ HSC.[3][4][5]
• The results of these clonal studies led to the notion of lineage bias. Using
the ratio of 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 3≤ρ≤10).
b)Myeloid-biased (My-bi) HSC give rise to too few lymphocytes resulting in
ratios 0<ρ<3,
c) Lymphoid-biased (Ly-bi) HSC generate too few myeloid cells, which results
in lymphoid-to-myeloid ratios of 10<ρ<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 the cluster of differentiation series,
like: CD34, CD38, CD90, CD133, CD105, CD45, and also c-kit, - the receptor
for stem 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 by FACS, a bunch of up to 14
different mature blood-lineage marker, e.g., CD13 & CD33 for
myeloid, CD71 for erythroid, CD19 for B cells, CD61 for megakaryocytic,
etc. for humans; and, B220 (murine CD45) for B cells, Mac-
1 (CD11b/CD18) formonocytes, Gr-1 for Granulocytes, Ter119 for erythroid
cells, Il7Ra, CD3, CD4, CD5, CD8 for T 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/-, C-kit/CD117+, lin-

http://commons.wikimedia.org/wiki/File:Fluorescence_Assisted_
Cell_Sorting_%28FACS%29_A.jpg
http://cytometry.nencki.gov.pl/?a=S2vlp8PU

• T-cell progenitors retain myeloid potential after terminating B cell potential.
Early T-cell progenitors in the adult thymus that have lost B-cell potential still
retain a substantial capacity to generate macrophages
• certain proportion (∼30%) of thymic macrophages are produced by myeloid–T
progenitors, by firstly making bone marrow chimeric mice carrying bone
marrow cells from wild-type mice and from human-CD3ϵ 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 GFP−DN2 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 TCRβ 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 XYZ-progenitors, 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.

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