Hemopoiesis

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Hemopoiesis
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http//en.wikipedia.org/wiki/Haematopoiesis
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• Haematopoiesis (from Ancient Greek a?µa,
  "blood" p??e?? "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.12

http//en.wikipedia.org/wiki/Haematopoiesis
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Nagasawa Nature Reviews Immunology 6, 107116
(February 2006) doi10.1038/nri1780
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• 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, megakaryoc
  ytes 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.

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

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• 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 unitspleen (CFUS) 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.

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• 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
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• 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-mesoneph
  ros), 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
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http//en.wikipedia.org/wiki/Haematopoiesis
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• 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
http//en.wikipedia.org/wiki/Haematopoiesis
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Cell Morphology
http//www.anatomyatlases.org/MicroscopicAnatomy/S
ection04/Plate0458.shtml

• Exercise
• http//www.dartmouth.edu/anatomy/Histo/lab_4/bone
  marrow/DMS104/popup.html

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Erythropoiesis
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Granulopoiesis
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Cell Differentiation

•  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.
• 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
  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.

http//en.wikipedia.org/wiki/Haematopoiesis
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Transcription factors

• Growth factors initiate signal transduction pathwa
  ys, 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

http//en.wikipedia.org/wiki/Haematopoiesis
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• 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-stimulat
  ing factors (CSFs) and include granulocyte-macroph
  age 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-formi
  ng cells).3

http//en.wikipedia.org/wiki/Haematopoiesis
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Nagasawa Nature Reviews Immunology 6, 107116
(February 2006) doi10.1038/nri1780
21
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-alphaTGF-ß  Transforming growth factor
beta
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Nagasawa Nature Reviews Immunology 6, 107116
(February 2006) doi10.1038/nri1780
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• 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.

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• 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.345 
• 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?10).
• b)Myeloid-biased (My-bi) HSC give rise to too few
  lymphocytes resulting in ratios 0lt?lt3,
• c) Lymphoid-biased (Ly-bi) HSC generate too few
  myeloid cells, which results in
  lymphoid-to-myeloid ratios of 10lt?ltoo.
• 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

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• Cluster of differentiation and other markers
• Many of markers belong to the cluster of
  differentiation series, like CD34, CD38, CD90, CD
  133, 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//en.wikipedia.org/wiki/Haematopoiesis and
Hematopoietic_stem_cell
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http//cytometry.nencki.gov.pl/?aS2vlp8PU
http//commons.wikimedia.org/wiki/FileFluorescenc
e_Assisted_Cell_Sorting_28FACS29_A.jpg
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• 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.
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• 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 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.

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• 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.

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• 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.

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• 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 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.

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• Schematic illustration of the early
  differentiation and proliferation of thymic T
  lineage cells. A single early thymic progenitor
  undergoes gt10 cell divisions during the DN1 and
  DN2 stages to generate gt1000 DN3 cells. The
  shutoff of myeloid potential occurs during the
  transition step from the GFP-DN2 stage to the
  GFPDN2 stage and subsequently the T-cell
  lineage-determined progenitors undergo several
  cell divisions before they enter the DN3 stage to
  initiate TCRß chain gene rearrangement.

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• 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.

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• 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.

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• 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.