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Andres Soosaar
http://biomedicum.ut.ee/~andres
s
 Unlike RBCs leukocytes can penetrate blood vessel
wall without injury of it. This process is sometimes
called the leukodiapedesis.
 Leukocyte migration is important in both
hematopoiesis and reactions of immunological
defence.
 Positive chemotaxis is a process where cell moves
towards higher content of certain chemotactic
substance (e.g. Some factors of the complement
system).
 Leukocyte migration is driven by chemokines and
adhesion molecules.
 A big family of proteins which contain 67-127 amino
acids. Chemically CXC and CC subfamilies are
differentiated. There are several types of chemokine
receptors.
 Functionally are there inflammatory chemokines,
homeostatic chemokines and dual-function
chemokines.
 The inflammatory chemokines control recruitment of
WBCs into inflammation, tissue injury and tumors,
e.g. CX3CL1 or fractalkine.
 The homeostatic chemokines control migration of cells
through hematopoiesis, e.g. CXCL12 (SDF-1).
 Chemokines act over G-protein coupled
surface receptors after what several important
intracellular become activated, among them
are phospholipase C (PLCbeeta),
phosphoinositid 3-kinases (Ptdlns3-Ks), and
tyrosin kinases of C-Src family.
 The Ptdlns3-Ks are crucially important to
switch on cellular contractile machinery.
 In hematopoiesis different hematopoietic cells
have different sensitivity to chemokines and as
a final result only mature cells can reach
circulation.
Blood
In adult organism main place for
hematopoiesis is red bone marrow, only
some lymphocytes (T type) are coming
from lymphatic
Before birth erythropoiesis is going in yolk
sac (I trimester), liver, spleen, lymphatic
tissue (II trimester) and red bone marrow
(III trimester).
 All mature cells are originated from the
pluripotent hematopoietic stem cells (HSCs)
 Maturation of cells is going through several
intermediate steps.
 Capacity to differentiate is increasing and
capacity to divide and sel-production is
decreasing during maturation. Mature blood
cells are not able to divide.
 Usually only mature cells can reach blood
 Hematopoiesis must and is very carefully
regulated to hold stable number of cells in the
blood
http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2/
RBCs: 3,5x1011 cells per day
Neutrophils: 1011 cells per day
Monocytes: 8,4x109 cells per day
Platelets: 1011 cells per day
http://www.oup.com/uk/booksites/content/0198585276/
Mazur E, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
 HCSs have been discovered some 50 years ago.
These cells are able to self-reproduce and
differentiate in a unlimited way. There are
findings that in certain circumstances HCSs can
produce other cell types, eg hepatocytes, renal
cells, myocytes etc.
 An adult person has ~50 million HPCs
 A HCS is able to produce altogether ~1013 mature
blood cells
They are pluripotent, i.e. they may change
through several steps of development to
different cell types.
They have high level of proliferation and
self reproduction.
They are able to leave bone marrow and
exist and function in other tissues.
 There is big number regulatory substances,
hematopoietic factors, which may influence
almost all phases of hemaotpoiesis.
 Hematopoietic factors are members cytokine
family.
 Hematopoietic factors are released from
hematopoietic, stromal and other cells and can
interact through specific receptors with different
types of cells and change their functional activity.
 Better understanding of hematopoiesis would
improve treatment of hematological diseases
http://www.copewithcytokines.de/cope.cgi?004470
http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2
HEMATOPOIETIC FACTORS
NAME CELLULAR SOURCE CELL TYPES
PRODUCED IN
INCREASED
NUMBERS
Erythropoietin (EPO) Kidney cells, Kupffer
cells
rbc
G-CSF Monocytes, fibroblasts,
endothelial cells
n
M-CSF Monocytes, fibroblasts,
endothelial cells
m
GM-GSF T cells, monocytes,
fibroblasts, endothelial
cells
n, m, e, meg, rbc
IL-1 Macrophages,
endothelial cells,
fibroblasts
n, m, e, b, meg, rbc
IL-3 T cells n, m, e, b, meg, rbc
IL-4 T cells b
IL-5 T cells e
IL-6 Macrophages,
endothelial cells,
fibroblasts
n, m, e, b, meg, rbc
n, neutrophils; m, monocytes; e, eosinophils; b, basophils; meg, megakaryocytes; rbc, red blood cells
IL – interleukin , CSF – colony stimulating factor
Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
GATA-2, TAL-1/SCL, and HOXB4 are
important in early phases of hematopoiesis
and stem cells functioning
GATA-1 is important in differentiation and
development RBCs and other myeloid
blood cells.
Data about hematopoietic gene regulation
are rapidly increasing.
 Programmed cell death (apoptosis) is a normal physiological form of
cell death that plays a key role both in the maintenance of adult
tissues and in embryonic development. In adults, programmed cell
death is responsible for balancing cell proliferation and maintaining
constant cell numbers in tissues undergoing cell turnover. For
example, about 5 × 1011 blood cells are eliminated by
programmed cell death daily in humans, balancing their
continual production in the bone marrow.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSection
&searchterm=cell&rid=cooper.section.2281
 Apoptosis is a powerful regulatory process which is influenced by
different pathways of cell signalling. See respective chapters on cell
biology.
Cross-antagonism of transcription factors
There is cross-antagonism between GATA-1
and PU.1 in different cell lines which is
important in development of RBCs and
other myeloid cells
The negative feedback mechanisms
The classical example is EPO role in RBC
development
Glycoprotein with 165 amino acids,
produced mainly in kidneys and only small
amount in liver. The name comes from the
Bonsdorff and Jalavisto’s paper (1948).
History of the issue is much longer, already
in 1906 Paul Carnot possibility of humoral
regulation of erythropoiesis.
 In 1985 recombinant EPO (rHuEPO) was get and
new perspectives for scientific study and clinical
use were open.
 The EPO receptors (EPO-R) were firstly
described in 1989/1990.
 Currently EPO is widely used in therapy of
different anemias, especially those have renal or
cancerous origin.
 EPO is a tempting but dangerous doping
substance in sport
EPO release into blood is increased 1-2 h
after kidney hypoxia and is disrupted when
hypoxia is removed. It is an example of
typical negative feedback loop regulation
Activation of EPO gene in response to
hypoxia goes through special transcription
factor HIF-1alpha (hypoxia induced
factor) which amount goes up by hypoxia.
O2 detection
in kidneys
EPORBCs in blood
Erythropoiesis
in bone marrow
EPO receptors are located on BFU-E, CFU-
E, and normoblasts’ cell membranes, also
on other cells (neurons, myocytes,
endotheliocytes etc)
Signalling in EPO receptors goes over
JAK2 tyrosin kinases and later on via
pathways of Jak/STAT and Ras/MAP
kinases.
 EPO’s influence on erythropoiesis in based on its
antiapoptotic effect in respective cell types (CFU-
E, normoblasts)
 According to new data EPO wide spectrum of
other biological effects outside of hematopoiesis.
EPO is able to stimulate angiogenesis ja
neurogenesis, also proliferation different cell
types (e.g. myosytes) and antihypoxic effects in
several experimental conditions.
 Horst Ibelgaufts' C O P E Cytokines Online Pathfinder
Encyclopaedia: http://www.copewithcytokines.de/cope.cgi
 Barreda D.R, Hanington P.C, Belosevic M. Regulation of myeloid
development and function by colony stimulating factors.
Developmental and Comparative Immunology, 2004, 28, 509-554.
 Fisher JW. Erythropoietin: physiology and pharmacology
update. Experimental Biology and Medicine, 2003, 228, 1-14.
 Shivdasani RA, Orkin SH. The transcriptional control of
hematopoiesis. Blood, 1996, 87, 4025-4039.
 Szilvassy SJ. The biology of hematopoietic stem cells. Archives of
Medical Research, 2003, 34, 446-460.
A good overview and illustrations:
http://ntri.tamuk.edu/homepage-
ntri/lectures/clotting.html
1. Platelets adhesion and aggregation,
formation of the platelet plug
2. Vasoconstriction
3. Blood clotting
4. Final repair by connective tissue
NB! The phases are not separated but rather
manyfold interconnected
http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2
 Alexander Schmidt and Paul Morawitz
They discovered the enzymatic cascade nature of
blood clotting
1st phase – activation (of thrombokinase which
converts prothrombin to thrombin)
2nd phase -- coagulation (fibrinogen is converted
to soluble fibrin)
3rd phase – retraction (production of stable fibrin)
http://cwx.prenhall.com/bookbind/pubbooks/silverthorn2
Production from megakaryocytes, 1,5-3,0
x 1011 in 1L blood
Reservoirs of bioactive substances
Serotonin (5-HT) and thromboxan A2
potent vasoconstrictors
Collageen and plasma von Willebrand
faktor (vWf) iniate adhesion.
Adhesion is blocked by negative surface
charge of platelets, certain biochemical
regulators (e.g. NO, prostacyclin etc), and
endothelial barrier between collagen and
blood.
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
The extrinsic pathway is critical in
initiating of blood clotting.
The intrinsic pathway plays an important
role in maintenance of coagulation.
There is no bleeding disorders in case of lack
XII
Serine protease inhibitors (antithrombin
III)
The protein C system activated by
thrombin
The regulatory influences of intact
endothelial and blood cells
The fibrinolytic system
Antithrombin III, tissue factor pathway
inhibitor (TFPI), alpha2-macroglobulin, C1
inhibitor jt.
Antithrombin III inhibits mainly factor X,
and factors VII, IX, XI, XII.
Heparin and glycosaminoglycans increase
the antithrombin III activity 1000 times.
Thrombomodulin and protein C are
members of an endogenous anticoagulant
system.
Thrombin complexed with
thrombomodulin loses its procoagulatory
activity, while readily activating protein C
Proteiin C destroys factors V and VIII
http://ntri.tamuk.edu/homepage-ntri/lectures/clotting.html
 There is no coagulation in case of intact
endothelium
 Endothelial cells can produce under influence of
thrombin, IL-1 or TNF tissue factor, which has
procoagulatory activity
 The surface of endothelial cells contains heparin-
like compounds, which bind antithrombin III
and block thrombin formation
 Endothelial cells can produce the plasminogen
activators.
Platelets contain procoagulant
anticoagulant substances
Polymorphonuclear leukocytes and
monocytes produce tissue factor, factor V
and present phospholipids, which all
support blood coagulation
Hypercoagulation – thrombi and emboli,
thrombophilia
Hypocoagulation – bleeding disorders,
hemophilia
Thrombocytopenia
Deficiency of coagulation factors
• Hemofiilia A (lack of factor VIII)
• Hemofiilia B (lack of factor IX)
Deficiency of vitamiin K
Vitamiin K is important to add gamma-
carboxyglutamate (gla) to factors II, VII,
IX ja X.
Platelets contain both substances which
activate or inhibit blood clotting
Neutrophilic granulocytes and monocytes
produce the tissue factor, the factor V, and
phospholipids which all support blood
clotting processes.
 In case of intact endothelium there is no clotting
 Endothelial cells can produce under influence of
thrombin, IL-1, TNF the tissue factor, which can
iniate external pathway of blood clotting
 On the surface of endothelium are heparin-like
substances which bind antithrombin III ühendid,
mis seovad antitrombiin III and inhibit thrombin
activity.
 Endothelial cells produce plasminogen
activators.

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Blood

  • 2.  Unlike RBCs leukocytes can penetrate blood vessel wall without injury of it. This process is sometimes called the leukodiapedesis.  Leukocyte migration is important in both hematopoiesis and reactions of immunological defence.  Positive chemotaxis is a process where cell moves towards higher content of certain chemotactic substance (e.g. Some factors of the complement system).  Leukocyte migration is driven by chemokines and adhesion molecules.
  • 3.  A big family of proteins which contain 67-127 amino acids. Chemically CXC and CC subfamilies are differentiated. There are several types of chemokine receptors.  Functionally are there inflammatory chemokines, homeostatic chemokines and dual-function chemokines.  The inflammatory chemokines control recruitment of WBCs into inflammation, tissue injury and tumors, e.g. CX3CL1 or fractalkine.  The homeostatic chemokines control migration of cells through hematopoiesis, e.g. CXCL12 (SDF-1).
  • 4.  Chemokines act over G-protein coupled surface receptors after what several important intracellular become activated, among them are phospholipase C (PLCbeeta), phosphoinositid 3-kinases (Ptdlns3-Ks), and tyrosin kinases of C-Src family.  The Ptdlns3-Ks are crucially important to switch on cellular contractile machinery.  In hematopoiesis different hematopoietic cells have different sensitivity to chemokines and as a final result only mature cells can reach circulation.
  • 6. In adult organism main place for hematopoiesis is red bone marrow, only some lymphocytes (T type) are coming from lymphatic Before birth erythropoiesis is going in yolk sac (I trimester), liver, spleen, lymphatic tissue (II trimester) and red bone marrow (III trimester).
  • 7.  All mature cells are originated from the pluripotent hematopoietic stem cells (HSCs)  Maturation of cells is going through several intermediate steps.  Capacity to differentiate is increasing and capacity to divide and sel-production is decreasing during maturation. Mature blood cells are not able to divide.  Usually only mature cells can reach blood  Hematopoiesis must and is very carefully regulated to hold stable number of cells in the blood
  • 9. RBCs: 3,5x1011 cells per day Neutrophils: 1011 cells per day Monocytes: 8,4x109 cells per day Platelets: 1011 cells per day
  • 11. Mazur E, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
  • 12.  HCSs have been discovered some 50 years ago. These cells are able to self-reproduce and differentiate in a unlimited way. There are findings that in certain circumstances HCSs can produce other cell types, eg hepatocytes, renal cells, myocytes etc.  An adult person has ~50 million HPCs  A HCS is able to produce altogether ~1013 mature blood cells
  • 13. They are pluripotent, i.e. they may change through several steps of development to different cell types. They have high level of proliferation and self reproduction. They are able to leave bone marrow and exist and function in other tissues.
  • 14.  There is big number regulatory substances, hematopoietic factors, which may influence almost all phases of hemaotpoiesis.  Hematopoietic factors are members cytokine family.  Hematopoietic factors are released from hematopoietic, stromal and other cells and can interact through specific receptors with different types of cells and change their functional activity.  Better understanding of hematopoiesis would improve treatment of hematological diseases
  • 17. HEMATOPOIETIC FACTORS NAME CELLULAR SOURCE CELL TYPES PRODUCED IN INCREASED NUMBERS Erythropoietin (EPO) Kidney cells, Kupffer cells rbc G-CSF Monocytes, fibroblasts, endothelial cells n M-CSF Monocytes, fibroblasts, endothelial cells m GM-GSF T cells, monocytes, fibroblasts, endothelial cells n, m, e, meg, rbc IL-1 Macrophages, endothelial cells, fibroblasts n, m, e, b, meg, rbc IL-3 T cells n, m, e, b, meg, rbc IL-4 T cells b IL-5 T cells e IL-6 Macrophages, endothelial cells, fibroblasts n, m, e, b, meg, rbc n, neutrophils; m, monocytes; e, eosinophils; b, basophils; meg, megakaryocytes; rbc, red blood cells IL – interleukin , CSF – colony stimulating factor
  • 18. Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
  • 19. Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
  • 20. Mazur Em, Cohen JL, Clin Pharmacol Ther, 1989, 46, 250-256
  • 21. GATA-2, TAL-1/SCL, and HOXB4 are important in early phases of hematopoiesis and stem cells functioning GATA-1 is important in differentiation and development RBCs and other myeloid blood cells. Data about hematopoietic gene regulation are rapidly increasing.
  • 22.  Programmed cell death (apoptosis) is a normal physiological form of cell death that plays a key role both in the maintenance of adult tissues and in embryonic development. In adults, programmed cell death is responsible for balancing cell proliferation and maintaining constant cell numbers in tissues undergoing cell turnover. For example, about 5 × 1011 blood cells are eliminated by programmed cell death daily in humans, balancing their continual production in the bone marrow. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?tool=bookshelf&call=bv.View..ShowSection &searchterm=cell&rid=cooper.section.2281  Apoptosis is a powerful regulatory process which is influenced by different pathways of cell signalling. See respective chapters on cell biology.
  • 23. Cross-antagonism of transcription factors There is cross-antagonism between GATA-1 and PU.1 in different cell lines which is important in development of RBCs and other myeloid cells The negative feedback mechanisms The classical example is EPO role in RBC development
  • 24. Glycoprotein with 165 amino acids, produced mainly in kidneys and only small amount in liver. The name comes from the Bonsdorff and Jalavisto’s paper (1948). History of the issue is much longer, already in 1906 Paul Carnot possibility of humoral regulation of erythropoiesis.
  • 25.  In 1985 recombinant EPO (rHuEPO) was get and new perspectives for scientific study and clinical use were open.  The EPO receptors (EPO-R) were firstly described in 1989/1990.  Currently EPO is widely used in therapy of different anemias, especially those have renal or cancerous origin.  EPO is a tempting but dangerous doping substance in sport
  • 26. EPO release into blood is increased 1-2 h after kidney hypoxia and is disrupted when hypoxia is removed. It is an example of typical negative feedback loop regulation Activation of EPO gene in response to hypoxia goes through special transcription factor HIF-1alpha (hypoxia induced factor) which amount goes up by hypoxia.
  • 27. O2 detection in kidneys EPORBCs in blood Erythropoiesis in bone marrow
  • 28. EPO receptors are located on BFU-E, CFU- E, and normoblasts’ cell membranes, also on other cells (neurons, myocytes, endotheliocytes etc) Signalling in EPO receptors goes over JAK2 tyrosin kinases and later on via pathways of Jak/STAT and Ras/MAP kinases.
  • 29.  EPO’s influence on erythropoiesis in based on its antiapoptotic effect in respective cell types (CFU- E, normoblasts)  According to new data EPO wide spectrum of other biological effects outside of hematopoiesis. EPO is able to stimulate angiogenesis ja neurogenesis, also proliferation different cell types (e.g. myosytes) and antihypoxic effects in several experimental conditions.
  • 30.  Horst Ibelgaufts' C O P E Cytokines Online Pathfinder Encyclopaedia: http://www.copewithcytokines.de/cope.cgi  Barreda D.R, Hanington P.C, Belosevic M. Regulation of myeloid development and function by colony stimulating factors. Developmental and Comparative Immunology, 2004, 28, 509-554.  Fisher JW. Erythropoietin: physiology and pharmacology update. Experimental Biology and Medicine, 2003, 228, 1-14.  Shivdasani RA, Orkin SH. The transcriptional control of hematopoiesis. Blood, 1996, 87, 4025-4039.  Szilvassy SJ. The biology of hematopoietic stem cells. Archives of Medical Research, 2003, 34, 446-460.
  • 31. A good overview and illustrations: http://ntri.tamuk.edu/homepage- ntri/lectures/clotting.html
  • 32. 1. Platelets adhesion and aggregation, formation of the platelet plug 2. Vasoconstriction 3. Blood clotting 4. Final repair by connective tissue NB! The phases are not separated but rather manyfold interconnected
  • 34.  Alexander Schmidt and Paul Morawitz They discovered the enzymatic cascade nature of blood clotting 1st phase – activation (of thrombokinase which converts prothrombin to thrombin) 2nd phase -- coagulation (fibrinogen is converted to soluble fibrin) 3rd phase – retraction (production of stable fibrin)
  • 36. Production from megakaryocytes, 1,5-3,0 x 1011 in 1L blood Reservoirs of bioactive substances Serotonin (5-HT) and thromboxan A2 potent vasoconstrictors
  • 37. Collageen and plasma von Willebrand faktor (vWf) iniate adhesion. Adhesion is blocked by negative surface charge of platelets, certain biochemical regulators (e.g. NO, prostacyclin etc), and endothelial barrier between collagen and blood.
  • 49. The extrinsic pathway is critical in initiating of blood clotting. The intrinsic pathway plays an important role in maintenance of coagulation. There is no bleeding disorders in case of lack XII
  • 50. Serine protease inhibitors (antithrombin III) The protein C system activated by thrombin The regulatory influences of intact endothelial and blood cells The fibrinolytic system
  • 51. Antithrombin III, tissue factor pathway inhibitor (TFPI), alpha2-macroglobulin, C1 inhibitor jt. Antithrombin III inhibits mainly factor X, and factors VII, IX, XI, XII. Heparin and glycosaminoglycans increase the antithrombin III activity 1000 times.
  • 52. Thrombomodulin and protein C are members of an endogenous anticoagulant system. Thrombin complexed with thrombomodulin loses its procoagulatory activity, while readily activating protein C Proteiin C destroys factors V and VIII
  • 54.  There is no coagulation in case of intact endothelium  Endothelial cells can produce under influence of thrombin, IL-1 or TNF tissue factor, which has procoagulatory activity  The surface of endothelial cells contains heparin- like compounds, which bind antithrombin III and block thrombin formation  Endothelial cells can produce the plasminogen activators.
  • 55. Platelets contain procoagulant anticoagulant substances Polymorphonuclear leukocytes and monocytes produce tissue factor, factor V and present phospholipids, which all support blood coagulation
  • 56. Hypercoagulation – thrombi and emboli, thrombophilia Hypocoagulation – bleeding disorders, hemophilia
  • 57. Thrombocytopenia Deficiency of coagulation factors • Hemofiilia A (lack of factor VIII) • Hemofiilia B (lack of factor IX) Deficiency of vitamiin K Vitamiin K is important to add gamma- carboxyglutamate (gla) to factors II, VII, IX ja X.
  • 58. Platelets contain both substances which activate or inhibit blood clotting Neutrophilic granulocytes and monocytes produce the tissue factor, the factor V, and phospholipids which all support blood clotting processes.
  • 59.  In case of intact endothelium there is no clotting  Endothelial cells can produce under influence of thrombin, IL-1, TNF the tissue factor, which can iniate external pathway of blood clotting  On the surface of endothelium are heparin-like substances which bind antithrombin III ühendid, mis seovad antitrombiin III and inhibit thrombin activity.  Endothelial cells produce plasminogen activators.