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Flashcards in Hematopoiesis Deck (135):
0

where do embryonic hematopoietic stem cells (HSCs) originate?

in the yolk sac and aorta-gonad-mesenephros (AGM) region of the embryo

1

**what produces hematopoietic stem cells (HSCs) and endothelial cells?**

**common embryonic stem cells called hemangioblasts**

2

what species is the exception when it comes to blood cell types in utero?

cats - they produce a wider spectrum of blood cell types

3

describe the appearance of embryonic cells

they are huge and nucleated

4

when does bone marrow organization begin?

during the second trimester

5

**describe bone development in 4 steps**

**
1. cartilage is calcified
2. chondroclasts degrade mineralized cartilage
3. vessels invade marrow space that is created
4. osteoblasts form bony trabeculae
**

6

what two things form a connective tissue meshwork?

1. vascular sinuses
2. extravascular mesenchymal stromal cells

7

**when do hematopoietic cells from liver form circulating blood cells?**

**once hematopoietic microenvironment forms**

8

what is extravascular space?

space between the vascular sinuses in bone marrow

9

what does extravascular space create?

a hematopoietic microenvironment

10

**what does the extravascular space contain?**

- **stromal elements (cells and extracellular matrix)**
- **osteoclasts, plasma cells, mesenchymal stem cells, mast cells (rare)**
- accessory cells for hematopoiesis
- hematopoietic cells

11

what cells are produced in the vascular space in birds?

erythrocytes and thrombocytes

12

where are all blood cells created in mammals? where do blood cells then go?

in extravascular space. they then have to migrate through the endothelium and into sinus, then circulatory system once its developed

13

where are quiescent hemaopoietic stem cells (HSCs) concentrated?

near endosteal and trabecular bone (osteoblasts)

14

where are more active HSCs and hematopoietic cells found?

near vascular sinuses

15

where are erythroid cells found?

around macrophages

16

where are megakaryocytic cells found?

near sinusoidal endothelial cells

17

where are granulocytic cells found?

near stromal cells located away from vascular sinuses

18

what cells are found in bone marrow stroma (connective tissue)?

- endothelial cells
- *stromal cells*
- adipocytes
- *autonomic nerves*
- extracellular matrix

19

what is the function of bone marrow endothelial cells?

they synthesize hematopoietic growth factors

20

**what do bone marrow endothelial cells regulate?**

** they regulate transendothelial movement of cells to and from the extracellular space**

21

what do bone marrow endothelial cells and stromal cells produce?

extracellular matrix components

22

describe some characteristics of bone marrow stromal cells

- fibroblastic-type or vascular smooth muslce like cells
- extensive branched cytoplasmic processes that provide structural support for the bone marrow

23

**what is the function of bone marrow stromal cells?**

** they synthesize collagen fibers and other extracellular matrix components **

24

what is the function of adventitial stromal cells in bone marrow?

they support the endothelium of the venous sinuses

25

** how do bone marrow stromal cells support hematopoiesis? **

** through cell-to-cell contacts and synthesis of growth factors **

26

what do bone marrow adipocytes develop from?

stromal cells

27

** what is the main function of bone marrow adipocytes? **

they accumulate increased lipid when the numbers of hematopoietic cells in the marrow decrease (reversible)

28

what is the main function of nerves in bone marrow?

largely vasomotor in function

29

** what may nerves in bone marrow promote ? **

** HSC mobilization **

30

what might nerves in bone marrow do (we are not sure)?

regulate hematopoietic growth factor synthesis by other cells

31

what is the function of collagen fibers in the extracellular matrix?

provide scaffolding

32

what does the extracellular matrix consist of?

collagen fibers
basal laminae of the sinuses
adhesion molecules
proteoglycans

33

which accessory cells are involved in regulating hematopoiesis that reside in the extravascular space of bone marrow?

- macrophages
- T-lymphocytes, B-lymphocytes, and NK cells
- osteoblasts

34

which accessory cell is most important for erythropoiesis?

macrophages

35

what is the function of the various lymphocytes and NK cells in the extravascular space of bone marrow?

some produce positive growth factors
other subsets produce factors that inhibit proliferation of hematopoietic cells

36

what are osteoblasts important for in the extravascular space of bone marrow?

stem cell maintenance

37

** what are HSCs positive for?**

** the CD34 surface antigen **

38

what is the appearance of HSCs and HPCs? (hematopoietic stem cells and hematopoietic progenitor cells)

they are lymphocyte-like in appearance

39

** what is CD an abbreviation for ? **

** clusters of differentiation antigens **

40

what is the function of hematopoietic stem cells?

- proliferation and sustained self-replication

41

**what do hematopoietic stem cells (HPCs) have the capacity to do? **

** to differentiate into all blood cell types and some tissue cell types (like macrophages, dendritic cells, osteoclasts, mast cells) **

42

briefly describe the cell cycle (G1, S, G2, M, Go)

G1 = protein synthesis and preparation of DNA replication
S = DNA synthesis
G2 = protein synthesis and preparation for mitosis
M = mitosis
Go = resting phase

43

what is the function of hematopoietic progenitor cells (HPCs)?

proliferation, they replicate more rapidly than HSCs

44

**describe the replication of hematopoietic progenitor cells**

limited self-replication - not sustained without replenishment from HSCs

45

*describe the differentiation of hematopoietic stem cells*

more restricted lineage potential than HSCs

46

**describe the amounts of HPCs relative to HSCs**

* hamatopoietic progenitor cells are much more common in neonates than adults. HPCs represent about 1% of bone marrow cells in adults *

47

what do HSCs produce?

- common lymphoid progenitor cells (CLP)
- common myeloid progenitor cells (CMP)

48

what do CLPs (common lymphoid progenitors) give rise to?

B lymphocytes, T lymphocytes and NK cells

49

what do CMPs (common myeloid progenitors) give rise to?

non lymphoid blood cells, macrophages, dendritic cells, osteoclasts and mast cells

50

what are colony forming units (CFUs)?

progenitor cells that are recognized in bone marrow cultures by the types of colonies they form

51

what are some examples of colony forming units (CFUs)?

- common myeloid progenitor
- GM progenitor
- erythroid progenitors

52

what types of cells do mesenchymal stem cells produce?

- stromal cells and adipocytes
- endothelial cells
- fibroblasts and myoblasts
- osteoblasts and chrondrocytes

53

what can additional stem cells in marrow grow?

- hepatocytes and cholangiocytes
- **neural cells **
- epithelial cells of skin and GI tract

54

define homing of HSCs and HPCs

the process by which circulating HSCs and HPCs bind to luminal surfaces of endothelial cells in the bone marrow

55

what is the process of homing of HSCs and HPCs

1. migrate through endothelial cells
2. migrate through extravascular space and bind to appropriate microenvironment location
3. proliferate, self-replicate and differentiate

56

what is the most important adhesion molecule?

beta-1-integrin

57

what do adhesion molecules do?

they bind to glycoproteins including VCAM-1 in ECM

58

**what type of adhesion molecules do hematopoietic cells express on their surface? **

** it varies depending on the hematopoietic cell**

59

**what does the binding of hematopoietic cells to ECM glycoproteins play a role in?**

**activating signal pathways for cell growth, survival and differentiation or modulating responses to growth factors **

60

describe the appearance of proteoglycans

they have a protein core with negatively charged repeating charbohydrate glycosaminoglycans (GAGs) such as chondroitin sulfate

61

what is the function of proteoglycans?

they bind growth factors and strengthen the bonding of hematopoietic cells through binding with receptors on hematopoietic cells

62

what are hematopoeitic growth factors?

they are glycoproteins that promote the proliferation, maturation and survival of hematopoietic cells

63

** where are hematopoietic growth factors produced? **

** locally in the marrow (paracrine and autocrine) and/or by cells in peripheral tissues (endocrine) **

64

what do cytokines include?

colony stimulating factors (CSFs), interleukins, and poietins

65

**what must hematopoietic cells have?**

**an appropriate surface receptor to respond to a specific hematopoeitic growth factor **

66

what does binding and activation of hematopoietic growth factor receptors do? (4 things)

1. generation of transcription factors
2. **synthesis of molecules that inhibit apoptosis**
3. formation of cell cycle regulators (cyclins)
4. **synthesis of additional HGF and HGF receptors **

67

**what is an identifying characteristic in the cell types or stages stimulated by hematopoietic growth factors (HGFs)?**

**there is considerable redundancy and overlap in the cell types or stages stimulated by HGFs **

68

what are some examples of early-acting factors within HGFs?

- stem cell factor
- flt3 ligand (FL)
- thrmbopoietin (TPO)

69

what do early-acting factors require the presence of?

other cytokines including IL3, IL6, IL11 and G-CSF

70

what are some examples of intermediate-acting HGF factors?

IL3 (multi-CSF), GM-CSF, and IL-4

71

what are some examples of late acting HGFs?

G-CSF, M-CSF, EPO, TPO, and IL5

72

define indirect stimulation

TNF and IL1 stimulate stromal and accessory cells to release various HGFs

73

what can CMP give rise to? what can that then differentiate into?

CMP can give rise to MkEP which can differentiate into MkP (megakaryocyte progenitors) and EPs (erythroid progenitors)

74

what is the production of EP (erythroid progenitors) stimulated by?

SCF, IL-3, GM-CSF, and TPO in presence of EPO

75

where do erythroid cells develop?

around macrophages

76

what do macrophages help create?

microenvironment

77

in what ways do macrophages help create a microenvironment?

- early intermediate-acting growth factors
- erythropoietin
- inflammatory cytokines which can inhibit erythropoiesis

78

**what is the function of erythroid islands?**

** they phagocytize expelled nuclei and damaged or aged erythrocytes **

79

what do erythroid islands store from phagocytized erythrocytes?

iron

80

what nutrients are needed for erythropoiesis?

amino acids
essential fatty acids
metals
vitamins

81

name some examples of metals needed as nutrients for erythropoiesis

iron - for heme synthesis
copper - hephaestin, ceruplasmin
cobalt - component of B12

82

name some examples of vitamins needed for erythropoiesis

vitamin B6 - heme synthesis
tetrahydrofolic acid - DNA, RNA synthesis
vitamin B12 - folate metabolism

83

in what step of the maturational divisions is marrow released?

during the development of reticulocytes

84

when are reticulocytes formed?

when metarubicytes expel their nuclei, usually while still bound to macrophages

85

how many reticulocytes can be formed by one rubiblast?

one rubiblast produces about 16 reticulocytes in about 4 days

86

where does reticulocyte maturation occur?

in marrow, blood, and spleen

87

what type of reticulocytes do dogs have in blood?

aggregate reticulocytes

88

what type of reticuolcytes do cats have in blood?

many punctate reticulocytes, sometimes no aggregate reticulocytes

89

what type of reticuolcytes do cattle and goats have in blood?

none

90

what type of reticuolcytes do sheep have in blood?

small numbers of punctate reticulocytes

91

what type of reticuolcytes do horses have in blood?

none, even in response to anemia

92

what are howell-jolly bodies

small pieces of nuclei that may be left behind in teh cell after nuclear extrusion

93

how do H-J bodies (howell-jolly) form?

either karyorrhexis (fragmentation) of the metaurbricyte nucleus or during abnormal mitosis

94

which organ removes H-J bodies?

the spleen

95

what is erythropoietin growth factor?

the principal growth factor that promotes the viability, proliferation and differentiation of EPs expressing specific cell surface EPO receptors

96

when do EPO receptors peak?

at CFU-E stage and decline

97

what is the main mechanism of erythropoietin?

inhibition of apoptosis

98

what is the effect of high concentrations of erythropoietin?

shorten marrow transit time and promote early release of large "stress" reticulocytes

99

what are the sites of EPO synthesis?

renal interstitial cells
extrarenal production - liver, bone marrow macrophages and erythroid cells

100

what increases the number of cells producing EPO?

hypoxia

101

what causes inhibitionof erythropoiesis?

- lack of HGFs
- inhibitors

102

what are some examples of growth factors?

IL-3, GM-CSF, G-CSF

they act on CMP, GMP and GP

103

what is the effect of G-CSF? which cells does it effect?

increased cell division, decrease marrow transit time

GPs to myeloblasts

104

what cells produce growth factors?

T-lymphocytes and mononuclear phagocytes

fibroblasts and endothelial cells

105

how is granulopoiesis inhibited? (3 ways)

1. mature neutrophils in marrow release inhibitory substances like serine proteases
2. neutrophil clearance of circulating G-CSF by binding to receptors
3. mature neutrophils in peripheral tissues can remove bacterial stimulus for granulopoiesis

106

how are eosinophils produced (3 ways)?

1. **marrow storage pool like neutrophils**
2. IL-3 and GM-CSF for early progenitors
3. **IL-5 from Th2 lymphocytes for terminal maturation **

107

how are basophils produced? (4 ways)

1. GMP produces bipotential basophil/mast cell progenitor
2. **basophil progenitor for basophils**
3. granules at myelocyte stage
4. ** specific factor not recognized - growth factors similar to those for eosinophils**

108

how are mast cells produced (3 ways)?

1. mast cell progenitor (MaP)
2. mast cells develop in tissues
3. SCF is especially important for mast cell formation, multiple cytokines involved

109

what are examples of growth factors used for the production of monocytes?

IL-3, GM-CSF, M-CSF, and IL-34

110

what is an unique characteristic about monocytopoiesis?

short generation time and little marrow reserve

111

what may monocytes become?

macrophages or inflammatory dendritic cells in tissues, depending on the amounts of various cytokines present

112

what does CDP form?

pre-classical dendritic cells and plasmacytoid dendritic cells

113

where are CDP products released?

into the blood and enter the tissues

114

what stimulates production of CDP?

various cytokines

115

what are osteoclasts?

multinucleated cells which degrade bone

116

what do osteoclasts develop from?

monocyte progenitors

117

what are SCF and flt3 ligand?

early lymphoid progenitor cells in marrow

118

where are most B-cells produced in mammals? birds?

in mammals - mostly marrow.
dogs, pigs, ruminants - peyer's patches
in birds - bursa of fabricius

119

where are T-cells produced?

in the thymus
progenitors in the marrow
final development in thymus

120

what is the most important growth factor needed for B-lymphocyte production?

Il-7

121

what inhibits B-lymphocyte production

certain cytokines including interferons

122

where do activated B-lymphocytes migrate to?

cortex of lymph nodes and follicles in peyer's patches and spleen

123

what may B-lymphocytes developinto?

mature plasma cells

124

what growth factors promote development of T-lymphocyte production?

Flt3L and IL-7

125

where do T-lymphocytes accumulate?

in paracortical areas of lymph nodes
periarteriolar lymphoid sheaths of spleen
interfollicular areas of peyer's patches

126

where are NK cells primarily produced? are growth factors required?

in bone marrow

yes

127

where do subsets of NK cells develop?

thymus, lymph nodes, liver and spleen

128

do non-mammals have megakaryocytes?

no; the only giant cell in the marrow is the osteoclast

129

where is the megakaryocyte niche located?

just outside the vascular sinuses

130

what stimulates thrombopoiesis

proliferation and expansion of megakaryocyte progenitor cells

131

what are the 2 main functions of thrombopoietin?

- promotes differentiation of progenitor cells into megakaryocytes
- stimulates increased endomitosis, results in increased ploidy and size

132

where is the major site of thrombopoietin production?

endothelial cells of liver

133

where are TPO (thrmbopoietin) receptors located and what do they do?

located on platelets and megakaryocytes, they bind and remove TPO, providing negative feedback

134

what stimulates thrombopoietin (TPO) synthesis by liver during inflammation?

IL-6

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