Hematopoiesis & Bone Marrow Flashcards

1
Q

Hematopoiesis can be divided into these three subsections of blood cell production

A
  1. Granulopoiesis (WBCs)
  2. Erythropoiesis (RBCs)
  3. Megakaryopoiesis (platelets)
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2
Q

Terminal, differentiated, committed

A

Mature blood cells

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3
Q

What is the amount of bone marrow transplants a year in US?

A

4,500

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4
Q

6 important properties of HSCs

A
  1. Differentiate into blood and immune cells
  2. Can be isolated from blood (1/100,000 blood cells) or bone marrow (1/10,000 cells)
  3. Self renewable
  4. Can mobilize out of bone marrow
  5. Restore long term hematopoietic function
  6. Can do apoptosis
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5
Q

How many blood cells does the bone marrow produce a day?

A

500 billion

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6
Q

Multilineage maturation of HSC (6)

A
  1. WBC
  2. RBC
  3. Platelets
  4. Mast Cells
  5. Dendritic Cells (i.e. immune cells, langerhans)
  6. Osteoclasts
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7
Q

Percentage of HSC out of notal nucleated cells in bone marrow

A

<0.01% RARE

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8
Q

How are HSC identified?

A

By flow cytometry

-laser based technology, biomarker detection

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9
Q

5 important markers on HSC

A

CD34, Thy1, MDR-1, c-MPL, c-kit

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10
Q

glycoprotein involved in cell adhesion (marker)

A

CD34

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11
Q

Drug efflux pump

A

MDR (multi-drug resistant)

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12
Q

What are the 3 sources of HSCs?

A
  1. Bone Marrow
  2. Peripheral blood
  3. Umbilical cord
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13
Q

Where does hematopoiesis start?

A

Yolk sac

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14
Q

What arise from the mesoderm in the aortogonadal nodeand become HSCs?

A

Hemangioblasts

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15
Q

At 5 weeks this organ takes over and becomes the primary source of hematopoiesis

A

Liver

spleen supports

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16
Q

When does bone marrow become major hematopoietic organ?

A

Mid-fetal development (8 weeks)

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17
Q

In abnormal circumstances, where can hematopoiesis occur in the adult?

A

Spleen, will be huge

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18
Q

How many HSCs do we have?

A

20,000

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19
Q

How many times do HSCs divide?

A

18 times

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20
Q

1 stem cell produces X progenitor cells, which produce Y precuror cells, which produce Z terminal cells

A

X=10,000 progenitor Y=50,000 precursor Z=25,000 terminal cels

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21
Q

What type of division can Stem cells undergo?

A

Asymmetric: 1 stem cell and 1 progenitor (has new markers)

can also divide symmetrically

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22
Q

Two main progenitor branches

A

Myeloid progenitor (granulocyte precursor), lymphoid progenitor

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23
Q

Myeloid progenitors

A

CFU-GEMM–>CFU-GM (->myeloblasts, granulocytes, osteoclasts) and CFU-EMK
(->megakaryocytes and erythroblasts)

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24
Q

Order of differentiation

A

HSC>Progenitor>Precurror>Differentiation>

Particular, mature cell(terminal)

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25
``` Reconstitutes all hematopoiesis....? Stem Cell: Progenitor: Precursor: Mature Cell: ```
Stem Cell: Yes Progenitor: No Precursor: No Mature Cell: No
26
``` Self renewal...? Stem Cell: Progenitor: Precursor: Mature Cell: ```
Stem Cell: Yes Progenitor: No Precursor: No Mature Cell: No
27
``` Response to cytokines...? Stem Cell: Progenitor: Precursor: Mature Cell: ```
Stem Cell: Yes, IL-3, SCF (Stem cell factor), TPO (thombopoietin) Progenitor: Yes Precursor: Yes, G-CSF, M-CSF, GM-CSF, EPO Mature Cell: Yes, G-CSF, M-CSF, GM-CSF, EPO G-CSF= granulocyte colony stimulating factor M=macrophage
28
Which is the only form of cell that has drug efflux pump?
Stem cell; MDR
29
Why are bad stem cells difficult to treat?
They are resting in G0 or prolonged G1 phase, have drug efflux pump so can resist
30
In adults, where do stem cells in bone marrow of large flat bones spend most of their time?
Iliac bones (widest part of pelvis) and sternum
31
Most of "bone marrow" transplants are stem cells collected from
Peripheral blood, NOT bone marrow
32
Stem cell plasticity latest reports
Scientists have been able to induce bone marrow or HSCs to differentiate into other types of tissue
33
What encases the bone marrow?
Cortical bone (transversed by trabecular)
34
What is the meshwork of blood vessels in between the bone called?
Sinusoids
35
How is the extracellular matrix maintained?
Reticulin fibers (reticular framework)
36
These two ingredients provide a sponge-like netowkr to support stromal and hematopoietic cells
Fibers and matrix
37
Where is yellow marrow found?
Medullary cavity of long bones
38
Where is red marrow found? | 1(5), 2(1)
1. Flat bones (skull, sternum, ribs, vertebrae, pelvis) | 2. Long bones (trabecular bone at epiphysis)
39
List 5 important stromal cells
1. Fibroblasts (produce fibers, collagens, ECM) 2. Osteoblasts 3. Adipocytes 4. Endothelial cells (line sinuses, vessels) 5. Macrophages (store iron)
40
What is the CXCR-4 - SDF-1 interaction? ``` CXCR-4 = cytokine receptor type 4 SDF-1= Stromal derived factor ```
One example of how stroma/microenvironment interact with stem cell Neutrophils secrete enzymes that inactivate SDF-1 located on osteoblasts, encourage HSC to be released from cozy little area and mobilize. Can harvest them
41
What causes the release of enzymes from neutrophils in the CXC-R4 - SDF-1 interaction? What enzymes are released?
- G-CSF | - elastase, cathepsin G, MMP-2, MMP-9
42
What produces SDF-1 and regulates its expression?
Osteoblasts (they secrete many cytokines and overall help to regulate hematopoietic environment)
43
Endothelial cells (stromal) secrete what cytokine and express which adhesion molecules?
cytokine IL5; E-selectin adhesion molecule
44
During differentiation, what do adipocytes express to promote hematopoiesis and influence osteogenesis?
Leptin, osteocalcin, increased prolactin receptors
45
What are 4 secreted ECM components in the bone marrow?
1. Proteoglycans 2. Fibers 3. Glycoproteins 4. Other matrix proteins
46
What types of collagens make up the fibers secreted in the bone marrow?
I, III, V
47
What is difference between bone marrow aspiration and biopsy?
Aspiration-removes bone marrow fluid and cells through a needle put into bone. Usually done first Biospy-removes bone with marrow inside
48
What do cytokines play a role in? (list 4)
1. Inflammation 2. Infection 3. Tumorigenesis * *4. Hematopoiesis
49
The action of cytokines may be these 3 types of signaling
Autocrine, paracrine, endocrine
50
These cytokine stimulate hematopoiesis (2)
Growth factors, colony-stimulating factors
51
True or False: Bone marrow stromal cells are the only cells that control hematopoiesis
FALSE. T-lymphocytes, monocytes/macrophages, and many others. Bone marrow stromal are most important though. Mature blood cels can also produce cytokines, feeding back into signaling system
52
How are cytokines polyfunctional?
Can affect proliferation, differentiation, functional activation/stimulation, survival
53
True or False: Cytokines can be early-acting or late-acting
TRUE.
54
What is physical make-up of cytokines and why is it important?
Glycoproteins, sugar part helps stabilize and increases their half life. Typically small, low molecular weight
55
Cell secretes a cytokine that stimulates itself
Autocrine
56
Cell secretes a cytokine that stimulates a nearby cell
Paracrine
57
Cell secretes a cytokine that stimulates another cell elsewhere in body
Endocrine (acts like hormone)
58
Hematopoietic cytokines can ave additive, synergistic and what other type of effect?
Antagonistic
59
How do cytokines communicate with target cells?
By binding to specific receptors; interaction results in activation of signaling cascade
60
What are two important properties that differentiate cytokines (endocrine) from hormones?
- Cytokines are very potent at low concentrations, circulating levels are almost undetectable. 1000x increase during trauma or infection - Cytokines are made by many cell types throughout body
61
Erythropoitin is made in what organ (and where specifically)?
Kidney, juxtatubular interstitial cells
62
These transcription factors respond to changes in available oxygen, particularly a decrease in oxygen
HIP, hypoxia inducible factor
63
EPO causes a number of events in signaling cascade, but in a very specific cell line. What step of differentiation contain receptors to communicate and recognize EPO? Be specific about step and specific cell name
RBC progenitors (under myeloid branch), CFU-EMK (leads to erythroblast/normoblast and then erythrocytes) SELECTIVE INTERACTION WITH CYTOKINE AND CERTAIN CELLS
64
Where is thrombopoietin made?
In liver (and minor in kidney and skeletal muscles)
65
What is the main function of thrombopoitein?
Makes platelets (+some effect on HSC)
66
Describe TPO feedback regulation
Platelets take up TPO via receptors and remove from circulation. If low platelet count, more TPO circulating and is a signal to tell precursors to make more platelets!
67
How many platelets are made a day?
100 billion. 10-20% are in spleen
68
Function of G-CSF
Increases neutrophil numbers and function G-CSF can be given clinically, white blood cell count will increase, neutrophil count will explode. Bone marrow responds to this exogenous insertion
69
Function of GM-CSF
Increases neutrophil, monocyte, and eosinophil numbers and function
70
What makes G-CSF, and where
Made by macrophages, fibroblasts, and endothelial cells. In all organs
71
What makes GM-CSF
Made by stromal cells, endothelial cells, and T cells
72
Neupogen is used clinically to mobilize HSC from bone marrow into blood for harvest. What is Neupogen an example of?
It's a cytokine, an example of clinical uses of G- and GM-CSFs Used in hematology oncology in bone marrow transplant
73
How do enzymes released from neutrophil inactivate SDF-1 ?
Cleaves its NH2 terminal signal sequence
74
This cytokine almost exclusively works way up at HSC level before differentiation
Stem Cell Factor
75
c-Kit ligand, mast cell growth factor, and steel factor are all different names for which cytokine? Why does it have these different names?
Stem Cell Factor: stimulates HSCs c-kit ligand: binds to c-kit receptors Mast cell growth factor: stimulates growth of mast cells Steel factor: steel locus, affects pigmentation (melanogenesis)
76
In addition to playing an important role in hematopoiesis, SCF (stem cell factor cytokine) also affects what other developments? (3)
Gametogenesis, Melanogenesis, Mast cell development
77
Stem cell factors have not been used clinically yet. What might they be used for in future?
- mobilize stem cells from donors - use it to grow stem cells - use as tumor marker - block it as tumor therapy - use it to deliver toxins to leukemia stem cells
78
Kidney failure wold be most likely to cause reduction of which cytokine and which cell type?
EPO, red blood cells (anemia)
79
Ossobuco
bone marrow in the kitchen, SOUP. great with sprinkled coarse sea salt