[DISCUSSION] MODULE 2: QUIZ 2 COVERAGE Flashcards
1961: Till and McCulloch
- irradiated [?] and [?] of mice = aplasia
spleens and BM
1961: Till and McCulloch
- Aplastic mice given IV injection of
BM
1961: Till and McCulloch
- Colonies of HSCs were seen [?] later in the spleens
7-8 days
1961: Till and McCulloch
- Colonies =
Colony Forming Unit-Spleen (CFU-S)
Capable of self renewal and production of differentiated progeny
Colony Forming Unit-Spleen (CFU-S)
“committed myeloid progenitors”
colony forming unit granulocyte, erythrocyte, monocyte, megakaryocyte “CFU-GEMM
capable of giving rise to multiple lineages of blood cells
Colony Forming Unit-Spleen (CFU-S)
HEMATOPOIETIC PROGENITOR CELLS
2 Major types
I. Noncommitted/Undifferentiated hematpoietic stem cells (HSCs)
II. Committed projenitor cells
HEMATOPOIETIC PROGENITOR CELLS (committed and noncommitted) give rise to
all of the mature blood cells
2 Theories of Hematopoietic Progenitor cell origin
- Monophyletic theory
2. Polyphyletic theory
Pluripotent hematopoietic stem cell
Monophyletic theory
Most widely accepted theory
Monophyletic theory
vCapable of self-renewal
HEMATOPOIETIC STEM CELLS
vAre pluripotent
HEMATOPOIETIC STEM CELLS
vGive rise to diff progeny
HEMATOPOIETIC STEM CELLS
vAble to reconstitute the hematopoietic system of a lethally irradiated host
HEMATOPOIETIC STEM CELLS
Can differentiate into progenitor cells committed to either lymphoid or myeloid lineages
UNDIFFERENTIATED HSCS
Proliferates and Differentiates into: T, B, natural killer lymphocyte, dendritic cells
Common lymphoid progenitor
Proliferates and differentiates into: individual granulocytic, erythrocytic, monocytic and megakaryocytic lineages
Common myeloid progenitor
FATES OF HSCS
- Self-renewal
- Differentiation
- Apoptosis
When the HSC divide, it gives rise to two identical daughter cells
a. Symmetric division
b. Asymmetric division
**Till and Mculloch: Proposed that hematopoiesis is a random process whereby the JSC randomly commits to self-renewal or differentiation
STOCHASTIC model of hematopoiesis
Later studies suggest that the microenvironment in the BM determines whether the HSC will sef-renew or differentiate
INSTRUCTIVE model of hematopoiesis
Current thinking suggests that the ultimate decision made by the HSC can be describes by both
stochastic and instructive
Initial decision to self renew is probably
stochastic
which occurs later is determined by various signals from the HIM in response to spp requirements of the body
Lineage differentiation
parent cell produces identical cells with identical chromosomes; chromosomes are visible with light microscope
Mitotic phase
-Cytoplasm and nucleus mature at the same rate
- Synchronous
-Cytoplasm or nucleus mature first before the other Can lead to abnormality in shape and size
- Asynchronous
- Blast cells do not have
granules
- Blast cells contain a (?) ([?] to [?] of cell area) and a (?)
large nucleus - 3/3 to 7/8
small amount of cytoplasm
- As cells mature, the cytoplasm becomes
less basophilic
4. As cells mature, the (?) of the nucleus becomes heavier, and the darker the (?) stains, the heavier the chromatin is
chromatin
nucleus
- As the cells mature, they become
smaller
- (?) tend to disappear in mature cells
Nucleoli
- As cells mature, specific granules become
less prominent and smaller
- There are 4 different types of granules:
neutrophilic, basophilic, eosinophilic, azurophilic (primary)
-Group of specific glycoproteins secreted by cells
Cytokine
-in Hematopoiesis, they regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells (include: IL, lymphokines, monokines, interferons, chemokines, colony stimulating factors)
Cytokine
•Have direct and indirect effects on hematopoietic cells
CYTOKINES OR GROWTH FACTORS
•Cytokines with a positive influence on hematopoietic stem cells and progenitor cells with multilineage potential
KIT ligand, FLT3 ligand, GM-CSF, IL-1, 6, 11
KIT ligand, FLT3 ligand, GM-CSF, IL-1, IL-6, IL-11
Cytokines with a positive influence on hematopoiesis
Cytokines with a negative influence on hematopoiesis
Transforming growth factor-B, Tumor necrosis factor-a, interferons
Cytokines with multiple actions
Interleukins
a. Proteins exhibiting
multiple biologic activities
b. Have [?] with other cytokines
synergistic interactions
c. Part of interacting systems with [?]
amplification potential
d. effective at
very low concentrations
-have high specificity for their target cells
Colony Stimulating Factors (CSF)
-active at low concentrations
Colony Stimulating Factors (CSF)
Can be classified accdg to the part of the development process that they influence
Growth Factors
Multilineage in action
Early acting growth factors
Ex: KIT ligand, FLT3 Ligand, GM-CSF, IL-3
Early acting growth factors
formerly erythrocytes
RBCs
Erythroblasts
nucleated red cell precursors
Normoblasts
developing nucleated cells with normal appearance
Megaloblast
abnormal appearance of developing nucleated cells in megaloblastic anemia
Three nomenclatures are used in naming for the erythroid precursors
NORMOBLASTIC
RUBRIBLASTIC
ERYTHROBLASTIC
-The glycoprotein hormone produced by the kidneys (renal peritubular interstitial cells)
ERYTHROPOIETIN
-ERYTHROPOIETIN Main effect:
Place more erythrocytes into the circulation at a faster rate
Main effect: Place more erythrocytes into the circulation at a faster rate.
HOW?
- Early release of reticulocytes
- Prevent apoptotic cell death
- Reduces maturation time inside the bone marrow
MATURATION SEQUENCE
I. Erythroid progenitors
II. Erythroid Precursors
I. Erythroid progenitors
a. Pluripotential hematopoietic stem cells
b. CFU-GEMM/CFU-S
c. CFU-MegE
d. BFU-E
d. CFU-E
II. Erythroid Precursors
a. Pronormoblast
b. Basophilic normoblast
c. Polychromatic normoblast
d. Orthochromic normoblast
e. Reticulocyte/Polychromatic (polychromatophilic)
erythrocyte
f. Erythrocyte
is a process encompassing replication (division) to increase cell numbers and development from immature to mature cell stages.
Normoblastic proliferation
Period between cell divisions; chromosomes not visible under the light microscope
Interphase
Limbo phase; Cells that are not dividing and possibly never to divide again
G0 phase
Metabolically active cell duplicates most of its organelles and cytosolic components
G1 phase (8-10 hours)
Replication of chromosome begins
G1 phase (8-10 hours)
Replication of DNA and chromosomes
S phase (8 hours)
Cell growth, enzyme and protein synthesis continue
G2 phase (4-6 hours)
Replication of centrosome complete
G2 phase (4-6 hours)
Parent cell produces identical cells with identical chromosomes; chromosomes visible under the light microscope
Mitotic Phase
▪ Nuclear division
Mitosis
▪ Distribution of two sets of chromosomes into separate nuclei
Mitosis
Chromatin fibers condense into paired chromatids
Prophase
Nucleolus and nuclear envelope disappear
Prophase
Each centrosome moves to an opposite pole of the cell
Prophase
Centromeres of chromatid pairs line up at the metaphase plate
Metaphase
Centromeres split
Anaphase
Identical sets of chromosomes move to opposite poles of cell
Anaphase
Nuclear envelopes and nucleoli reappear
Telophase
Chromosome resume chromatin form
Telophase
Mitotic spindle disappears
Telophase
▪ Cytoplasmic division
Cytokinesis
▪ Usually begins in late anaphase with the formation of a cleavage furrow & is completed after the telophase
Cytokinesis
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
EPO
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
G-CSF
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
GM-CSF
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IL-2
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IL-3
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IL-6
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IL-10
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IL-12
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IL-15
Primary Cell Source:
Primary Target Cell:
Biological Activity:
Current/Potential Therapeutic Applications:
IFN-a
-Stimulus to red cell production
Hypoxia
Primary oxygen sensing system
kidneys (peritubular fibroblasts)
Hypoxia = detected by [?] which release EPO
peritubular cells
detected by peritubular cells which release EPO
Hypoxia
They receive 20% of cardiac output with little loss of O2 levels leaving the heart =
early detection of oxygen level decline
kidneys
Regardless of the source of hypoxia, having more [?] should help to overcome it.
red blood cells
A true hormone
Erythropoietin – EPO
Produced at the kidneys
Erythropoietin – EPO
Acting at a distant location (the bone marrow)
Erythropoietin – EPO
A growth factor that initiates an intracellular message to the developing red cells = SIGNAL TRANSDUCTION
EPO
**EPO must bind to its [?] to initiate the signal or the message.
receptor on the surface of the cells
Criteria used in the ID of the erythroid precursors:
Trends affecting the red cell appearance throughout maturation:
- Overall diameter of the cell decreases
- Diameter of the nucleus decreases l=more rapidly than does the size of the cell = N:C ratio decreases
- Nuclear chromatin becomes coarser, clumped, condensed
- Nucleoli disappear