HEMATOPOIETIC STEM CELLS AND CYTOKINES Flashcards
Stem Cell Theory
In 1961, _______conducted a series of experiments in which they irradiated spleens and bone marrow of mice, creating a state of aplasia.
These aplastic mice were given an intravenous injection of______ cells.
Colonies of HSCs were seen 7 to 8 days later in the spleens of the irradiated (re-cipient) mice.
These colonies were called…
Till and McCulloch
marrow
colony-forming units-spleen (CFU-S).
investigators later found that these colonies were capable of self-renewal and the production of differentiated progeny.
colony-forming units-spleen (CFU-S)
The CFU-S represents what we now refer to as committed ____________ granulocyte, erythrocyte, monocyte, and megakaryocyte (CFU-GEMM).
myeloid progenitors or colony-forming unit
These cells are capable of giving rise to multiple lineages of blood cells.
myeloid progenitors or colony-forming unit
Morphologically unrecognizable hematopoietic progenitor cells can be divided into two major types: (2)
These two groups give rise to all of the mature blood cells.
noncommitted or undifferentiated HSCs
committed progenitor cells.
The_______ theory suggests that all blood cells are derived from a single progenitor stem cell called a_______
monophyletic
pluripotent hematopoietic stem cell
The______ theory suggests that each of the blood cell lineages is derived from its own unique stem cell.
polyphyletic
The______ theory is the most widely accepted theory among experimental hematologists.
monophyletic
HSCs by definition are capable of_______, are______ and give rise to differentiated progeny, and are able to reconstitute the hematopoietic system of a lethally irradiated host.
self-renewal
pluripotent
The undifferentiated HSCs can differentiate into progenitor cells committed to either ______ or _______lineages.
lymphoid or myeloid
These lineage-specific progenitor cells are the_________ which proliferates and differentiates into T, B, and natural killer lymphocyte and dendritic lineages; and the_________, which proliferates and differentiates into individual granulocytic, erythrocytic, mono-cytic, and megakaryocytic lineages.
common lymphoid progenitor,
common myeloid progenitor
These lineage-specific progenitor cells are the common lymphoid progenitor, which proliferates and differentiates into:
T, B, and natural killer lymphocyte and dendritic lineages
proliferates and differentiates into individual granulocytic, erythrocytic, mono-cytic, and megakaryocytic lineages.
common myeloid progenitor
Despite the limited numbers of HSCs in the bone marrow,______ blood cells per kilogram of body weight are produced each day for the entire life span of an individual.
Most of the cells in normal bone marrow are precursor cells at various stages of maturation.
6 billion
HSCs are directed to one of three possible fates:
self-renewal
differentiation
apoptosis
When the HSC divides, it gives rise to two identical daughter cells.
Both daughter cells may follow the path of differentiation, leaving the________, or one daughter cell may return to the stem cell pool and the other daughter cell may follow the _________ or undergo apoptosis.
stem cell pool (symmetric division)
_______proposed that hematopoiesis is a random process whereby the HSC randomly commits to self-renewal or differentiation
This model is also called the______
Till and McCulloch
stochastic model of hematopoiesis.
Later studies suggested that the microenvironment in the bone marrow determines whether the HSC will self-renew or differentiate (model???)
instructive model of hematopoiesis
Researchers believe that the ultimate decision made by the HSC can be described by both the stochastic and instructive models of hematopoiesis.
The initial decision to self-renew or differentiate is probably_______, whereas lineage differentiation that occurs later is determined by various signals from the hematopoietic inductive microenviron-ment in response to specific requirements of the body.
stochastic
The _______ model suggests that HSCs receive low-level signals from the hematopoietic inductive microenvi-ronment to amplify or repress genes associated with commitment to multiple lineages.
multilineage priming model
The implication is that the cell’s fate is determined by intrinsic and extrinsic factors.
multilineage priming model
________ regulation involves proliferation and differentiation signals from specialized niches located in the hematopoietic inductive microenvironment via direct cell-to-cell or cellular-extracellular signaling molecules.”
Some of the cytokines released from the hematopoietic inductive microenvironment include factors that regulate proliferation and differentiation, such as….
Extrinsic
KIT ligand
thrombopoietin (TPO)
FLT3 ligand
_______ regulation involves genes such as_____, which is expressed in cells in the hemangioblast, a bipotential progenitor cell of mesodermal origin that gives rise to hematopoietic and endothelial lineages; and GATA2, which is expressed in later-appearing HSCs. Both these genes are essential for primitive and definitive hematopoiesis
Intrinsic
TAL1
In addition to factors involved in differentiation and regulation, there are__________, such as Notch-1 and Notch-2, that allow HSCs to respond to hematopoietic inductive microenvironment factors, altering cell fate.
regulatory signaling factors
As hematopoietic cells differentiate, they take on various morphologic features associated with maturation.
These include an overall decrease in_____ and a decrease in the ______ratio.
Additional changes that take place during maturation occur in the cytoplasm and nucleus. Changes in the nucleus include (5)
Changes occurring in the cytoplasm include decrease in (3)
cell volume
nucleus to cytoplasmic (N to C)
loss of nucleoli, decrease in the diameter of the nucleus, condensation of nuclear chro-matin, possible change in the shape of the nucleus, and possible loss of the nucleus.
Decrease in basophilia, increase in the proportion of cytoplasm, and possible appearance of granules in the cytoplasm.
A group of specific glycoproteins called________ regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells.
hematopoietic growth factors or cytokines
are a diverse group of soluble proteins that have direct and indirect effects on hematopoietic cells.
Its classification has been difficult because of their overlapping and redundant properties.
Cytokines
The terms cytokine and growth factor are often used synonymously; cytokines include (6)
interleukins (ILs)
lymphokines
monokines
interferons
chemokines
colony-stimulating factors (CSFs)
are responsible for stimulation or inhibition of production, differentiation, and trafficking of mature blood cells and their precursors.
Cytokines
Many of these cytokines exert a positive influence on HSCs and progenitor cells with multilineage potential (e.g., KIT ligand, FLT3 ligand, GM-CSE, IL-1, IL-3, IL-6, and IL-11).
Cytokines
Cytokines that exert a negative influence on hematopoiesis include (3)
transforming growth factor-B
tumor necrosis factor-o
Interferons
_________ cells require cytokines on a continual basis for their growth and survival.
Hematopoietic progenitor
Cytokines prevent hematopoietic precursor cells from dying by inhibiting________; they stimulate them to_____ by decreasing the transit time from Go to G, of the cell cycle; and they regulate cell differentiation into the various cell lineages.
apoptosis
divide
________ refers to programmed cell death, a normal physiologic process that eliminates unwanted, abnormal, or harmful cells.
It differs from______, which is accidental death from trauma
Apoptosis
necrosis
When cells do not receive the appropriate cytokines necessary to prevent cell death,_______ is initiated.
In some disease states ______ is “turned on,” which results in early cell death, whereas in other states _______ is inhibited, which allows uncontrolled proliferation of cells.
apoptosis
_________ are produced by many different cells.
They have a high specificity for their target cells and are active at low concentration.
Colony-Stimulating Factors
CSFs
The names of the individual factors indicate the predominant cell lines that respond to their presence.
CFUs
The primary target of G-CSF is the______ cell line, and GM-CSF targets the _______ cell line.
granulocytic
granulocytic-monocytic
Although GM-CSF stimulates the proliferation of granulocyte and monocyte progenitors, it also works synergistically with______ to enhance megakaryocyte colony formation.
IL-3
Ogawa described early-acting growth factors (multilineage), intermediate-acting growth factors (multilineage), and late-acting growth factors (lineage restricted).
Early-Acting Multilineage Growth Factors
Early stages
Pluripotent
Common myeloid/ lymphoid
_______, also known as_______, is an early-acting growth factor; its receptor is the transmembrane protein, KIT
KIT ligand
stem cell factor (SCF)
_______ is a receptor-type tyrosine-protein kinase that is expressed on HSCs and is down-regulated with differentiation.
The binding of_______ to the extracellular domain of the KIT receptor triggers its cytoplasmic domain to induce a series of signals that are sent via signal transduction pathways to the nucleus of the HSC, stimulating the cell to proliferate.
KIT
KIT ligand
As HSCs differentiate and mature, the expression of KIT receptor______.
Activation of the KIT receptor by KIT ligand is essential in the_____ stages of hematopoiesis.
decreases
early
_______is also a receptor-type tyrosine-protein kinase.
KIT ligand and FLT3 ligand work synergistically with IL-3, GM-CSE, and other cytokines to promote_____ HSC proliferation and differentiation.
FLT3
early
In addition,_____ regulates blood cell production by controlling the production, differentiation, and function of granulocytes and macrophages.”
IL-3
induces expression of specific genes that stimulate HSC differentiation to the common myeloid progenitor.
GM-CSF
Characteristics shared by interleukins include the following:
- They are proteins that exhibit multiple biologic activities, such as the regulation of autoimmune and inflammatory
reactions and hematopoiesis. - They have synergistic interactions with other cytokines.
- They are part of interacting systems with amplification potential.
- They are effective at very low concentrations.
- They are proteins that exhibit multiple biologic activities, such as the regulation of autoimmune and inflammatory
reactions and hematopoiesis. - They have synergistic interactions with other cytokines.
- They are part of interacting systems with amplification potential.
- They are effective at very low concentrations.
Na pressure Hahahahah
Erythropoiesis occurs in the ________and is a complex, regulated process for maintaining adequate numbers of erythrocytes in the peripheral blood.
bone marrow
The CFU-GEMM gives rise to the earliest identifiable colony of RBCs, called the_______
It then produces a large multiclustered colony that resembles a cluster of grapes containing_______.
These colonies range from a single large cluster to 16 or more clusters.
burst-forming unit-erythroid (BFU-E)
brightly colored hemoglobin
BFU-Es under the influence of IL-3, GM-CSE, TPO, and KIT ligand develop into___________
It has many EPO receptors and has an absolute requirement for EPO.
Some of it are responsive to low levels of EPO and do not have the proliferative capacity of the BFU-E.
EPO serves as a differentiation factor that causes the CFU-E to differentiate into pronormoblasts, the earliest visually recognized erythrocyte precursors in the bone marrow.
colony-forming unit-erythroid (CFU-E) colonies.
EPO is a lineage-specific glycoprotein produced in the________.
In addition, a small amount of EPO is produced by the_____.”
renal peritubular interstitial cells - kidney
liver
_______ in the kidney is the stimulus that activates production and secretion of EPO
EPO exerts its effects by binding to transmembrane receptors expressed by erythroid progenitors and precursors.
EPO serves to recruit CFU-E from the more primitive BFU-E compartment, prevents apoptosis of erythroid progenitors, and induces hemoglobin synthesis
Oxygen availability
Leukopoiesis
Leukopoiesis can be divided into two major categories:
myelopoiesis and lymphopoiesis.
Factors that promote differentiation of the CFU-GEMM into neutrophils, monocytes, eosinophils, and basophils include (7)
GM-CSF
G-CSE
macrophage colony-stimulating factor (M-CSF)
IL-3
IL-5
IL-11
KIT ligand
stimulates the proliferation and differentiation of neutrophil and macrophage colonies from the colony-forming unit-granulocyte-monocyte.
____ and _____ stimulate neutrophil differentiation and monocyte differentiation from the colony-forming unit-granulocyte and colony-forming unit-monocyte.
GM-CSF
G-CSF and M-CSF
IL-3 is a multilineage stimulating factor that stimulates the growth of (4)
granulocytes, monocytes, megakaryocytes, and erythroid cells
Eosinophils require (3) for differentiation.
GM-CSE
IL-5
IL-3
The requirements for basophil differentiation are less clear, but it seems to depend on the presence of (2)
IL-3
KIT ligand
Growth factors promoting______ differentiation include IL-2, IL-7, IL-12, and IL-15 and to some extent IL-4, IL-10, IL-13, IL-14, and IL-16.
lymphoid
Megakaryopoiesis
Earlier influences on megakaryopoiesis include (6)
The stimulating hormonal factor TPO (also known as MPL ligand), along with IL-11, controls the production and release of platelets.
The liver is the main site of production of TPO
GM-CSF
IL-3
IL-6
IL-11
KIT ligand
TPO
