MODULE 2 UNIT 1 INTRO TO HEMATOPOIESIS Flashcards
the process of cellular formation, proliferation, differentiation and maturation of blood cells.
Hematopoiesis
is generally categorized as primitive or definitive.
Hematopoiesis
occurs in the embryo during the first two weeks and lasts up to the eighth week of gestation. It is the time when the blood cells produced are mostly primitive erythrocytes.
Primitive hematopoiesis
occurs on the eighth week until adulthood. In this stage, different blood cells are produced which can be distinguished morphologically and functionally thus the term definitive.
Definitive hematopoiesis
• “Yolk sac phase”
Mesoblastic Phase
• Begins around 19th day of embryologic development
Mesoblastic Phase
Mesoblastic Phase
• PRIMARY SITE OF HEMATOPOIESIS: [?] (Hematopoiesis occurs intravascularly)
Blood islands of the YOLK SAC
i. Cells of the yolk sac
- Mesodermal cells
- Angioblasts
Develop to primitive erythroblasts
- Mesodermal cells
Forms the future blood vessels
- Angioblasts:
BLOOD CELL/S FORMED in MESOBLASTIC PHASE
(1st month of embryonic development)
Erythroblasts
BLOOD CELL/S FORMED: Mesoblastic Phase
Erythroblasts (1st month of embryonic development)
Embryogenic hemoglobins are formed:
i. [?] (2 zeta chains & 2 epsilon chains)
ii. [?] (2 zeta chains & 2 gamma chains)
iii. -?] (2 alpha chains & 2 epsilon chains)
- Gower I
- Portland
- Gower II
▪ Begins at around 5-7 gestational weeks
Hepatic Phase
▪ PRIMARY SITE/S OF HEMATOPOIESIS: FETAL LIVER
Hepatic Phase
• Becomes the primary site of hematopoiesis during the 3rd month of fetal development
• Retains minimal activity up to 1-2 weeks after birth
Liver
• First fully developed organ in the fetus
• Becomes the major site of T cell production
Thymus
• Production of B lymphocytes
Spleen & Kidneys
gradually decreases granulocytic production and involves itself solely in lymphopoiesis
Spleen
BLOOD CELL/S FORMED: Hepatic Phase
• Erythrocytes still in production
• Granulocytes & Megakaryocytes (3rd month of gestation)
• Lymphocytes (4th month of gestation)
• Monocytes (5th month of gestation)
FETAL HEMOGLOBIN (4th month of gestation) is the PREDOMINANT HEMOGLOBIN but detectable levels of adult hemoglobin may be present
i. HbF: 2 alpha & 2 gamma chains
• Begins prior to the 5th month of development
Myeloid Phase
• PRIMARY SITE/S OF HEMATOPOIESIS: BONE MARROW (end of 6th month)
Myeloid Phase
Hematopoiesis occurs inside the medulla of the bone (where the bone marrow is located)
“Medullary hematopoiesis”
At birth, [?] becomes the ONLY SITE FOR PRODUCTION of erythrocytes, granulocytes, monocytes, platelets, and B lymphocytes
bone marrow
Myeloid-to-erythroid ratio gradually approaches
3:1 (adult levels)
Measurable levels of Hemoglobins F and A
i. HbA :
ii. HbA2:
i. HbA : 2 alpha chains & 2 beta chains
ii. HbA2: 2 alpha chains & 2 delta chains
Adult hematopoietic tissues can be classified according to their roles in
lymphocyte development
function for the production and maturation of T and B lymphocytes. These include the bone marrow and the thymus.
primary lymphoid tissues
Consists primarily of adipocytes
Adult
Yellow marrow
Hematopoietically active
Fetal
Flat bones
Epiphysis of long bones
Red marrow
all bones in the body contain the red marrow.
during infancy and early childhood
By age 5 to 7, retrogression occurs. This is the process of replacing the haematopoietically active red marrow with yellow marrow. The yellow marrow is consisting of adipocytes that is capable of reverting back to active marrow in cases of increased demand for blood cell production in the body.
By age 5 to 7, [?] occurs. This is the process of replacing the haematopoietically active red marrow with yellow marrow.
retrogression
is consisting of adipocytes that is capable of reverting back to active marrow in cases of increased demand for blood cell production in the body.
yellow marrow
is consisting of adipocytes that is capable of reverting back to active marrow in cases of increased demand for blood cell production in the body.
yellow marrow
Structure of the BM
A. Vascular region: Vascular sinuses
B. Hematopoietic cords
C. Trilaminar sinus wall
specialized blood vessels
Vascular sinuses
These are extravascular cords that are composed of hematopoietic cells and macrophages. They are located in spaces between the vascular sinuses and are supported by trabeculae of spongy bone.
Hematopoietic cords
It is noted that hematopoietic cells develop in specific [?] within the cords.
niches
separates the extravascular cords from the vascular sinuses
trilaminar sinus wall
Components (From the extravascular cords to the vascular sinus)
a. (Reticular) Adventitial cells
b. Basement membrane
c. Endothelial cells
Incomplete layer of cells on the abluminal surface of the vascular sinus (facing the extravascular cords)
(Reticular) Adventitial cells
Form a single, continuous layer along the luminal (inner) surface of vascular sinuses
Endothelial cells
play a very important role in nurturing and protecting hematopoietic stem cells
Niches/ Hematopoietic Microenvironment (within the cord)
Develop in small clusters; More mature forms located in outer surfaces of the vascular sinuses
Erythroblast
Found surrounding ironladen macrophages
Erythroblast
Adjacent to the walls of vascular sinuses
o Largest bone marrow cell
o Production of PLATELETS - Cytoplasmic fragments of megakaryocytes
Megakaryocytes
Deep within the cords (as the mature, they move closer to the vascular sinuses)
Immature myeloid cells (up to metamyelocyte stage)
ENTRY OF MATURE BLOOD CELLS FROM THE BONE MARROW TO PERIPHERAL CIRCULATION
Mature blood cell → Adventitial cell layer (contracts) →
Basement membrane → Endothelial cell layer →
Receptor-mediated process → Mature cells bind to the surface of endothelial cells →
Cells pass through pores in the endothelial cytoplasm → Vascular sinus →
Peripheral circulation
Bone Marrow Specimens: Collection
- Trephine/ Core biopsy
- Aspiration
▪ Utilizes Trephine biopsy needle ([?] needle)
Jamshidi needle
▪ Aspiration needle (?)
University of Illinois sternal needle
Collection is oftentimes carried out to observe the patient’s
myeloid to-erythroid ratio
Myeloid-to-Erythroid ratio:
Normal:
Infection:
Leukemia:
2:1 to 4:1 (Average of 3:1)
6:1
25:1
Normal marrow cells
a. All developing hematopoietic cells
b. Macrophages
c. Mast cells
d. Osteoblasts
e. Osteoclasts
▪ Misidentified as megakaryocytes
▪ Waterbug or comet appearance
▪ Confused with plasma cells
d. Osteoblasts
▪ Misidentified as megakaryocytes
e. Osteoclasts
a small, flat bilobed organ (Fig. 2-8, left) found in the thorax that has an average 30g weight at birth, 35 g weight at puberty and gradually atrophies. It is where T-cell maturation happens.
thymus
separates the two lobes of the thymus. It has extensions known as Trabeculae that penetrate the thymus and divides the two lobes into lobules
Capsule
It is the outer part of the thymic lobule and consists of a large amount of pre-T cells and scattered dendritic cells, epithelial cells, and macrophages.
Cortex in the Lobules
It is the outer part of the thymic lobule and consists of a large amount of pre-T cells and scattered dendritic cells, epithelial cells, and macrophages.
Cortex in the Lobules
are immature T cells that migrate from the red marrow to the thymic cortex and proliferate and start to mature at the cortex.
Pre-T cells
are derived from the monocytes. They exhibit long dendrite-like projections and assist the maturation process of the pre-T cells.
Dendritic cells
are specialized to carry out the positive selection process of pre-T cells. They have long processes that serves as a framework for the T cells and produce thymic hormones that are thought to aid in the maturation of T cells
Epithelial cells
help clear out the debris of dead and dying cells.
thymic macrophages
help clear out the debris of dead and dying cells.
thymic macrophages
is the inner part of the thymic lobule. It consists of more mature T cells, dendritic cells, and epithelial cells, and macrophages.
Medulla
is the inner part of the thymic lobule. It consists of more mature T cells, dendritic cells, and epithelial cells, and macrophages.
Medulla
In the medulla are* [?] which are clusters of epithelial cells that become arranged into concentric layers of flat cells that degenerate & become filled with keratohyalin granules and keratin.
Thymic (Hassall’s) corpuscles
These tissues are where lymphoid cells become competent (where lymphoid cells respond to foreign antigens). These consist of the spleen, lymph nodes, and lymphatic nodules.
Secondary lymphoid tissues
are bean-shaped structures found along lymphatic vessels which are specialized to filter lymph flowing through the lymphatic vessels.
Lymph Nodes
The [?] contains the primary and secondary follicles.
cortex
The [?] contain mature B cells, follicular dendritic cells, and macrophages. They are located are B cells that are not yet introduced and stimulated by any antigen thus become the site of antigen recognition of the mature B cells.
primary follicles
The [?] arises from the primary follicles after its B cells have recognized a specific antigen.
secondary follicles (B-cell area)
It has a central portion known as [?] which is the site of blast transformation of B cells and also of plasma cell and memory B cell formation.
germinal center
This is the region between cortex and the medulla.
Paracortex (T-cell area)
Paracortex (T-cell area) contains structures known as [?] which are specialized venules in the paracortex where numerous lymphocytes enter from the bloodstream.
high endothelial venules
Paracortex (T-cell area) are composed mainly of T cells and antigen presenting cells known as the
interdigitating cells.
The [?] is less densely populated and contains T cells, B cells, macrophages, and numerous plasma cells.
medulla
is the largest secondary lymphoid organs that functions as a large discriminating filter. It removes damaged cells and foreign antigens from the blood.
spleen
consists of capsule, trabeculae, reticular fibers and fibroblasts.
stoma
is the functional part of the spleen. It consists of two different kinds of tissue.
parenchyma
is the functional part of the spleen. It consists of two different kinds of tissue.
parenchyma
is approximately 20% of the weight of the spleen and consists of lymphoid tissues
white pulp
The structures of the white pulp are the following:
i. Periarteriolar lymphoid sheath (PALS)
ii. Primary follicles
iii. Marginal Zones
iv. Germinal Centers in secondary follicles
- Contains mainly T cells
Periarteriolar lymphoid sheath (PALS)
- Surrounds the primary follicles
- Contains dendritic cell that traps antigens
Marginal Zones
- Site of blast transformation of B cells
- Site of formation of plasma cells and B memory cells
Germinal Centers in secondary follicles
makes up more than one half of the volume of the spleen
red pulp
Contains B cells that are not yet introduced and stimulated by the antigen
Primary follicles
red pulp has the following parts:
i. Venous sinuses
ii. Splenic (Billroth’s) Cords
- Blood-filled structures
i. Venous sinuses
- Cords of splenic tissue
ii. Splenic (Billroth’s) Cords
ii. Splenic (Billroth’s) Cords
- Consists mainly of:
➢ Red blood cells
➢ Macrophages
➢ Lymphocytes
➢ Plasma cells
➢ Granulocytes
are egg-shaped masses of lymphatic tissue that resembles lymph nodes but do NOT have capsules.
lymphatic nodules
lymphatic nodules may be present in:
Small, solitary form
Multiple, aggregated form
Small, solitary form
i. Mucosa associated lymphoid tissue
ii. Cutaneous associated lymphoid tissue
Small, solitary form
i. Mucosa associated lymphoid tissue
ii. Cutaneous associated lymphoid tissue
- Intraepidermal lymphocytes (mostly T cells)
- Scattered in the lamina propria of the mucosa of the gastrointestinal, urinary and the reproductive tracts
i. Mucosa associated lymphoid tissue
- Intraepidermal lymphocytes (mostly T cells)
ii. Cutaneous associated lymphoid tissue
Multiple, aggregated form
i. Tonsils
ii. Peyer’s patches
- Aggregated lymphatic follicles in the ileum of the small intestine
ii. Peyer’s patches
are undifferentiated/ slightly differentiated cells that may either self- renew or give rise to cells of different lineages
Stem cells
STEM CELLS TYPES
a. Totipotential stem cell
b. Pluripotential stem cell
c. Multipotential stem cell
that can differentiate into all possible cells of the organism, including the extra-embryonic membranes
a. Totipotential stem cell
that can give rise to all of the cells of the embryo, and therefore of a whole animal, but are no longer capable of giving rise to extraembryonic structures
b. Pluripotential stem cell
c. Multipotential stem cell
that can give rise to multiple lineages but has lost the ability to give rise to all body cells
c. Multipotential stem cell
states that blood cells are derived from a single progenitor cell (Pluripotent hematopoietic stem cell. It is the most widely accepted theory
Monophyletic theory
It states that each blood cell lineages are derived from own unique stem cell.
Polyphyletic theory
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
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
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
▪ Distribution of two sets of chromosomes into separate nuclei
Mitosis
Chromatin fibers condense into paired chromatids
Nucleolus and nuclear envelope disappear
Each centrosome moves to an opposite pole of the cell
Prophase
Centromeres of chromatid pairs line up at the metaphase plate
Metaphase
Centromeres split
Identical sets of chromosomes move to opposite poles of cell
Anaphase
Centromeres split
Identical sets of chromosomes move to opposite poles of cell
Anaphase
Nuclear envelopes and nucleoli reappear
Chromosome resume chromatin form
Mitotic spindle disappears
Telophase
Nuclear envelopes and nucleoli reappear
Chromosome resume chromatin form
Mitotic spindle disappears
Telophase
▪ Cytoplasmic division
▪ Usually begins in late anaphase with the formation of a cleavage furrow & is completed after the telophase
Cytokinesis
After completing the cell cycle, the stem cells have the following possible fates:
1. Apoptosis
▪ Programmed cell death
2. Self-renewal
▪ Returning of daughter cell to stem cell pool
3. Differentiation
▪ Stem cells differentiate to acquire new morphologic features and give rise to
more mature forms
After completing the cell cycle, the stem cells have the following possible fates:
- Apoptosis
- Self-renewal
- Differentiation
▪ Programmed cell death
- Apoptosis
▪ Returning of daughter cell to stem cell pool
- Self-renewal
▪ Stem cells differentiate to acquire new morphologic features and give rise to more mature forms
- Differentiation
Types of Division
- Symmetric division
- Asymmetric division
▪ Both daughter cells follow the path of differentiation
- Symmetric division
▪ One daughter cell returns to stem cell pool while the other differentiates
- Asymmetric division
Models of Stem Cell Fate
- Stochastic model
- Instructive model
- Current model
▪ Random commitment of stem cells to either self-renew or differentiate
- Stochastic model
▪ Random commitment of stem cells to either self-renew or differentiate
- Stochastic model
▪ Signals from the hematopoietic inductive microenvironment determine the fate of the hematopoietic stem cell
- Instructive model
▪ Incorporate both stochastic and instructive model
▪ Initial decision follows stochastic model while lineage differentiation follows instructive model
- Current model
Types of Development
- Synchronous development
- Asynchronous development
▪ Cytoplasm and nucleus mature at the same rate
- Synchronous development
▪ Cytoplasm or nucleus mature first before the other
▪ Can lead to abnormality in shape and size
- Asynchronous development
- Blast cells do not have
granules
- Blast cells contain a large [?] (3/3 to 7/8 of cell area) and a small amount of [?]
nucleus
cytoplasm
- As cells mature, the cytoplasm becomes [?] (Exception:
Plasma cell)
less basophilic
- As cells mature, the [?] of the nucleus becomes heavier, and the darker the nucleus stains the heavier the chromatin is
chromatin
- As the cells mature, they become smaller (Exception: [?])
Megakaryocyte
- [?] tend to disappear in mature cells
Nucleoli
- As cells mature, specific granules become
less prominent and smaller
- There are four different types of granules:
neutrophilic, basophilic, eosinophilic, and azurophilic (primary).
are group of specific glycoproteins secreted by cells. In hematopoiesis, they regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells. These include interleukins, lymphokines, monokines, interferons, chemokines, and colony-stimulating factors (CSF).
Cytokines
are cytokines with multiple actions and are numbered by scientists in the order in which they were identified.
Interleukins
a. Interleukins are proteins that exhibit multiple biologic activities, such as
regulation of autoimmune and inflammatory reactions and hematopoiesis
b. Interleukins have [?] interactions with other cytokines.
synergistic
c. Interleukins are part of interacting systems with
amplification potential.
d. Interleukins are effective at
very low concentrations
have high specificity for their target cells and are active at low concentrations.
Colony-stimulating Factors (CSF)
The names of the individual factors indicate the [?] that respond to their presence.
predominant cell lines
Examples of CSF
G-CSF (Granulocyte Colony-stimulating Factor)
GM-CSF (Granulocyte-Macrophage Colony-stimulating Factor)
• Stimulates the proliferation of the granulocytic cell line
G-CSF (Granulocyte Colony-stimulating Factor)
• Stimulates the proliferation of the granulocytic-monocytic cell line
• Also works synergistically with Interleukin-3 (IL-3) to enhance megakaryocyte colony formation
GM-CSF (Granulocyte-Macrophage Colony-stimulating Factor)
Growth factors can be classified according to the part of the [?] that they influence
development process
▪ Multilineage in action
a. Early-acting growth factors
a. Early-acting growth factors examples:
i. KIT ligand
ii. FLT3 ligand
iii. GM-CSF
iv. Interleukin-3 (IL-3)
i. KIT ligand
• Also known as stem cell factor (SCF)
• An early-acting growth factor which attaches to the receptor transmembrane KIT
• Binding of KIT ligand to the KIT receptor triggers the cell to proliferate; Activation of the KIT receptor which is essential in the early stages of hematopoiesis.
i. KIT ligand
• Works synergistically with IL-3, GM-CSF, and other cytokines to promote early hematopoietic stem cell proliferation and differentiation.
• Regulates blood cell production by controlling the production, differentiation, and function of granulocyte and macrophages
ii. FLT3 ligand
• Induces expression of specific genes that stimulate hematopoietic stem cell differentiation to the common myeloid progenitor.
iii. GM-CSF
• Aka Multi-CSF
iv. Interleukin-3 (IL-3)
Subsequently, they give rise to mature T cells that express either CD4 or CD8 surface antigen as they move toward the medulla
- Thymic (Hassall’s) corpuscles
leave the thymus to populate specific regions of other lymphoid tissues
mature T cell
*An outer region forms the trabeculae that radiate through the
cortex which provide support to the macrophages and lymphocytes located in the node
LYMPH NODES
After antigenic stimulation, the cortical region of some follicles
develop foci of activated B cell proliferation called:
germinal centers
-contains predominantly T cells and numerous
macrophages
Paracortex
b/n cortex and medulla
Paracortex
lie toward the interior of the lymph node
Medullary cords
-Consists primarily of plasma cells and B cells
Medullary cords
LYMPHATIC NODULES
a. Small, solitary form
b. Multiple aggregated form
a. Small, solitary form
i. MALT(Mucosa associated lymphoid tissue
ii. CALT (Cutaneous associated lymphoidtissue)
b. Multiple aggregated form
i. Tonsils
ii. Peyer’s Patches
largest lymphoid organ in the body
SPLEEN
Fxn: indiscriminate filter of circulating blood
SPLEEN
Located within the spleen regions are three types of splenic tissue
a. White pulp
b. Red pulp
c. Marginal zone
fxnal part of the spleen containing white and red pulp
Parenchyma
Two methods of removing red cells
a. Culling
b. Pitting
cells are phagocytized with subsequent degradation of cell organelles
Culling
Splenic macrophages remove inclusions or damaged surface membrane from circulating red cells
Pitting
Constists of capsule, trabeculae, reticular fibers,
fibroblasts
Stroma
