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CHAPTER 7 Cheat Sheet (DRAFT) by

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This is a draft cheat sheet. It is a work in progress and is not finished yet.

HEMATO­POIESIS

Cell renewal, prolif­era­tion, differ­ent­iation, and maturation
Hemato­poietic inductive microe­nvi­ronment (niche) in the bone marrow = regulate hemato­poietic stem cell mainte­nance, self-r­enewal, and differ­ent­iation; where hemato­poietic stem/p­rog­enitor cells (HSCs/­HPCs) grow and develop

Site of Hemato­poiesis

Adults
bone marrow
Fetal develo­pment
yolk sac > aorta-­gonad mesone­phros (AGM) region (mesob­lastic phase) > fetal liver (hepatic phase) > bone marrow (medullary phase)

ADULT HEMATO­POIETIC TISSUE

Located in the bone marrow, lymph nodes, spleen, liver, and thymus
Lymphoid develo­pment occurs in primary and secondary lymphoid tissue.
Primary lymphoid tissue
bone marrow and thymus = (T&B lympho­cytes)
Secondary lymphoid tissue (lymphoid cells that respond to foreign antigens)
spleen, lymph nodes, and mucosa­-as­soc­iated lymphoid tissue

Medullary (Myeloid) Phase

5th month of develo­pment = hemato­poiesis begins in the Bone Marrow (Chief Site)
“Medul­lary” = occurs in the medulla or inner part of the bone
Myeloi­d-t­o-e­ryt­hroid ratio = 3:1
Production of adult hemogl­obins (HbA1 and HbA2)

Bone Marrow

Location = within the cavities of the cortical bones
Contains hemato­poietic cells, stromal cells, and blood vessels
Red marrow = hemato­poi­eti­cally active; developing blood cells and their progen­itors
Yellow marrow =hemat­opo­iet­ically inactive marrow; composed primarily of adipocytes (fat cells)
Retrog­ression = replacing the active marrow by adipocytes
Infancy and early childhood = primarily red (active) marrow
5 and 7 years of age = adipocytes become more abundant
Yellow marrow is capable of reverting back to active marrow in cases of increased demand on the bone marrow, such as in excessive blood loss or hemolysis

Stromal cells

Stromal cells play a critical role in the regulation of hemato­poietic stem and progenitor cell survival and differ­ent­iation

Types of Stromal Cells

1. Endoth­elial cells
form a single layer along inner surface of the arteries, veins, and vascular sinuses; regulate what enters or leaves the vascular sinuses
2. Adipocytes
large cells with a single fat vacuole; regulating volume of the marrow in which active hemato­poiesis occur
3. Macrop­hages
phagoc­ytosis; secrete various cytokines
4. Osteob­lasts
bone-f­orming cells
5. Osteoc­lasts
bone-r­eso­rbing cells
Originate from mesenc­hymal cells
Secrete a semifluid extrac­ellular matrix to promote cell adhesion = matrix contains fibron­ectin, collagen, laminin, thromb­osp­ondin, tenascin, and proteo­glycans

Spleen Pathop­hys­iology

Blood route entering the spleen:
1. Slow-t­ransit pathway
RBCs > cords > sinuses > RBC have hard time entering sinus thus, slow passage > but RBC metabolism is continuous > creates acidic, hypogl­ycemic, and hypoxic enviro­nment > enviro­nment stress in spleen > possible hemolysis
2. Rapid-­transit pathway
RBC > sinuses > venous system > exit spleen

Spleen

Largest lymphoid organ in the body
Storage site for platelets (30% total plt are kept in spleen)
2 methods to remove senescent or abnormal RBCs from the circul­ation:
1. Culling = cells are phagoc­ytized
2. Pitting = splenic macrop­hages remove inclusions or damaged surface membrane from the circul­ating RBCs.
Blood enters the spleen through the central splenic artery
senescence = loss of a cell's power of division and growth

Thymus

Densely populated with progenitor lymphoid cells that migrated from the bone marrow and will soon give rise to T cells.
T cells from bone marrow > go to thymus > No surface markers yet (CD4 CD8) > go to cortic­ome­dullary junction > once influenced by chemok­ines, cytokines, and receptors > T cells go to cortex > express CD4 CD8 marker > go to medulla > T cell matures > leave thymus > go to T cell dependent areas (spleen, lymph nodes, and other lymphoid tissues)
Medulla holds mature T cells until they are needed by the peripheral lymphoid tissues

Lymph Nodes

Lymph
fluid portion of blood escapes into the connective tissue
Lymph > Enter in Afferent vessels > lymph nodes filter lymph > Exit in Efferent vessels
Three main functions:
1. Site of lymphocyte prolif­eration from the germinal centers
2. Initiation of the specific immune response to foreign antigens
3. Filter partic­ulate matter, debris, and bacteria entering the lymph node

Cytokines and Growth Factors

Cytokines - group of specific glycoproteins
-Such as interl­eukins (ILs), lympho­kines, monokines, interf­erons, chemok­ines, and colony­sti­mul­ating factors (CSFs) have an effect on other cells.
-Regulate the prolif­era­tion, differ­ent­iation, and maturation of hemato­poietic precursor cells
Cytokines promote growth and survival to hemato­poietic progenitor cells
Cytokines prevent hemato­poietic precursor cell death by inhibiting apoptosis
Apoptosis - programmed cell death; eliminates unwanted, abnormal, or harmful cells.
Note: Cytokine and Growth Factor are often used synony­mously

Cytokine Influence

Cytokines negative influence on hemato­poiesis
transf­orming growth factor-b, tumor necrosis factor-a, and the interf­erons
Cytokines positive influence on hemato­poiesis
stimulate production and differ­ent­iation of precursor cell
TGFβ - inhibit the growth of many types of cells; antagonize many immune responses

CFU

Early-­Acting Multil­ineage GF

KIT ligand (stem cell factor) - early-­acting growth factor
recept­or-type tyrosi­ne-­protein kinase
KIT ligand > bind to KIT receptor > signals from transd­uction pathways to the HSC nucleus > stimulate the cell to prolif­erate
FLT3
recept­or-type tyrosi­ne-­protein kinase
KIT ligand + FLT3 ligand
Work synerg­ist­ically with IL-3, GM-CSF, and other cytokines to promote early HSC prolif­eration and differ­ent­iation.
IL-3
control granul­ocytes and macrop­hages produc­tion, differ­ent­iation, and function to regulate blood cell production
Activation of the KIT receptor by KIT ligand is essential in the early stages of hemato­poi­esis.
GM-CSF stimulate HSC differ­ent­iation to common myeloid progenitor
 

Hemato­poietic Stem Cells

Hemato­poietic stem cells (HSCs) are capable of self-r­enewal
They are plurip­otent and can differ­entiate into all the different types of blood cells.

Mesobl­astic Phase

Begins during nineteenth day of embryonic develo­pment
1. Cells from the mesoderm migrate to the yolk sac> form primitive erythr­obl­ast­s> produce hemoglobin (Gower-1, Gower-2, and Portland) for delivery of oxygen
2. Cells from the mesoderm migrate to the AGM>give rise to HSC
Occurs intrav­asc­ularly

Hepatic Phase

5 to 7 gestat­ional weeks
Liver = remaining the major site of hemato­poiesis during the second trimester of fetal develo­pment
Liver Hemato­poiesis = peak by the third month, declines after the sixth month
Thymus = site of T cell production
Kidney and spleen = site of B cell production
Production of megaka­ryo­cytes begins
Lymphoid cells begin to appear
Fetal hemoglobin (Hb F) is the predom­inant hemoglobin
Spleen, kidney, thymus, and lymph nodes contribute to the hemato­poietic process during this phase.
Occurs extrav­asc­ularly
Thymus - the first fully developed organ in the fetus

Site of Hemato­poiesis

Red Marrow

Composed of extram­edu­llary cords that contain all developing cells (stem and progenitor cells, advent­itial cells, and macrop­hages)
Bone foramina
where nutrient and periosteal arteries enters to provide nutrient and oxygen to the marrow; also where the blood exits from BM

Liver

Second trimester of fetal develo­pment
Major site of hemato­poiesis
Hepato­cytes functions:
Protein synthesis and degrad­ation, coagul­ation factor synthesis, carboh­ydrate and lipid metabo­lism, drug and toxin clearance, iron recycling and storage, and hemoglobin degrad­ation (bilirubin is conjugated and transp­orted to the small intestine for excretion)
Kupffer cells (macro­phages)
Remove senescent cells and foreign debris from the blood in the liver; secrete mediators that regulate protein synthesis in the hepato­cytes

Liver Pathop­hys­iology

Porphyrias
Defects in the enzymes involved in heme biosyn­thesis = accumu­lation of interm­ediary porphyrins = damage hepato­cytes, erythr­ocyte precur­sors, and other tissues
Severe hemolytic anemia
Liver > increases the conjug­ation of bilirubin and storage of iron
Liver removes membra­ne-­damaged RBCs from circul­ation
If BM is damaged (myelo­fib­rosis)
Liver can extram­edu­llary hemato­poiesis - keep hemato­poietic stem&­pro­genitor cells to produce various blood cells

Spleen Pathop­hys­iology

Spleno­megaly
Spleen becomes enlarged and is palpable
Caused by: chronic leukemias, inherited membrane or enzyme defects in RBCs, hemogl­obi­nop­athies, Hodgkin disease, thalas­semia, malaria, and the myelop­rol­ife­rative disorders
Splene­ctomy
Excessive destru­ction of RBCs due to autoimmune hemolytic anemia (corti­cos­teroids does not effect­ively suppress hemolysis) or severe hereditary sphero­cytosis
After splene­ctomy = platelet and leukocyte counts increase
Autosp­len­ectomy
Sickle cell anemia = sickled RBCs trapped in the small-­vessel circul­ation of the spleen = tissue damage­/ne­crosis
Hypers­plenism
Enlarg­ement of the spleen (pancy­top­enia)
Most common causes 1. congestive spleno­megaly 2. cirrhosis of the liver 3. portal hypert­ension

Lymph Node Pathop­hys­iology

Antigenic stimul­ation > cortical region develop cluster of activated B cell called germinal centers
Paracortex region = contains T cells and macrophage
Medullary cord region = contains plasma cells and B cells
Too much microo­rganism enter lymph node > macrophage are overwh­elmed > result to adenitis (infection of the lymph node)
Worst case: malignant cells from tumors enter lymph node > spread to nearby lymph nodes
Follicles with germinal centers are called secondary follicles, while those without are called primary follicles
Germinal centers = Site of lymphocyte prolif­eration

Stem Cell Theory

Monoph­yletic theory
Suggests that all blood cells are derived from a single progenitor stem cell called a plurip­otent hemato­poietic stem cell; widely accepted theory
Polyph­yletic theory
Suggests that each of the blood cell lineages is derived from its own unique stem cell
Common lymphoid progenitor
T, B, and natural killer lymphocyte and dendritic lineages
Common myeloid progenitor
granul­ocytic, erythr­ocytic, monocytic, and megaka­ryo­cytic lineages

SC Phenotypic & Functional Charac­ter­ization

Origin of HSCs can be determined by immuno­phe­notypic analysis using flow cytometry
General charac­ter­istics of maturation include decrease in nuclear and cell diameter, loss of nucleoli, conden­sation of nuclear chromatin, and decreased basophilia in cytoplasm.

Colony­-St­imu­lating Factors

Interl­eukins

Protei­ns/­group of cytokines that regulates autoim­mune, inflam­matory reactions, and hemato­poiesis
Synergize with other cytokines
Effective at very low concen­tra­tions

LINEAGE: Erythr­opo­iesis

The CFU-GEMM gives rise to the earliest identi­fiable colony of RBCs, called the burst-­forming unit–e­ryt­hroid (BFU-E)
BFU-Es under the influence of IL-3, GM-CSF, TPO, and KIT ligand develop into colony­-fo­rming unit–e­ryt­hroid (CFU-E) colonies
CFU-E has many EPO receptors and has an absolute requir­ement for EPO
Small amount of EPO is produced by the liver
Oxygen availa­bility in the kidney is the stimulus that activates production and secretion of EPO

LINEAGE: Megaka­ryo­poiesis

The liver is the main site of production of TPO

BLOOD CELL LINEAGE