Hematopoiesis

Cortex

- "waiting zone" OF THYMUS

Cytoplasmic maturation

- Decrease / loss of basophilia - Increase in the proportion of cytoplasm - Cytoplasmic granules - Elaboration of Hgb for RBC

Intrinsic regulation

- Involves genes such as SCL (TAL 1), w/c is expressed in cells in the hemangioblast, and GATA 2, w/c is expressed in later-appearing HSCs

Extrinsic regulation

- Involves proliferation & differentiation signals f ro m s p e c i a l i ze d n i c h e s via direct cell-to-cell extracellular signaling molecules

liver

Capable of extramedullary hematopoietic production in case of bone marrow shutdown

Endothelial cells

Cells along the wall of marrow. Regulate the flow of particles entering and leaving hematopoietic spaces in the vascular sinuses.

1. Capable of self-renewal 2. Give rise to differentiated progeny 3. Able to reconstitute the hematopoietic system of a lethally irradiated host

Characteristics of Stem Cells

periarteriolar lymphatic sheath, or PALS.

Aggregates of T lymphocytes surround arteries that pass through these germinal centers, forming a region called the

Stromal cells

originate from ___. include endothelial cells, adipocytes (fat cells), macrophages and lymphocytes, osteoblasts, osteoclasts, and reticular adventitial cells (fibroblasts).

hematopoietic inductive microenvironment, or niche,

plays an important role in nurturing and protecting HSCs and regulating a balance among their quiescence, self-renewal, and differentiation

primitive erythroblasts

predominant cell in the 9th week of fetal lfe

primitive erythroblasts

produce hemoglobin needed for delivery of oxygen to rapidly developing embryonic tissues

periosteal arteries

provide nutrients for the osseous bone and the marrow.

pitting

splenic macrophages remove inclusions or damaged surface membrane from the circulating RBCs.

white pulp

splenic tissue which consists of lymphocytes, macrophages and dendritic cells

hepatocytes

structural units of liver

multilineage priming model

suggests that HSCs receive low-level signals from the hematopoietic inductive microenvironment to amplify or repress genes associated with commitment to multiple lineages.

polyphyletic theory /Dualistic Theory

suggests that each of the blood cell lineages is derived from its own unique stem cell.

nutrient artery

supplies blood only to the marrow.

fetal hemoglobin (Hb F) adult hemoglobin (Hb A, A2)

During the hepatic phase, ___ is the predominant hemoglobin, but detectable levels of ___ may be present

bone foramina.

The nutrient and oxygen requirements of the marrow are supplied by the nutrient and periosteal arteries, which enter via the __

physiologic need

The determining factor controlling the rate of production is

niche

The hematopoietic cells develop in specific ___ within the cords

retrogression

The process of replacing the active marrow by adipocytes (yellow marrow) during development is called

350 mL/min.

The spleen has a rich blood supply receiving approximately

committed myeloid progenitors or colony-forming unit- granulocyte, erythrocyte, monocyte, and megakaryocyte (CFUGEMM).

These cells are capable of giving rise to multiple lineages of blood cells.

mitotic index

calculated to establish the percentage of cells in mitosis in relation to the total number of cells.

Adventitial cells

capable of contraction to allow mature cells to pass through the basement membrane

Porphyria

defects in heme & iron metabolism. result in the accumulation of porphyrins that damage hepatocytes

Adenitis

inflammation of lymph node

Instructive model

microenvironment in the bone marrow determines whether the HSC will self-renew or differentiate

3:1

myeloid-to-erythroid ratio Indicates the readily available cells

1-2% increased proliferation

normal mitotic index increased index means

Thymus (T-Cells) kidney and spleen

the first fully developed organ in the fetus, becomes the major site of __ cell production, whereas the ___ produce B cells.

yolk sac

the major site of adult blood formation in the embryo.

Primitive Cells - hemocytoblast,hemohistioblast, hemopoietic reticulum cell, lymphoidocytes

undifferentiated mesenchymal cells that can produce only blood cells other term: 4

Monophyletic Theory / Unitarian

- most widely accepted theory; all cells came f r o m a s i n g l e p r o g e n i t o r c e l l (pluripotential)

Stem cell

- one in which the daughter cells of the cell division are IDENTICAL in appearance and potential to the mother cell

Homoplastic

- young cells in BM undergo mitotic division

Heteroplastic

- young cells in BM undergo mitotic division and multiplication

splenomegaly Hypersplenism

-the spleen becomes enlarged and is palpable -enlargement of the spleen resulting in some degree of pancytopenia despite the presence of a hyperactive bone marrow.

6th month

BM becomes the primary site of hematopoiesis.

central longitudinal vein,

Blood exits the marrow via the

3 2.5 1.5

Bone marrow (per kg daily) produces __ billion RBCs __ billion platelets __ billion granulocytes

bone marrow

By the end of 24 weeks' gestation, the ___ becomes the primary site of hematopoiesis

KIT ligand, FLT3 ligand, IL-1, IL-3, IL-6, IL-11, GM-CSF

Cytokines • Positive effect-

1. Interleukins (Ils) 2. Lymphokines 3. Monokines 4. Interferons 5. Chemokines 6. Colony-stimulating factors

Cytokines 6

Transforming growth factor-β - Tumor necrosis factor-α - Interferons

Cytokines Negative effect

Go to G1

Cytokines Stimulate the dying precursor cells to divide by decreasing the transit from

yolk sac -aorta-gonad mesonephros (AGM) region -fetal liver -bone marrow

During fetal development, the restricted, sequential distribution of cells initiates in the ___ and then progresses in the ___ (mesoblastic phase), ___ (hepatic phase), and finally resides in the __ (medullary phase).

Thymus

Efficient, well-developed organ at birth; but decreases at later ages, then begins to atrophy (old age)

1 per 1000

HSCs exist in the marrow in the ratio of __ per __ nucleated blood cells.

hepatic phase

Hematopoiesis in the aorta-gonad-mesonephros region and the yolk sac disappear during this stage

formation, development, and specialization

Hematopoiesis result in the _, __, __ of all of the functional blood cells that are released from the bone marrow to the circulation.

nutrient artery

Hematopoietic cells located in the endosteal bed receive their nutrients from the

Bone Thymus Spleen Liver Lymph nodes

In adults, hematopoietic tissue is located in the

bone marrow

In healthy adults hematopoiesis is restricted primarily to the __

red

Infancy and early childhood: BM consists primarily of __BM.

AGM region

It is believed that hematopoietic stem cells arise here

spleen

It is vital but not essential for life - functions as an indiscriminate filter of the circulating blood.

osteoblasts, osteoclasts, endothelial cells, mesenchymal stem cells, adipocytes and macrophages

Key stromal cells thought to support HSCs in bone marrow niches include

19th

Mesoblastic Phase is considered to begin around the ____ day of embryonic development after fertilization.

symmetric division assymetric division

Path of Differentiation of HSC -leaving the stem cell pool. -return to the stem cell pool

Cytokines

Prevent hematopoietic precursor cells from dying by inhibiting apoptosis

Dyspoiesis

Profound defect in the maturation of the formed elements

Primitive cells

Progenitor cells

trabeculae

Projections of calcified bone that provide structural support for the developing blood cells.

red pulp

This creates a sponge-like matrix that functions as a filter for blood passing through the region in spleen

stochastic model of hematopoiesis

Till and McCulloch proposed that hematopoiesis is a random process whereby the HSC randomly commits to selfrenewal or differentiation.

excessive blood loss or hemolysis

Yellow marrow is capable of reverting back to active marrow in cases of increased demand on the bone marrow, such as in

intravascularly,

Yolk sac hematopoiesis differs from hematopoiesis that occurs in the fetus and the adult bec it occurs

5-7 years old

adipocytes become more abundant and begin to occupy the spaces in the long bones previously dominated by active marrow

Cytokines

are a diverse group of soluble proteins that have direct and indirect effects on hematopoietic cells.

Osteoblasts osteoclasts

are bone-forming cells bone-resorbing cells.

Adipocytes cytokines or growth factors

are large cells with a single fat vacuole; they play a role in regulating the volume of the marrow in which active hematopoiesis occurs. They also secrete

Thymus

area of maturation of T cell

red bone marrow

assumes chief role in myeloid phase

Lymph Nodes

bean-shaped structures located along the lymphatic capillaries

culling

cells are phagocytized with subsequent degradation of cell organelles,

• CD 33 & CD 38 = • CD 10 and CD 38 = • CD 7 = • CD 19 =

committed MYELOID progenitors committed LYMPHOID progenitors T lymphoid progenitor cells & NK B lymphoid progenitors

Primary lymphoid tissues

consists of the bone marrow and thymus and is where T and B lymphocytesare derived.

Extravascular cords

contains all of the developing blood cell lineages, stem cell, progenitor cell, adventitial cell and macrophage

Lymph

fluid portion of blood that escapes into the connective tissue and is characterized by a low protein concentration and the absence of RBCs

Stromal cells

form an extracellular matrix in the niche to promote cell adhesion

marginal zone

forms a reticular meshwork containing blood vessels, macrophages, memory B cells, and CD41 T cells.

angioblast

give rise to blood vessel

2nd month

granulocyte and megakaryocyte prod

Myeloid phase/medullary stage 5th month

hematopoiesis begins in the bone marrow cavity. Month

extramedullary hematopoiesis

hematopoiesis outside bone marrow (e.g., liver spleen)

Extravascular cords trabeculae

hematopoietic cells and macrophages are arranged in here. Located between __ of spongy bones

red marrow

hematopoietically active marrow consisting of the developing blood cells and their progenitors

yellow marrow

hematopoietically inactive marrow composed primarily of adipocytes (fat cells), with undifferentiated mesenchymal cells and macrophages.

Gower 1, Gower 2, Portland

hemoglobin produced by primitive erythroblast

4-5 AOG

hepatic phase happens at

3rd month

hepatic phase peak

Hematopoiesis

is a continuous, regulated process of blood cell production that includes cell renewal, proliferation, differentiation, and maturation.

red pulp

is composed primarily of vascular sinuses separated by cordscords of Billroth

spleen

is the largest lymphoid organ in the body

hematopoietic microenvironment

it is responsible for providing semifluid matrix which serves as an anchor for the developing hematopoietic cells

Nuclear Maturation

loss of nucleoli, decrease in the diameter of the nucleus, condensation of nuclear chromatin,possible change in the shape of the nucleus, and possible loss of the nucleus

CD 38 HLA-Drlow

loss of stemness

4th month

lymphocyte production month

Kupffer cells

macrophages that remove senescent cells and foreign debris from the blood that circulates through the liver;

liver, spleen

major site of hematopoiesis during the second trimester of fetal life.

hematopoietic growth factors or cytokines

regulate the proliferation, differentiation, and maturation of hematopoietic precursor cells.

G0 phase

resting phase

liver

sequesters mebrane damaged RBCs and eliminates them from the circulation

spleen - 30%

serves as a storage site for platelets. __% of the total platelet count is sequestered in the spleen

Liver

serves as the major site of blood cell production during the second trimester of fetal development.

Secondary lymphoid tissue

where lymphoid cells respond to foreign antigens, (MATURATION) consists of the spleen, lymph nodes, and mucosa-associated lymphoid tissue.

mesenchymal cells

which are a type of embryonic tissue, differentiate into structural elements that support the developing blood cells.

myeloid progenitor

which proliferates and differentiates into individual granulocytic, erythrocytic, monocytic, and megakaryocytic lineages.

lymphoid progenitor

which proliferates and differentiates into T, B, and natural killer lymphocyte

Asynchronism

• Characterized by different rates of maturation of the different parts of the cell producing cells that are atypical or bizarre but whose external structure is easily recognized as that of normal cell

Synchronism

• Characterized by simultaneous changes or transformation of the individual components of the cell

culture assays (CFUs) -methylcellulose transplantation to animals

• In vitro : - Semi-solid media (___) • In vivo: __