HEMATOPOIESIS

120 days (+/- 20 days for RBCs)

Mature blood cells have a limited lifespan of

hematopoietic stem cell (HSC)

is capable of self renewal and directed differentiation into all required cell lineages

TOTIPOTENTIAL STEM CELLS (NON-COMMITTED)

• present in the first few hours after ovum is fertilized

• the most versatile type of stem cell

• can develop into any cell type, including development from embryo into fetus

PLURIPOTENTIAL STEM CELLS (NON-COMMITTED)

• present several days after fertilization

• can develop into any cell type, except they cannot develop into a fetus

MULTIPOTENTIAL STEM CELLS (COMMITTED)

• derived from pluripotent stem cells

• can be found in adults, but they are limited to specific types of cells to form tissues

Mesoblastic, hepatic, and medullary phase

3 phases of pre-natal/primitive hematopoiesis

yolk sac phase

MESOBLASTIC PHASE is Also called as the

Yolk sac (blood islands)

Site of primitive hematopoiesis

19th - 20th day

Yolk sac phase Begins during the _____ of gestation in the blood islands of the yolk sac (mesodermal extraembryonic layer → yolk sac)

erythropoiesis

Hematopoietic activity is confined to

8th to 12th week of gestation (or 2-3 months)

Production of cells in yolk sac phase lasts until the:

primitive erythroblasts and angioblasts

Erythrocyte, Megakaryocyte, Macrophages

Cells produced in the yolk sac: ___ and ___ (form blood vessels)

Gives rise to: ____, ____, ____ (but not Lymphocyte and granulocytes)

PRIMITIVE ERYTHROBLASTS

▪ important in early embryogenesis to produce embryonic hemoglobin (up to the 3rd month only)

Aorta-Gonad Mesonephros (AGM) region

Primitive erythroblast migrates to ____ to become definitive erythroblasts

4 globin chains or 2 pairs of globin chains

Composition of hemoglobin

(2 epsilon and 2 zeta globin chains)

Globin chains for Gower-I

(2 alpha and 2 epsilon globin chains)

Gower-II

(2 zeta and 2 gamma globin chains)

Portland hemoglobin

AORTA-GONAD MESONEPHROS (AGM)

Site of Pro-definitive Hematopoiesis

Give rise to Erythroid-Myeloid-Progenitors

1-2 days later than yolk sac phase

Pro-definitive Hematopoiesis starts

RUNX-1 & CBF-beta

AGM

• Major Regulator: ___

• Partner Regulator: ___

fetal liver

After 3rd month, yolk sac stops producing blood cells and is replaced by the ____

fetal liver

Primary site for hepatic phase

5th – 7th week of gestation

hepatic phase starts at:

3rd month

hepatic phase peaks

6th month

Decline: primary site until the ____ (and continue to produce until 1st to 2nd week of life)

Thymus

first organ to be developed and produces T cells (T-cell maturation)

Kidney and spleen

B-cell maturation happens in?

Spleen

Granulopoiesis gradually declines but remains active for lymphopoiesis

Definitive erythroblasts

Blood cells formed in the hepatic phase:

o ___

o Granulocytes and megakaryocytes: 3rd month

o Lymphocytes: 4th month

o Monocytes: 5th month

Hgb F

predominant hemoglobin in the hepatic phase is the ___

2 alpha and 2 gamma globin chains

Globin chains of Hgb F

2 alpha and 2 beta globin chains

Globin chains for Hgb A1

2 alpha and 2 delta globin chains

Globin chains for Hgb A2

MEDULLARY/ MYELOID PHASE

it occurs in the medulla or inner part of the bone cavity

red bone marrow

Primary site of hematopoiesis is the ____ starting 24 weeks of gestation (remains throughout life**)

4th and 5th month

MEDULLARY/ MYELOID PHASE Begins between the ____ of fetal development

Mesenchymal cells

- type of embryonic tissue which differentiate into structural elements that support developing hematopoietic elements

3:1 – 4:1

Myeloid activity is apparent during this stage with a normal M:E ratio of ____

6:1

Instances wherein the M:E ratio changes:

• Infections: ____

• Leukemia: 25:1

• Myeloid Hyperplasia: 20:1

• Myeloid Hypoplasia: 3:20

• Erythroid Hyperplasia: 1:20

• Erythroid Hypoplasia: 5:1

EPO, Granulocyte colony- stimulating factor (G-CSF), Granulocyte-macrophage colony-stimulating factor (GM-CSF)

Detectatble cytokines:

97.5%

Hgb A1 → ____ Hgb A2 → 2.5%

A1 is ALWAYS higher than A2

Adult Hgb

IN ADULTS (>1 Year old) – The predominant Hemoglobin is the ___

Fetal hemoglobin

IN NEWBORNS (Up to 1 year old) – The predominant Hemoglobin is the ___

adult hemoglobin (Hgb A1) and fetal hemoglobin (Hgb F)

In the medullary phase – there is an increasing production of ____ and decreased ____

Gamma to Beta switching

– Switching of Hgb F (Alpha and Gamma) to Hgb A1 (Alpha and Beta)

Beta-Thalassemia Major

– Absence of beta chains; compensation is increased levels of Hgb F

Sternum and other flat bone

– principal source of blood cell production in adults.

Lymph nodes, Spleen, Liver, and Thymus

(extramedullary hematopoiesis)

Bone marrow and Thymus

Primary lymphoid tissues → where T and B cells are derived

Secondary lymphoid tissues

Red marrow → hematopoietically active marrow (blood cells and precursors) → lymphoid cells respond to foreign antigens

Red marrow

→ hematopoietically active marrow (blood cells and precursors)

Yellow marrow

→ hematopoietically inactive marrow (adipocytes, with undifferentiated mesenchymal cells and macrophages)

80-90%

Infancy and early childhood

• ____ active marrow

• All the bones in the body contain primarily red (active) marrow

• 60%

5 to 7 years of age:

• ___ active marrow o Adipocytes become more abundant and begin to occupy the spaces in the long bones previously dominated by active marrow

40%

Adults:

• ___ active marrow

50:50 or 1:1

Ratio of the red to yellow marrow is

STERNUM.

main source of blood cell production is in the:

ILLIAC CREST

Safest, most accessible site for bone marrow aspiration/biopsy:

Iron 52, Iron 59, Technetium 99m-Colloid

→ Dyes for identification of active hematopoietic tissue.

RETROGRESSION

Process in which the red marrow is replaced by the yellow marrow

POOP!

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

30-70%

Normal marrow cellularity

Aplastic

marrow has few or no hematopoietic cells

Trabeculae:

• honeycomb-like projections of calcified bones created after the resorption of bones

• Provide structural support for the developing blood cells maturing in between adipocytes

Bone marrow aspirate

→ obtained by bone marrow aspiration

Trephine biopsy

Core biopsy → obtained by

Anterior medial surface of the tibia

– For young children.

14-to-18-gauge aspiration needle with obturator

recommended gauge

Direct Aspirate Smears

wedge-shape smear; avoids crushing the spicules

STROMAL CELLS

• originate from mesenchymal cells that migrate into the central cavity of the bone

Adipocytes

Secretes steroids that influences erythropoiesis and maintains bone integrity

Osteoblasts

Bone forming cells; confused with plasma cells, water-bug or comet appearance

Osteoclasts

Bone resorbing cells or destroying cells; **confused with megakaryocytes

Niches

→ aka hematopoietic microenvironment; plays an important role in nurturing and protecting HSCs and regulating their quiescence, self-renewal, and differentiation

Monophyletic theory

Suggests that all blood cells are derived from a single progenitor stem cell called a pluripotent hematopoietic stem cell (PHSC)

Polyphyletic theory

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

Stochastic Model

suggests that HSCs randomly commits to self-renewal or differentiation.

Instructive Model

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

Multilineage Priming Model

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

b. The implication is that the cell's fate is determined by intrinsic and extrinsic factors.

TAL1 (hemangioblasts)

▪ a bipotential progenitor cell of mesodermal origin that gives rise to hematopoietic and endothelial lineages

GATA2

▪ expressed in later-appearing HSCs

CYTOKINES AND GROWTH FACTORS

❖ Regulate the proliferation differentiation, and maturation of hematopoietic precursor cells

Are responsible for stimulation or inhibition of production, differentiation, and trafficking of mature blood cells and their precursors

❖ Are a diverse group of soluble proteins that have direct and indirect effects on hematopoietic cells

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

Cytokines that are positive influence

Transforming growth factor-b (TGF-B), tumor necrosis factor-a (TNF-a), and interferons (IFN)

Cytokines that are negative influence