• Haemopoiesis Erythropoiesis & Its Regulation

• LEARNING OBJECTIVE

• At the end of lecture student should be able to know,

• What is haemopoiesis.

• Types of stem cells.

• Classification of stem cells.

• Sited of haemopoisis.

• Regulation of haemopoeitic cells.

• Interactions.

• Erythropoiesis.

• Requirements.

• Production of erythrocytes

• Stem cell: human body has very specialized type of cells called stem cell. They have the

remarkable ability to produce many types of other cell of the body.

• When stem cell divides, it has the potential to remain as a stem cell or turn into another type of

cell with differentiated and specialized functions.

• Types of stem cells

• Embryonic stem cell

• Haemopoiesis

• Adult stem cell

• Classification of stem cell

• Totipotent Multipotent Pluripotent

• Stem Cell Stem Cell Stem Cell

• Progenitor cell

• Committed stem cell

• Colony Forming unit

CVS is the first system to function in embryos

blood begins to circulate by the end of the 3rd week

earliest blood vessels develop from cell aggregations called blood islands

(insulae sanguineae)

Cells of blood islands differentiate into 2 cell lines:

- central cells - hematogoniae or hemoblasts - they give rise to primitive

red blood corpuscles (erythrocytes)

- outer or peripheral cells - angioblasts - they become flattened and give rise to endothelial cells

angioblasts then join up to form primitive blood vessels

blood islands appear as red spots and gradually

develop in 3 locations /sites/:

1) in the extraembryonic mesoderm of the yolk sac -

at about day 17 after fertilization - the vitelline

vasa

2) in the extraembryonic mesoderm of the

connecting stalk - at about day 18 after

fertilization – the umbilical vasa

3) in the mesenchyme of the embryo -

between day 19 - 20

here they give rise to embryonic blood vessels

- ventral and dorsal aortae that are interconnected

by branchial or aortic arches of the branchial apparatus

(future neck region)

in total, are 6 pairs of aortic arches

in the 21 st day, the vessels of all 3 regions join up

and connect with the primitive heart, so

that the primitive blood circulation is constituted

also, the primitive heart begins to beat in this time

• Blood

• Liquid connective tissue

• 3 general functions

1. Transportation

Gases, nutrients, hormones, waste products

2. Regulation

pH, body temperature, osmotic pressure

3. Protection

Clotting, white blood cells, proteins

• Components of Blood

– Blood plasma – water liquid extracellular matrix

• 91.5% water, 8.5% solutes (primarily proteins)

• Hepatocytes synthesize most plasma proteins

– Albumins, fibrinogen, antibodies

• Other solutes include electrolytes, nutrients, enzymes, hormones, gases and

waste products

– Formed elements – cells and cell fragments

• Red blood cells (RBCs)

• White blood cells (WBCs)

• Platelets

• Haemopoiesis

• Haemopoiesis is the process of formation of the formed (solid) elements of blood.

• It starts with the pluripotent stem cells, which are derived from uncommitted totipotent stem

cells.

• They have CD34+, CD38+, markers and has the approximate size of small or medium sized

lymphocytes.

• They have the capability of self renewal.

• There are separate pools of the progenitors cells for Megakaryocyte, Lymphocyte, Erythrocytes,

Eosinophil

• and Basophil.

• Where as Neutrophil and monocyte arise from common precursors.

• Sites of Haemopoiesis

• Yolk sac

• Liver and spleen

• Bone marrow

• Gradual replacement of active (red) marrow by inactive (fatty) tissue

• Expansion can occur during increased need for cell production

• Sites of Haemopoiesis

• Local and Humoral regulation of Haemopoiesis

• Interaction of stromal cells, growth factors and haemopoietic cells

• Erythropoiesis

• Erythropoiesis is a process by which the mature red cells are produced.

• Erythropoiesis starts from the stem cells in the bone marrow which are pluripotent stem cell.

• Erythropoiesis

• As these cells reproduce, continuously through out life.

• A small portion of them remains exactly like the original pluripotent cell and is retained in the

bone marrow to maintain a supply of these.

• Although their number do diminish with age.

• Most of the reproduced stem cells, however differentiated to form the other cells.

• The early off spring cell cannot be differentiated from pluripotanial stem cells, even though

they have already become committed to a particular line of cells and are called committed

stem cells.

• The different committed stem cell will produce colonies of specific types of blood cells, e.g. a

committed stem cell that produce erythrocytes is called colony forming unit erythrocytes

(Cfu -E).

• Requirements of Erythropoiesis

• Erythropoiesis require the following:

• Normal population of hemopoietic stem cells.

• Their differentiation and maturation under the influence of Burst promoting factor (growth

factors).

• Erythropoietin.

• Availability of other specific nutrients.

• Requirements of Erythropoiesis

• Vitamin B and foliate for normal DNA synthesis.

• Other Vitamins e.g. vitamin B6, Thiamine, Riboflavin, Vitamin C and E.

• Metals :

• Iron for hemoglobin synthesis

• Trace metal such as cobalt

•

Erythropoietin Mechanism

• ERYTHROPOIESIS

• Stages of Differentiation of RBC

• Formed Elements of Blood

• Formation of Blood Cells

• Negative feedback systems regulate the total number of RBCs and platelets in circulation

• Abundance of WBC types based of response to invading pathogens or foreign antigens

• Hemopoiesis or hemotopoiesis

• Red bone marrow primary site

• Pluripotent stem cells have the ability to develop into many different types of cells

• Formation of Blood Cells

• Stem cells in bone marrow

– Reproduce themselves

– Proliferate and differentiate

• Cells enter blood stream through sinusoids

• Formed elements do not divide once they leave red bone marrow

– Exception is lymphocytes

• Formation of Blood Cells

• Pluripotent stem cells produce

– Myeloid stem cells

• Give rise to red blood cells, platelets, monocytes, neutrophils, eosinophils and

basophils

– Lymphoid stem cells give rise to

• Lymphocytes

• Hemopoietic growth factors regulate differentiation and proliferation

– Erythropoietin – RBCs

– Thrombopoietin – platelets

– Colony-stimulating factors (CSFs) and interleukins – WBCs

• Red Blood Cells/ Erythrocytes

• Contain oxygen-carrying protein hemoglobin

• Production = destruction with at least 2 million new RBCs per second

• Biconcave disc – increases surface area

• Strong, flexible plasma membrane

• Glycolipids in plasma membrane responsible for ABO and Rh blood groups

• Lack nucleus and other organelles

– No mitochondria – doesn’t use oxygen

• Hemoglobin

– Globin – 4 polypeptide chains

– Heme in each of 4 chains

– Iron ion can combine reversibly with one oxygen molecule

– Also transports 23% of total carbon dioxide

• Combines with amino acids of globin

– Nitric oxide (NO) binds to hemoglobin

• Releases NO causing vasodilation to improve blood flow and oxygen delivery

• Shapes of RBC and Hemoglobin

• Red Blood Cells

• RBC life cycle

– Live only about 120 days

– Cannot synthesize new components – no nucleus

– Ruptured red blood cells removed from circulation and destroyed by fixed phagocytic

macrophages in spleen and liver

– Breakdown products recycled

• Globin’s amino acids reused

• Iron reused

• Non-iron heme ends as yellow pigment urobilin in urine or brown pigment

stercobilin in feces

• Formation and Destruction of RBC’s

• Erythropoiesis

– Starts in red bone marrow with proerythroblast

– Cell near the end of development ejects nucleus and becomes a reticulocyte

– Develop into mature RBC within 1-2 days

– Negative feedback balances production with destruction

– Controlled condition is amount of oxygen delivery to tissues

– Hypoxia stimulates release of erythropoietin

• White Blood Cells/ Leukocytes

• Have nuclei

• Do not contain hemoglobin

• Granular or agranular based on staining highlighting large conspicuous granules

• Granular leukocytes

– Neutrophils, eosinophils, basophils

• Agranular leukocytes

– Lymphocytes and monocytes

• Types of White Blood Cells

• Functions of WBCs

– Usually live a few days

– Except for lymphocytes – live for months or years

– Far less numerous than RBCs

– Leukocytosis is a normal protective response to invaders, strenuous exercise, anesthesia

and surgery

– Leukopenia is never beneficial

– General function to combat invaders by phagocytosis or immune responses

• Emigration of WBCs

• Many WBCs leave the bloodstream

• Emigration (formerly diapedesis)

• Roll along endothelium

• Stick to and then squeeze between endothelial cells

• Precise signals vary for different types of WBCs

• WBCs

• Neutrophils and macrophages are active phagocytes

– Attracted by chemotaxis

• Neutrophils respond most quickly to tissue damage by bacteria

– Uses lysozymes, strong oxidants, defensins

• Monocytes take longer to arrive but arrive in larger numbers and destroy more microbes

– Enlarge and differentiate into macrophages

• WBCs

• Basophila leave capillaries and release granules containing heparin, histamine and serotonin, at

sites of inflammation

– Intensify inflammatory reaction

– Involved in hypersensitivity reactions (allergies)

• Eosinophils leave capillaries and enter tissue fluid

– Release histaminase, phagocytize antigen-antibody complexes and effective against

certain parasitic worms

• Lymphocytes

• Lymphocytes are the major soldiers of the immune system

– B cells – destroying bacteria and inactivating their toxins

– T cells – attack viruses, fungi, transplanted cells, cancer cells and some bacteria

– Natural Killer (NK) cells – attack a wide variety of infectious microbes and certain tumor

cells

• Platelets/ Thrombocytes

• Myeloid stem cells develop eventually into a megakaryocyte

• Splinters into 2000-3000 fragments

• Each fragment enclosed in a piece of plasma membrane

• Disc-shaped with many vesicles but no nucleus

• Help stop blood loss by forming platelet plug

• Granules contain blood clot promoting chemicals

• Short life span – 5-9 days

• Stem cell transplants

• Bone marrow transplant

– Recipient's red bone marrow replaced entirely by healthy, noncancerous cells to

establish normal blood cell counts

– Takes 2-3 weeks to begin producing enough WBCs to fight off infections

– Graft-versus-host-disease – transplanted red bone marrow may produce T cells that

attack host tissues

• Cord-blood transplant

– Stem cells obtained from umbilical cord shortly before birth

– Easily collected and can be stored indefinitely

– Less likely to cause graft-versus-host-disease

• Hemostasis

• Sequence of responses that stops bleeding

• 3 mechanisms reduce blood loss

1. Vascular spasm

– Smooth muscle in artery or arteriole walls contracts

2. Platelet plug formation

– Platelets stick to parts of damaged blood vessel, become activated and accumulate large

numbers

3. Blood clotting (coagulation)

• Platelet Plug Formation

• Blood Clotting

3. Blood clotting

– Serum is blood plasma minus clotting proteins

– Clotting – series of chemical reactions culminating in formation of fibrin threads

– Clotting (coagulation) factors – Ca2+, several inactive enzymes, various molecules

associated with platelets or released by damaged tissues

• 3 Stages of Clotting

1. Extrinsic or intrinsic pathways lead to formation of prothrombinase

2. Prothrombinase converts prothrombin into thrombin

3. Thrombin converts fibrinogen (soluble) into fibrin (insoluble) forming the threads of the

clot

4. Blood Clotting

• Extrinsic pathway

1. Fewer steps then intrinsic and occurs rapidly

2. Tissue factor (TF) or thromboplastin leaks into the blood from cells outside (extrinsic to)

blood vessels and initiates formation of prothrombinase

• Intrinsic pathway

1. More complex and slower than extrinsic

2. Activators are either in direct contact with blood or contained within (intrinsic to) the

blood

3. Outside tissue damage not needed

4. Also forms prothrombinase

• Blood Clotting: Common pathway

1. Marked by formation of prothrombinase

2. Prothrombinase with Ca2+ catalyzes conversion of prothrombin to thrombin

3. Thrombin with Ca2+ converts soluble fibrinogen into insoluble fibrin

4. Thrombin has 2 positive feedback effects

• Accelerates formation of prothrombinase

• Thrombin activates platelets

• Clot formation remains localized because fibrin absorbs thrombin and clotting

factor concentrations are low

• Blood Groups and Blood Types

• Agglutinogens – surface of RBCs contain genetically determined assortment of antigens

• Blood group – based on presence or absence of various antigens

• At least 24 blood groups and more than 100 antigens

1. ABO and Rh

• ABO Blood Group

1. Based on A and B antigens

2. Type A blood has only antigen A

3. Type B blood has only antigen B

4. Type AB blood has antigens A and B

• Universal recipients – neither anti-A or anti-B antibodies

5. Type O blood has neither antigen

• Universal donor

6. Reason for antibodies presence not clear

• Antigens and Antibodies of ABO Blood Types

• Hemolytic Disease

• Rh blood group

1. People whose RBCs have the Rh antigen are Rh+

2. People who lack the Rh antigen are Rh-

3. Normally, blood plasma does not contain anti-RH antibodies

4. Hemolytic disease of the newborn (HDN) – if blood from Rh+ fetus contacts Rh-mother

during birth, anti-Rh antibodies made

• Affect is on second Rh+ baby