Lesson 1 - RBCs: Hematopoeisis

What kind of cells are capable of giving rise to all blood cell types?

Hematopoetic stem cells

Where are hematopoetics stem cells located?

Bone marrow

What does it mean when HSC’s are described as self-renewing?

Through asymmetrical division, one daughter cell remains as a pluripotent hematopoietic stem cell, whilst the other starts to differentiate, maintaining ‘stemness’

What two progenitor cell types can a hematopoietic stem cell give rise to?

• Myeloid progenitors

• Lymphoid progenitors

Myeloid progenitors

Progenitor cells that can differentiate into blood cell types involved in:

• Oxygen transport

• Immune responses

• Blood clotting

What are the branches of myeloid progenitors (3)?

• Granulocyte-monocyte progenitors

• Basophil-eosinophil progenitors

• Megakaryocytic-erythrocyte progenitors

Lymphoid progenitors

Progenitors of a cell lineage that gives rise to cells involved in the adaptive immune response

What are the branches of lymphoid progenitors cells; possible differentiation pathways?

• Dendritic cell

• Pre-B cell progenitors

• Pre-T cell progenitors

• Natural killer cell

What kind of cells are used as an indicator of the rate of erythropoiesis?

Reticulocytes; immature RBCs

What are the three main lineages of blood cells and their differentiation?

• Erythrocytes

• Lymphocytes

• Myeloid cells

What is Erythropoiesis?

Process of RBC production

What is Lymphopoiesis?

Production of lymphocytes

What are the subtypes of myeloid cells?

• Granulocytes

• Megakaryocytes

• Monocytes & Macrophages

What are the granulocytes?

• Neutrophils

• Eosinophils

• Basophils

What kind of immunity do granulocytes play a role in?

Innate immunity

Granulopoiesis

Process of granulocytes production/differentiation

What are megakaryocytes?

Precursor of platelets; clotting factors

What is thrombopoiesis?

Process of platelet production/differentiation

What two factors drive the differentiation of multipotent HSC’s?

• Cytokines

• Transcription factors

What is the potency of hematopoietic stem cells?

Multipotent

What factors drive the differentiation of a eosinophiloblast?

• Cytokine IL-5

• Transcription factor GATA-1

What substances are produced within immature eosinophils?

Granules that contain peroxidase and eosinophils cationic protein

What regulates the differentiation of hematopoietic stem cells?

Cytokines & growth factors

What stimulates the proliferation and differentiation of progenitor cells?

Colony-stimulating factors (CSFs)

What is a Hematopoiesis pool?

Different groups of blood cells at various stages of development or function

Name the different blood cells pools

• Hematopoiesis pools

  • Stem cell pool

  • Bone marrow pool

• Peripheral Circulation pools

  • Circulating pool

  • Marinating storage pool

Stem cell pool

Contains multipotent stem cells, located in bone marrow

Bone marrow pool

Contains both mature blood cells and developing precursors for storage and proliferation

Circulating pool

Cells actively moving through the blood stream

E.g) Neutrophils

Marginating storage pool

Blood cells temporarily attached to blood vessel walls and not circulating; consists of neutrophils for immune responses

• Can quickly enter circulation when stimulated (stress, infection, inflammation)

What type of bone marrow produces blood cells

Red bone marrow

Where is red bone marrow located?

• Vertebrae

• Cranium

• Sternum

• Ribs

What kind of bone marrow contains fat

Yellow bone marrow

What are the 2 main bone marrow niches?

• Osteoblastic niche

• Vascular niche

Osteoblastic niche

Bone marrow niche

• Located within endosteum where HSCs are kept in a quiescent state; self-renewing

Vascular niche

Bone marrow niche

• Located near blood vessels where HSC’s activate, proliferate, and differentiate into blood cells

What are CAR cells?

CXCL12-abundant reticular cells

• stromal cells that secrete the chemokine CXCL12 that attracts and retains HSCs in the bone marrow

What chemokine do CAR cells produce?

CXCL12 (SDF-1)

What is the main role of CAR cells in the bone marrow?

Attract, retain, and support HSC survival, quiescence, and proliferation

What are nestin-expressing cells?

Stromal cells near blood vessels and nerves that contain nestin (protein marker) expressed in progenitor cells

What is the function of Nestin+ cells in the bone marrow?

Support HSC quiescence, self-renewal, and provide structural support

How do CAR and Nestin+ cells contribute to the HSC niche?

They provide chemical signals and structural support to regulate HSC location, self-renewal, and differentiation

What is Medullary Hematopoiesis?

Blood cell production in the bone

What is Medullary Hematoparesis

The suppression of blood cells production

• Aplastic anemia, leukemia, chemotherapy/radiation damage

Extramedullary Hematopoiesis

• Production of blood cells outside the bone marrow

• Liver, spleen, lymph nodes

Under which developmental stage is extramedullary hematopoiesis normal?

Embryonic stage; fetal development

What stage of development is abnormal for extrameduallry hematopoiesis?

Abnormal in adults; it is a compensation method that occurs when the bone marrow is unable to meet the body’s blood cell production needs

What organs act as secondary sites for hematopoiesis?

• Liver

• Spleen

• Lymph nodes

What are the primary organs of the lymphatic system?

• Thymus

• Bone marrow

What are the secondary organs of the lymphatic system

• Spleen

• Lymph nodes

• Tonsils

• Peyer patches (GALT)

What are the two main divisions of tissues in the spleen?

• White pulp

• Red pulp

White pulp

Lymphoid tissue around central arteries in spleen

• Lymphocytes (T/B cells)

• Involved in immune response

Red Pulp

• Blood-filled sinusoids in spleen

• Contains macrophages

• Filters & breaks down RBCs

What is the largest lymphoid organ

Spleen

What are the roles of the spleen?

• Fetal hematopoiesis

• Filters blood

• Initiates immune response to bloodborne pathogens

• Reservoir for blood, restore blood volume & pressure

How do lymph nodes filter lymph?

Collect interstitial from fluid tissues → lymph is filtered and transported to thoracic duct → lymph drains into superior vena cava returning it into circulation

How is the lymphatic system involved with immune response?

• Lymphatic system is where antigens first encounter lymphocytes

• Lymphocytes enter lymph nodes from the blood and interact with antigens

• Antigens processed by macrophages and dendritic cells

• B cells proliferate and differentiate into plasma & memory cells

• Macrophages filter lymph of debris and foreign substances

What happens to lymph nodes during infection?

Become swollen due to B cells near blood proliferation

Lymph enters through _____ vessels and exit via _______ vessels

1) Afferent

2) Efferent

What happens to developing cells during the process of Erythropoiesis?

Cells compact, synthesize Hgb, and progressively lose intracellular structures

Under what conditions is erythropoiesis stimulated?

Low oxygen conditions

• Decrease in oxygen circulation is detected by kidneys, initiating the secretion of erythropoietin

Describe the maturation/differentiation process of an erythrocyte

Megakaryocyte-Erythrocyte progenitor → Proerythroblast → Early Erythroblast → Intermediate Erythroblast → Late Erythroblast → Nuclear extrusion → Reticulocyte → Mature RBC

What is the final immature stage of an RBC?

Reticulocyte

What stimulates erythropoiesis?

• Hypoxia; decrease in oxygen circulation detected by kidneys

What is secreted by the kidneys to promote erythropoiesis?

Erythropoietin (EPO)

What location does the differentiation of a Megakaryocyte-erythrocyte progenitor into proerythroblast occur?

Bone marrow

How long do reticulocytes remain in the bone marrow before maturing?

1 day

What should you look for in a total RBC count to ensure active RBC production is occurring?

Look for a reticulocyte concentration of ~1%; shows that RBC production is occurring on the RBC differential

What kind of conditions promote high EPO?

Conditions that reduce O2 levels in the blood

• COPD → triggers kidneys to produce more EPO in response to low oxygen; stimulates RBC production

How does low EPO lead to anemia?

Low EPO → less RBC production → less hemoglobin → anemia

How can EPO increase the risk of stroke?

EPO promotes increased RBC production which can increase the viscosity of blood, increasing risk of stroke

How does COPD cause high EPO?

COPD → chronic hypoxia due to difficulty breathing; damaged lungs → increase EPO production due to low O2

What are the components of a hemoglobin molecule?

• Globin chains

  • Two alpha & two beta polypeptide chains

• Heme groups

  • Protopotphyrin

  • Iron (Fe²+)

Where is heme synthesized?

Mitochondria and cytoplasm of RBC precursors

What is a Heme group composed of?

Protoporphyrin + Iron (Fe²+)

What form of iron is able to bind to oxygen?

Ferrous iron (Fe²+)

What happens to ferrous iron once bound to oxygen?

Becomes oxidized; ferric state

How many oxygen molecules can hemoglobin hold? Why?

1 Hgb molecule can hold 4 O2 molecules. Each heme group can carry 1 oxygen

What competes with O2 when binding to deoxyhemoglobin?

CO; carbon monoxide; higher affinity than O2

Why is Vitamin B12 a key component in erythropoiesis?

Required to form thymidine during DNA replication, important for rapidly dividing cells of BM

What happens to erythropoiesis in the absence of Vitamin B12?

Low Vitamin B12 → Impaired DNA synthesis → abnormal RBC production (megaloblast) → megaloblastic anemia

What is pernicious anemia?

Poorly developed RBC’s due to low intrinsic factor → poor B12 intestinal absorption

What is the difference between megaloblastic anemia and pernicious anemia

Megaloblastic anemia is caused by Vitamin B12 deficiency, while pernicious anemia is due to intrinsic factor deficiency which helps with Vitamin B12 absorption.

What is the role of iron in Erythropoiesis?

Required to form heme by combining with protoporphyrin

Iron is stored in the liver as ______

Ferritin

Why does iron-deficiency anemia occur

Low iron → impaired hemoglobin synthesis → abnormal RBC production (microcytic & hypochromin) → iron-deficiency anemia

Where is iron absorbed?

Small intestines

What is Apoferritin?

• Iron-free ferritin

• Can bind 1000s of Fe atoms

Several apoferrin complexes form a _______ ferritin, which stores iron in a bioavailable form

Michele ferritin

With large amount of iron, micelles aggregate into _____, a less accessible form of iron

Hemosiderin

Free-iron enters the bloodstream by binding to _____

Transferrin

What is transferrin?

A plasma protein that transports iron through the blood stream to carry it to cells that need iron

How does transferring deliver iron to cells?

Transferring binds up to two iron ions; delivers iron to cells that have transferrin receptors

• Once inside, iron is released, and transferrin returns to the blood to bind more iron

After iron delivery, transferrin returns to the blood stream as ______

Apotransferrin; iron-free transferrin

Where is transferrin synthesized?

Liver

Where are heme groups produced?

Inside Erythroblasts

How are heme groups produced in erythroblasts?

Inside erythroblasts, iron is transported to the mitochondria → heme sythetase inserts Fe²+ into protoporphyrin to form heme

What is hepcidin?

• Hormone made by the liver

• Controls how much iron enter blood stream

Under what conditions do hepcidin levels rise?

• High iron levels

• inflammation