lecture 10 - haemotopoiesis

Question 1

Define lineage

Answer 1

“Direct descent from a particular ancestor; ancestry.”

Question 2

Define -poiesis

Answer 2

“Production, formation, creation”

Question 3

Define haemopoiesis

Answer 3

“The formation of blood or blood cells in the body.”

Question 4

Give Examples of Adult Stem Cells and Lineages

Answer 4

Haematopoietic stem cells
Haematopoietic lineages

Epidermal stem cells
Epidermal lineages
Skin: Keratinocytes, hair, gland cells

Mesenchymal stem cells
Mesenchymal lineages
Bone: osteoblasts
Cartilage: chondrocytes
Adipose tissue: adipocytes

Question 5

What role do HSCs play?

Answer 5

Blood cells have a short life span.
The average human produces ~3.7 x 1011 blood cells a day
Made possible by the activity of HSCs (and their progeny)
HSCs reside in the bone marrow (1.1%) and peripheral blood (0.06%)
Self-renew and differentiate into specialised blood cell types.

Question 6

What is blood composed of?

Answer 6

Plasma portion:
water - solvent
salts (sodium,potassium, calcium, magnesium, chloride, bicarbonate) - osmotic balance, pH buffering, regulation of membrane potentials
plasma proteins (albumin, fibrinogen, immunoglobulins) - osmotic balance, pH buffering, clotting, immune responses

Cellular portion:
Erythrocytes (red blood cells) - transport oxygen and carbon dioxide
Leukocytes (white blood cells)
-> Basophils, eosinophils and neutrophils (granulocytes), lymphocytes and monocytes - destroy foreign cells, produce antibodies, roles in allergic responses
Platelets - blood clotting

Question 7

What are the roles of the cells in the lymphoid lineage?

Answer 7

B cells - make antibodies
T cells - kill virus infected cells, regulate activities of other leukocytes
Natural killer (NK) cells - kill virus infected and some tumour cells

Question 8

What are the roles of the cells in the myeloid lineage?

Answer 8

Neutrophils - phagocytose and destroy invading bacteria
Eosinophils - destroy larger parasites and modulate allergic inflammatory reponses
Basophils - release histamine in certain immune reactions
Monocytes - become tissue macrophages, phagocytose invading microorganisms, foreign bodies, damaged senescent cells

Question 9

How does early haemopoiesis take place?

Answer 9

takes place in blood vessels early in embryo development
During development, the first HSCs are found in the embryonic aorta-gonad-mesonephros (AGM) region.
HSCs bud from endothelial cells
Later, haematopoiesis moves to bone marrow.

Question 10

How does differentation work in HSCs?

Answer 10

Unidirectional – no reversion
No sideways movement between lineages
Decreased capacity for self-regeneration
However, new evidence suggests that reprogramming is possible (iPSCs) as well as direct reprogramming across lineages or “transdifferentiation”.

Haematopoiesis is regulated by intercellular signalling using a variety of secreted factors that modulate proliferation and differentiation pathways to generate specialised blood cell types, examples include:
Stem Cell Factor (SCF)
Interleukins (e.g. IL-3, IL-6)
Colony Stimulating Factors (G-CSF, M-CSF, GM-CSF)
Erythropoietin (EPO)
Thrombopoietin (TPO)

Question 11

How can HSCs be identified?

Answer 11

Cells express specific proteins that can act as a “fingerprint” guide to their identity
CD34+
CD133+
Thy1+

CD38- (negative for CD38, which is expressed by early progenitor cells)
Lin- (negative for markers expressed by cells differentiated along specific lineages)
Antibodies targeted to one or more of these cell surface proteins can be used to identify and isolate HSCs

Question 12

What is Erythropoiesis?

Answer 12

Regulated by erythropoietin (EPO) that controls differentiation of HSCs into erythrocytes via intermediate stages, BFU-E and CFU-E
BFU-E = Burst-Forming Unit Erythrocyte
CFU-E = Colony-Forming Unit Erythrocyte

Shortage of erythrocytes (e.g. following wounding) stimulates kidney to produce EPO.

Negative feedback controls EPO production and erythropoiesis:
EPO stimulates HSCs in bone marrow -> Increased erythrocyte formation -> Increased O2 Transport -> Negative feedback -.> Low O2 at proximal tubule

Question 13

What are megakaryocytes?

Answer 13

Are rare ~ 0.1% of the bone marrow population
Give rise to platelets (~3,000-10,000 platelets per MK)
The major hormone controlling megakaryocyte development is Thrombopoietin (TPO)

Question 14

Describe megakaryocyte ultrastructure

Answer 14

Indented, multilobed nucleus
Alpha granule formation
Dilated demarcation membrane system
Proplatelet formation

Question 15

Describe TPO regulation of megakaryocytopoiesis

Answer 15

TPO initiates Ras-dependent signalling cascade (MAP kinase)

Question 16

Describe Transcriptional control of megakaryocytopoiesis differentiation

Answer 16

Transcription factors that turn on target genes essential for megakaryocytopoiesis
HSC–FOG-1–>Megakaryocyte progenitor–GATA-1
FOG-1–>Mature megakaryocyte–NF-E2–>Proplatelet megakaryocyte -> platelets

Question 17

How do Myeloproliferative Disorders occur?

Answer 17

Result from the abnormal proliferation and differentiation of HSCs (e.g. Primary Thrombocythaemia: hypersensitive to thrombopoietin)