haemopoiesis & cytokines

8/14/2019 Haemopoiesis & Cytokines

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Haematopoiesis and cytokines

dr. veera sekaran nadarajan

department of pathology

Objectives

1. Define stem cells and explain its role in haematopoiesis

2. Describe how mature haematopoietic cells are generated

3. Illustrate the regulatory processes involved in drivinghaematopoiesis via transcription factor activations andcytokine regulatory networks

4. Describe the functions of certain important cytokines in

haematopoiesis I.e. EPO, TPO, G-CSF, GM-CSF, IL-3,SCL

Lecture contents

1. Brief overview on stem cells

2. Haematopoies is

3. Regulation of haematopoiesis via cytokine and TFpathways

4. Biology and function of key cytokines (assignment)

Haematopoietic cells

Normal bone marrow aspirate showing variety of haematopietic

cells in varying degrees of maturation


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Sites of Haematopoiesis

AdultsVertebrae, ribs, sternum, skull, sacrum & pelvis, proximal ends

of femur

Metcalf, D. Stem Cells 2007;25:2390-2395

Foetus0-2 months - yolk sac2-7 months - liver, spleen5 9 months bone marrow

Infantbone marrow (all bones)

True origin of the first HSC is stilldebated

Metcalf, D. Stem Cells 2007;25:2390-2395

The conventional view of hematopoiesis in which multipotential stem cells are self-generatingand also produce precursor cells with increasing restriction of their lineage and proliferativepotential

Demonstration of HSC

spleen colony assays in rodents

long term bone marrow cultures (limiting dilutionassays)

surrogate markers (CD34, CD38, c-kit, Thy-1,

Sca-1)

Earliest recognisable colony on

methylcellulose cell culture is CFU-GEMM


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Properties of HSC

capacity for self renewal/generation

capable of reconstituting all haematopoietic elements(multipotentiality)

confer radioprotection

capable of secondary transfer

The HSC niche

The fate of HSC to self renew or differentiate is decided by its

endosteal or vascular environment

Signals generated by cytokine network, work within this framework

to regulate HSC development

Wilson et al.Nature Reviews Immunology6, 93106 (February 2006) | doi:10.1038/nri1779

Transcriptional regulation of HSC

The switching on and offwith

complex interactions within

the genetic regulatory

network (GRN), mediated by

external signals decide on

HSC fate and lineage

restriction

PU.1 and GATA-1 TFs aredecisive in lineage

commitment of the HSC

Other important TF in early HSC

development include SCL

and GATA-2

http://www.nottingham.ac.uk/genetics/networks

/mouse/

Mechanism of HGF action

Cytokines regulate haematopoietic differentiation viaactivation/inactivation of downstream signals and functional

pathways

May be lineage restricted or act on multiple lineage

Metcalf, D. Blood 2008;111:485-491


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Mechanism of HGF action

HGF binding to its cognatereceptor causes approximationof the cytoplasmic domainallowing cross phosphorylationand activation of downstream

kinases

Multilineage HGF

Kit ligand (SCF)

Flt-3 (fms-like tyrosine kinase 3)

GM-CSF

IL2, IL-3,IL-7

Redundancy seen with most of the cytokines exceptfor possible SCF and IL-7

Lineage specific HGF

Erythropoietin (EPO)

G-CSF

Thrombopoietin (TPO)

Assignment

Write a ~ 500 word essay on any one of thelineage restricted HGFs, giving brief details onhow it it is regulated and how its actions aremediated. Also, briefly discuss how it has beenexploited for clinical therapeutic use.


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