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L1 Introduction and Haematopoiesis
Body maintains output of blood cells through haematopoietic stem cells – HSCs in bone marrow
HSCs are multipotent – can form several cell types
HSCs can give rise to all blood cell types
Control of HSCs numbers
 HSCs are self-renewing and proliferative – asymmetric division
 Long term HSCs (LT-HSC) can self-renew – symmetric division
 ST-HSC have limited self-renewal is more committed down a lineage
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These then populate the foetal liver, thymus, spleen which take oer
haematopoiesis
 This process is called definitive haematopoiesis
 HSCs capable of reconstituting adult bone marrow (LT-HSCs) are first found in the foetal liver
 Towards the end of gestation, LT-HSCs populate the bone marrow which becomes the primary source of
haematopoiesis in adults
The haematopoietic stem cell niche
 At all stages of primitive and definitive haematopoiesis, the environment in which the HSC finds itself is
important for proper function
 E
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in the transition from primitive to definite haematopoiesis, the environment of the AGM is important for
formation of LT-HSCs
 The bone marrow niche, which supports self-renewal and commitment to differentiation has several
components
o Cellular components
o Molecular components
 Secreted ligands and their receptors
 The extracellular matrix
 Adhesion molecules
 Chemical gradients
 Bone marrow niche is vital for the proper regulation and function of HSCs
 Cytokines, signalling molecules and transcription factors drive lineage specific differentiation

Megakaryocytes
 A highly specialised cell that is responsible for
the production of platelets and their release into
the blood
 They develop in the bone marrow from
haematopoietic stem cells and undergo
characteristic changes as they develop into
mature megs
 Under times of high demand, platelet
production can increase by up to 20x
 Cytokines: TPO
o Binding of TPO to cMpl drives a
signalling pathway which leads to the
proliferation and differentiation of
megakaryocytes and platelet production
o Liver and kidney produces TPO
o LOOK @ HANDOUT
 TFs: GATA-1, FOG-1 & FLI-1
 Signalling molecules: c-MPL
 Many TFs are common to both megs and erythroid differentiation
 But they have a couple specific factors the cause them to commit to one path
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o Binding of FLI-1 to FOG via protein-protein interactions represses transcription on erythroid promoter
 EKLF = erythroid lineage determining
o Binding of EKLF via DNA binding domain to erythroid promoter activates transcription downstream of
GATA/FOG
o Binding of EKLF to FOG via protein-proteins interaction represses transcription on meg promoter
 TPO induced signalling and gene regulation that drives Meg/platelet production causes:
o Mature megakaryocyte to become polyploidy – this occurs by endomitosis, the replication of DNA
without cell division = cell gets really big
o Cytoplasmic maturation – the cytoplasm of mature megakaryocytes fills up with membranes, organells
and platelets specific proteins ready for packing into platelets
 Platelets are anucleated cell fragments of megakaryocytes
 However, all platelets are very consistent in their size shape and composition – platelet formation is highly
regulation -elegant process known as Proplatelet formation



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