Haematopoiesis

Question 1

What are the different sites of haematopoiesis?

Answer 1

• Haematopoiesis: production of new blood, HSCs (haematopoietic stem cells) are multipotent cells that undergo proliferation and differentiate into limited cell types
• During early development, yolk sac is responsible for any haematopoiesis by primitive haematopoiesis, first blood cells are produced from the mesoderm layer
• Following onset of circulation, primitive HCSs are re-distributed from yolk sac to aorta-gonad-mesonephros region to form HSCs (definitive haematopoiesis)
• Definitive haematopoiesis continues as HSCs from AGM region populate to foetal liver, thymus, and spleen; these locations + placenta become main site of haematopoiesis from 2-7 months
• HSCs populate bone marrow (most important site from 8 months)
• After birth, bone marrow becomes main site of haematopoiesis
• Environment of HSC is important for proper function, e.g transition from primitive to definitive haematopoiesis, or AGM environment for LT-HSC formation
• Bone marrow niche supports self-renewal and commitment to differentiation, includes: cell component, cell that influence the process, and molecular component that drives different pathways
• Quiescent long term stem cells associate with preosetoblasts influenced by signals from immune cells (macrophages)
• Long term stem cells, found primarily with osteoblasts, lose input from other cell types
• Short term stem cells are found within bone marrow where signals from blood vessels influence cell behaviour
• Molecular compartment: various factors are secreted, e.g chemokines and other growth factors, cells which interact wither other cells, proteins of the ECM, fibronectins present in tissue, topographical/physical parameters like elasticity, shear force from fluid movements , and metabolites that effect HSC behaviour

Question 2

Stages of HSCs to red blood cells

Answer 2

• Red blood cells and platelets both initially start as HSCs, they have a common pathway up to a certain point (common myeloid progenitor)
• 3 classes of molecules important for differentiation of HSCs into mature blood cells:
  1. Cytokines: small proteins that control the behaviour of other cell types in haematopoiesis, combination of different cytokines drives the cell’s differentiations
  2. Transcription factors (TFs): proteins that bind to specific DNA sequences and regulate gene expression
  3. Signalling molecules: cells specific proteins and pathways change or regulate cell behaviour
• Signals from bone marrow niche regulate when and where blood cells mature
• Differentiation: cytokines and TFs drive gene expression and cell signalling pathways that regulate differentiation of progenitor cells into mature blood cells
• RBC differentiation drives formation of cells adapted to carry O2
• Megakaryocyte differentiation drives formation of cells adapted to carry out haemostasis and release growth factors for tissue repair
• HSCs gives rise to all blood cells types via oligopotent progenitor cell intermediates
• Symmetrical division: long term HSC divides, daughter cell are along long term HSCs, gene expression profile shows daughter cell are essentially same as parent, but is not passing down a lineage that allows daughter cell to differentiate into different types of blood cells
• Asymmetric division: cells divide, 2 daughter cells form, one will be designated to stop differentiating down a particular pathway (short term), this has some limited self-renewing capacity, whereas other cell will form long term stem cell and help to maintain stem cell pool (steady state of blood cell production)