Lecture 1 - Haematopoietic Stem Cells & Haematopoeisis

• Critical Requirements of Haematopoietic Stem Cells (HSCs)

  1. Self Renewal - for the generation of identical "daughter" cells

  2. Expansion - proliferate to increase numbers of multipotent progenitors

  3. Differentiation - progenitors must be capable of differentiating into mature cells
• Types of HSC cell division


  • Symmetric self-renewal - both daughter cells are stem cells
  • Asymmetric self-renewal - one daughter cell is a stem cell, the other has differentiated to a progenitor cell
  • Symmetric differentiation - both daughter cells have begun to differentiate into progenitor cells
• Quiescence


  A state of quietness or inactivity, critical to ensure lifelong tissue maintenance and to protect the stem cell pool from premature exhaustion under conditions of various stresses
• HSC niche in the bone marrow


  • Osteoblasts and endothelial cells express regulatory components that influence stem cell function
  • Egress into and out of the marrow by HSCs require transit into and out of the vascular niche, which is permissive for proliferation and differentiation. The endosteal niche facilitates HSC maintenance and quiescence.

  
• Self-renewing niche


  Quiescent stem cells are anchored in the center of the niche, whereas self-renewing stem cells are located close to the border separating the niche from the non-niche microenvironment
• Haematopoietic Stem Cell Transplants (HSCTs)


  Transplantation of HSCs, usually derived from bone marrow, peripheral blood, or umbilical cord blood
• Types of HSCTs


  • Autologous - patient's own stem cells used
  • Allogeneic - stem cells come from a donor
• Autologous HSCTs


  • Reduced risk of rejection due to graft versus host disease (GvHD)
  • No need to find a tissue-matched donor
• Allogeneic HSCTs


  • Donor is healthy, reducing the risk of transplanting cancerous stem cells
  • Effectively replacing the immune system. The new immune cells can attack the cancer cells (known as graft-verus-tumour effect)
• HSC mobilization for HSCTs


  Patients given combinations of synthetic G-CSF (Plerixafor) and EGFR inhibitor (Erlotinib) to expand and mobilize HSCs from bone marrow to peripheral blood for harvesting

  
• Haematopoietic cytokines


  Regulate and stimulate the production of different blood cell types, e.g. EPO for erythropoiesis, TPO for megakaryopoiesis
• Erythropoiesis


  1. Proerythroblast

  2. Erythroblasts

  3. Reticulocytes

  4. Erythrocyte
• Erythropoietin (EPO)


  Primary regulator of erythrocyte production, produced by kidney in response to hypoxia
• Thrombopoietin (TPO)


  Primary regulator of platelet production, produced mainly in the liver and kidney, levels inversely proportional to platelet count
• Megakaryopoiesis


  1. Megakaryoblast

  2. Promegakaryoblast

  3. Megakaryocyte

  4. Platelets
• Megakaryocyte ultrastructure allows remarkable cytoplasmic remodelling to develop platelets inside the cytoplasm