02. Intro to Stem Cells

• there is a high rate of cell replacement in the blood and skin and a slow rate in the brain and heart
• a stem cell has two ways of dividing:

  • asymmetrical = one cell will be identical to the parent, and one will have acquired a change in gene expression to push the cell down a different lineage, part of self renewal.
  • symmetrical = divides into two cells identical to the parent cell, part of expansion.
• symmetrically dividing cells are only available for a small amount of time in vivo, involved in the very early steps following fertilisation
• if a stem cell is quiescent, to signal it to move into division you must understand its orientation to the extracellular matrix
• extrinsic regulation of stem cells is governed by neighbouring cells on the outside of the extracellular matrix

  • growth factors and cytokines
• stem cycles will divide every 9 hours as the cell cycle blocks are different
• adult stem cells are those that are associated with a specific tissue
• embryonic stem cells have potential to give rise to every cell type in the body (but cannot differentiate into extra-embryonic tissues, like the placenta)
• adult stem cells have the potential to give rise to anything from one to several cell types, depending on which organ they are from
• when a sperm and egg fuse to form a zygote, it is a totipotent cell.

  • remains totipotent up until the 8 cell stage
  • has potential to give rise to any and all human cells
• after the 8 cell stage, the cells are pluripotent and can give rise to all tissue types apart from extra-embryonic tissues

  • on day 4 of development, the embryo forms two layers
  • outer = trophectoderm (forms placenta)
  • inner cell mass = embryo
• multipotent stem cells can self-renew and give rise to a multitude of different lineages, e.g. haemopoietic stem cells
• the proportion of total stem cells decreases during development
• the germ cells must remain pluripotent, in the embryo these move to the genital ridge
• gastrulation = inner cell mass forms three layer

  • mesoderm
  • endoderm
  • ectoderm
• for stem cells to undergo differentiation, pluripotent genes must be switched off

  • Oct4 is the master regulator, a POU domain transcription factor
  • Sox2
  • Nanog

  all three of these regulate each other
• LIF = leukaemia inhibitory factor, helps to keep stem cells pluripotent

  • binds to LIF receptor and gp130
  • activates JAK-STAT pathway
  • STAT maintains regulation
• if LIF is removed, MAP-kinase pathway is activated, causing differentiation
• stem cells do not have the normal cell cycle checkpoints

  • RB/E2F and p53 pathways are inactive
  • G1/S checkpoint not present
  • therefore cells go straight into S phase
• tumour cells have hyperactivation of Cdk/cyclin complexes, so mimic a stem cell like cell cycle