Stem Cells in Ageing and Cancer

Question 1

Imbalance of self-renewal and differentiation

Answer 1

HOMEOSTASIS is the balance between the adult stem cell splitting into a daughter stem cell (self renewal) and a differential progenitor cell (differentiation).

AGEING:
- DNA injury, Genetic instability, Telomere erosion > tumor suppression
- Elevated differentiation and impaired self renewal
- Leads to tissue degeneration, elevated apoptosis/senescence, stem cell exhaustion

CANCER:
- Genotoxic stress aberrations, genetic instability and oncogenes > tumorigenesis
- Elevated self renewal and less differentiation
- Leads to cancer stem cells and leukemia

Question 2

Ageing

Answer 2

Tissues DECLINE with ageing > stem cell activity decreases with age.
- Shaped by natural selection is the development and growth of SCs and the SCs formed in adult reproductive years.**
- There is a “protected ageing” state which is outside of evolutionary selective pressure (not under pressure as it doesnt effect offspring as PAST of reproductive phases). SC activity declines as stopped producing > decline means lower amount of SCs to renew.

*SHOWS FUNCTIONAL, MOLECULAR AND PHENOTYPIC CHANGES.
- loss of plasticity in skin
- decrease in bone cell density > risks of osteoperosis

**Morphogenesis: single cell to specialisation, development at early stages for formation of organs etc, adult years need SCs for tissue homeostasis to regenerate damage.

Question 3

Hematopoietic ageing:

Answer 3

INTRINSIC FACTORS:
- DNA damage: Quiescent (dormant) SC when the DNA is damaged by radiation, oxidation etc, and is repaired by NHEJ
In a cycling stem cell, there is an increase in DNA damage risks, and as someone ages it can lead to mutations and genomic instability in HSCs. They have higher metabolic demands

• Reactive Oxygen Species: free radicals derived from oxygen (byproducts of oxidative phosphorylation) Can damage nuclear DNA proteins and lipids
  > FoxO transcription factors
• Polarity Shift: Cdc42 (member of RhoGTPases) causes increased activity in aged HSCs.
• Altered Proteostasis: Accumulation of misfolded proteins and cellular damage results in decreased function and self0renewal of HSCs > decline in production of blood cells.
  Stress leads to production of misfolded proteins, which aggregate and degrade in the protasome/autophagosome into small peptides to be used.
  UPR (unfolded protein response) from misfolded proteins feeds into the mitochondria and ER, which inhibits further protein synthesis in the ribosomes.
• Impaired Autophagy
• Epigenetic Drift

EXTRINSIC FACTORS:

Question 4

Chromatin changes in aged stem cells

Question 5

“Intrinsic factors in aged stem cells are interconnected”

Question 6

Ageing bone marrow niche

Question 7

Increased propensity for malignancy

Question 8

Clonal hematopoiesis

Answer 8

PREDISPOSES TO CANCER

Question 9

From ageing to leukemia

Question 10

Rejuvenating aged HSC