Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

A Stem cell biology > Stem cells in ageing and cancer > Flashcards

Stem cells in ageing and cancer Flashcards

You may prefer our related Brainscape-certified flashcards:
AP® Biology flashcards Biology 101 flashcards
1
Q

What happens to tissue function when we age?

Examples

A

Decline in function:

  • Loss of skin elasticity
  • Bones more brittle
  • Injuries heal slower
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Why do we need research into ageing?

A

Population is ageing - aim to prolong health into old age

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What stages of ageing are shaped by natural selection?

How are they shaped by natural selection?

A

1) Development and growth
2) Adult reproductive years

Shaped by natural selection:
Due to reproduction - any traits contribute to the continuation of a species

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What stages of ageing are outside of evolutionary pressure?

A

1) Protected ageing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What occurs in the development and growth stages of ageing?

A
  • High stem cell activity

- Morphogenesis and tissue growth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What occurs in the adult reproductive stages of ageing?

A
  • Growth CEASES

- Still relatively high stem cell activity to maintain tissue homeostasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Why can you not select for traits and mechanisms that would maintain stem cell function in old age?

A

No continuation of the species??

Outside of evolutionary pressure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Why is it difficult to prove the relationship between ageing and stem cells?

A

It is hard to isolate stem cells from different tissues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Why are HSCs easy to isolate?

A
  • Easily accessible
  • Known surface antigens (can isolate, purify and analyse their function in different scenarios)
  • Have good assays to assess the decline in function of the HSCs (irradiation of the mouse and transplantation of the HSCs)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the affect of ageing on the hematopoietic system?

A
  • Decreased immunity
  • Anemia
  • Increased incidence of bone marrow failure
  • Implications for bone marrow transplants
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the major predictor for a successful bone marrow transplant/

A

The AGE of the donor (younger the donor, the better the transplant)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What do we see in relation to HSCs with ageing?

Why?

A

INCREASE in number

BUT, these HSCs have:
- LOWER reconstitution potential

  • LINEAGE BIAS
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is described by the reconstitution potential of HSCs?

A

Ability to give rise to differentiated progenitors in the blood

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

When aged, what is the lineage bias fo HSCs?

A

Preferentially give rise to MYELOID lineage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What are the intrinsic factors that are drivers of HSC ageing?

A

Linked to the cell (transplatable):
- DNA damage

  • ROS
  • Polarity shift
  • Altered proteostasis
  • Impaired autophagy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the extrinsic factors that are drivers of HSC ageing?

A
  • Inflammation
  • Diet

Causing changes in:

  • The stem cell niche (cellular and molecular aspects)
  • The factors in the blood (systemic system) - cytokines etc
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Why are the majority of HSCs quiescent?

A

Protects the HSC from DNA damage (DNA damage is error prone)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

How is DNA replication in HSCs error prone?

A

When DNA damage occurs, they can ONLY repair by NON-HOMOLOGOUS END-JOINING (random sticking back together of the broken pieces)

–> Get further mutations (insertions and deletions)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What happens to HSCs as they age?

What does this cause?

A

The leave the quiescent state and become more cycling

Causes an increase in DNA damage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Why is there an increase in ROS in ageing HSCs?

A

Cycling cells have a different metabolism to quiescent cells:

  • Quiescent cells use mainly GLYCOLYSIS
  • Actively cycling cells –> glycolysis is increased BUT not producing enough energy

SO cells tend to use more oxidative phosphorylation through the MITOCHONDRIA METABOLIC PATHWAYS
–> Production of ROS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What are ROS?

Examples?

A

Free radicals derived from oxygen that are byproducts of OXIDATIVE PHOSPHORYLATION

Eg.

  • Superoxide
  • Hydroxyl radical
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the effects of ROS?

A

DAMAGE to mitochondrial and nuclear DNA, proteins and lipids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What are the FoxO TF involved in?

A

The regulation of metabolic stress through the regulation of metabolic enzymes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the relevance of the FoxO TF ini HSC ageing?

A

Deleted in many mouse models of HSC ageing

CONDITIONAL DELETION of certain FOXO TF members leads to the depletion of SC (eg. HSCs and neural stem cells)

As FOXO TF are important for the protection of SC from STRESS

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What happened when treated aged mice with antioxidants?

Why?

A

Mice were almost rejuvenated

As caused a decrease in ROS - allowing aged HSCs to reconstitute haematopoeisis better

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What happens to Cdc42 in aged HSCs?

A

Increase in Cdc42 activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What family is Cdc42 a member of?

A

Small RhoGTPases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

How does cell polarity change upon ageing? (in mice)

A

Asymmetric distribution of Cdc42 and tubulin in HSCs is lost

(prior to ageing they are located in ONE PART of the cell)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What restores the polarity shift in HSCs in aged mice?

What do these cause?

What does this show?

A

Inhibitors of Cdc42

In these cells:

  • Rejuvenated cells
  • Better reconstructive potential

Shows:
Certain aspects of ageing can be reversed at the CELLULAR LEVEL

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is protoestasis?

A

Protein homeostasis

The BALANCE between protein SYNTHESIS and DEGREDATION

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What causes altered proteostasis in aged HSCs?

A
  • Stresses in the cell (eg. oxidative stress) –> missfolds proteins

Can be fixed by processes in the cells OR if the problems persist - get protein aggregates which are then DEGRADED by: - The ubiquitin proteasome system
- OR by triggering autophagy

BUT in aged HSCs:
- These degradation processes are decreased/depleted (balance between synthesis and degradation is changed)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is autophagy important for?

A

The degradation of impaired mitochondria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What happens to autophagy in aged cells HSCs?

What does this cause?

A

Autophagy is decreased/depleted

–> Accumulation of protein aggregates and aberrant mitochondria

–> Increased production of ROS from aberrant mitochondria

–> ROS damages more mitochondria and DNA

–> This damage triggers the DNA repair response (If the cells fail to successfully repair this damage, the cell undergoes cell senescence or death –> depleting the stem cell pool (in terms of function, not number)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

As well as the increase in ROS, what else does mitochondrial damage cause?

What does this result in?

A

Inhibits oxidative phosphoylation, leading to a different composition of the products of glycolysis

–> Leading to differences in the epigenetic modifications in the cell

–> Leading to the aberrant proliferation and differentiation of the HSCs

–> Depletion the stem cell pool (in terms of function, not number)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Describe chromatin modification in aged HSCs

A
  • Modification can be either +ve or -ve regulators of the expression of the gene
  • Upon ageing, certain marks are put MORE FREQUENTLY in certain regions
36
Q

What is DNA methylation?

A

Epigenetic modifications that effect the expression of genes

37
Q

Describe DNA methylation in aged HSCs

A

Very different upon ageing:
- Levels go down upon ageing

  • But certain sites in the genome are HYPERMETHYLATED
38
Q

What are some of the specific DNA methylation marks that are put down on ageing?

A

H3K4 - Activating modification

HCK27 - Repressor modification

39
Q

What is epigenetic drift?

What could it be caused by?

A

Epigenetic modifications that occur as a direct consequence of ageing

Possibly caused by:

  • Molecular damage –> changes in metabolism (epigenetic cofactors/regulators)
  • Changes in the stem cell niche

OR

  • Changes to the DNA methylation and histone modifications
  • Stochastic events
40
Q

Why is there a completely different set of genes expressed in daughter HSCs compared to the adult HSCs?

What does this cause?

A

When the adult HSC (which has certain chromatin modifiers that are either activating or repressive) divides –> epigenetic drift

  • Causes the epigenetic modifiers to no longer be in the appropriate places

Causes:
- Changes to the gene expression profile

  • Changes to the behaviour of the cells
  • -> Stem cells to increase self-renewal and impair differentiation?
  • -> Promotion of stem-cell dysregulation?

(Functions of the adult and daughter cells to be completely different even without changes to the DNA sequence)

41
Q

What were the experiments to determine the extrinsic factors in HSC ageing?

A

1) Transplantation experiments

2) Parabiosis experiments

42
Q

Describe the transplantation experiments that helped to determine the extrinsic factors in HSC ageing

What is this evidence for?

A
  • Take HSC from young mice and transplant them into YOUNG host or OLD host
  • OR take HSC from old mice and transplant them into YOUNG or OLD host

(y-y, y-o, o-o, o-y)

Evidence for the contribution of the changing niche during ageing?

43
Q

Describe the parabiosis experiments that helped to determine the extrinsic factors in HSC ageing

What is this evidence for?

A
  • Join the skin of the mice together (join circulatory systems and allow them to exchange cytokines and growth factors)
  • Do this in different pairs (y-y, y-o, o-o)

Evidence for the contribution of circulating systemic factors that change during ageing

44
Q

What were the results of the transplantation and parabiosis experiments?

A

Showed:
- Environment can affect stem cell function

  • Not just the SC that age, the environment does
45
Q

What are the differences between non-aged and aged bone marrow?

A

Differences in both the SYSTEMIC and LOCALISED environment:

  • Vasculature changes
  • Bone thinning
  • Set of cytokines and factors have changed
46
Q

What are cytokines important in?

A

Maintenance of the HSCs

47
Q

What are the strategies for rejuvenation of SC?

A

1) Reduction of nutrient supply
2) ROS scavenging
3) Epigenetic modulation

48
Q

Why does the reduction of nutrient supply cause the rejuvenation of HSC?

A
  • Improved repopulation ability of the aged HSC

- Reversion of the myeloid differentiation bias

49
Q

Why is there an increased propensity for malignancy of aged HSCs?

A

Changes from young to aged HSCs (genetic changes, increase in ROS, polarity shift of proteins, epigenetic drift)

Gives rise to an increased MYELOID DIFFERENTIATION of the cells

–> these cells have increased propensity for developing MALIGNANCIES (aged individuals 300x more prone to developing acute myeloid leukaemia)

50
Q

What happens to the composition of the blood in terms of which stem cells are contributing to the whole to the differentiation output?

A

As age - this changes

YOUNG:
- Differentiated cell types come from ~1000 different activated HSCs

OLD:
- Diversity COLLAPSES

  • Tend to find one dominant clone that produces the MAJORITY of the cell types of the blood (clonal hematopoesis)
51
Q

Why is it thought that clonal haematopoesis occurs in aged individuals?

Describe this

A

Natural selection:
- Cell has a mutation (epigenetic or genetic) and gains a SELECTIVE ADVANTAGE

  • Can OUTCOMPETE the other cells within the population to become DOMINANT
52
Q

Are aged individuals with clonal heamatopoesis otherwise healthy?

A

YES (do not have leukaemia)

BUT are 10-fold more likely to get it later on in life

53
Q

What genes are COMMONLY mutated in the DOMINANT clones (that contribute to clonal heamatopoesis) in aged individuals?

A

DNMT3A

TET2

ASXL1

54
Q

What is DNMT3A important for?

A

The normal methylation of DNA

55
Q

What is TET2 important for?

A

Removal of the methylation of DNA

56
Q

What do the genes that are COMMONLY mutated in the DOMINANT clones (that contribute to clonal heamatopoesis) in aged individuals encode?

What does this mean?

A

Encode proteins involved in EPIGENETIC MODIFICATIONS (not tumour supressor genes or oncogenes)

Suggesting:
- Alterations in the genome underpin the development of haematopoesis

57
Q

What is the proposed model from ageing to leukemia?

A

Young HSCs are fine

1) BUT, through the:
- Accumulation of molecular damage
- Changes to metabolism
- Alterations in the local and systemic environment of the SC (signals from the inflammatory niche)
- -> Leads to changes in the epigenetic landscape

2) Changes can give cells a selective advantage
- -> selection of dominant clones (clonal hematopoesis)

These clones often have MUTATIONS in epigenetic genes (that normally regulate developmental pathways - including the balance between self renewal and differentiation)

–> creating a platform for FURTHER mutations that may give rise to leukemic clones

–> Once acquire these mutations, leukemia can occur

58
Q

What can further interaction between the leukemia clones and the niche cause?

What does this mean?

A

Tells the ageing niche to promoter the SURVIVAL and PROLIFERATION of the leukemic cells

Means that ONCE ESTABLISHED, leukemic cells also:
- REMODEL the bone marrow and stroma

  • Creating an environment where they have a better ability to SURVIVE compared to NORMAL human cells
59
Q

What can epigenetic drift also lead to?

A

Aberrations in haematopoesis:

  • Lesser ability of the HSCs to repopulate the haematopoietic system
  • Myeloid bias
60
Q

What can epigenome instability lead to?

How?

A

Genome instability

How: Interconnected process

Can impact on the epigenetic silencing of the DNA repair genes and DNA replication-dependent mechanisms

61
Q

How are tumours heterogenous?

A
  • Different cell types (morphologically and functionally)
  • Some are more proliferative
  • Some are more differentiated
62
Q

What are the 2 models that could explain tumour heterogeneity?

A

1) Stochastic model

2) Cancer stem cell model

63
Q

What is the stochastic model of tumour heterogeneity?

A
  • All tumour cells are EQUIPOTENT
  • Decision if the cell proliferates or differentiates in entirely STOCHASTIC (determined by extrinsic factors)
  • Some proliferate (tumour growth) and some differentiate
64
Q

What is the cancer stem cell of tumour heterogeneity?

A

Hierarchy:
- Tumours are hierarchically organised, with CSC at the TOP

  • CSC are BIOLOGICALLY DISTINCT from all of the other SC in the cancer (can self-renew or differentiated)
  • Only CERTAIN cells contribute to the long term growth of tumours
  • Progenitors have a LIMITED growth potential
65
Q

How can we distinguish between the 2 models of tumour heterogeneity?

A

Functional experiments:

S model
- When fractionate the tumour, transplantation of ANY of the fractions should give an EQUAL PROBABILITY of transplanting the tumour (all should be the same)

CSC model

  • Cells are NOT the same
  • Should get a PARTICULAR FRACTION of cells that when transplanted gives rise to the rumour SEQUENTIALLY
66
Q

What are teratocarcinomas?

A
  • MALIGNANT germ cell tumours that occur mostly un young men
  • Contain SC-like undifferentiated cells (embryonal carcinoma cells)
  • Also contain cells that derive from ALL 3 germ layers (suggesting pluripotent SC)
67
Q

What are embryonal carcinoma cells?

A

Stem cells of teratocarcinomas

68
Q

Why are ECC Tumour initiating cells?

A

Can be transplanted from a teratocarcinoma into another mouse and recapitulate the entire tumour

69
Q

What did Kleinsmith and Pierce do? (1964)

A

Gave the FIRST, EARLY definition of the CSC concept

AND

Suggested the differentiation of these cells could be a good therapeutic strategy for the treatment of malignant carcinomas (less likely to proliferate if they have been differentiated)

70
Q

What was Kleinsmith and Pierce’s definition of the CSC concept?

A

…

71
Q

What is AML?

A

Actue myeloid leukemia:

  • Increase in the number of myeloid cells that are rested in the development stage
  • -> hematopetic deficiency
72
Q

What are the leukemic stem cells? (LCS)

A

The very rare cells within the leukemic clone that has the ability to initiate AML growth when transplanted into immunodeficient mice

73
Q

At what frequency are the LCS transplanted?

A

At very low frequency

74
Q

How were scientists able to identify the cancer stem cell in the leukemic clone?

A

Based on the cell surface antigen properties:

CD34+ and CD38- cells

75
Q

What happens when purify the CD34+ CD38- cells?

A

Incidence of tumour initiating cells is much higher

76
Q

Describe the assessment of tumour-propagating potential

A

Take the bulk of the tumour and graft into a mouse to check if get a SECONDARY TUMOUR

77
Q

Why do we need to be able to distinguish between different cells in cancer research?

A

So we can ISOLATE the tumour propagating cells and DISTINGUISH them

78
Q

Describe the tumour propagating potential after the TPCs are purified?

A

Frequency of tumours is HIGHER

79
Q

Why do we need to do serial transplantation of the suspected tumour propagating cells?

A

To distinguish between progenitor cells (that sit high in the hierarchy) and the stem cells

ONLY SC have an infinite self-renewal capacity

80
Q

Why are the assays of tumour potential flawed?

How can they be improved?

What does this show?

A

Some tumour cells may NOT form secondary tumours in the absence of the stromal cells

Sometimes need STRONG SUPPORT of the stromal cells

Can be improved by:
- CO-TRANSPLANTING the stem cells with the stomal cells

Shows:

  • Improvement of tumour initiating property
  • -> Niche-dependence of the tumour cells
81
Q

Under what conditions must tumorgenic potential be tested under?

A

PERMISSIVE CONDITIONS

82
Q

Why might some cells that have tumourgenic potential not show this potential?

A

Not tested in the appropriate environment

83
Q

What are the implications of cancer stem cells in therapy?

A

Majority of therapies focus on SHRINKING the tumour

BUT, majority of stem cells are quiescent (not highly proliferative)

Traditional therapies LEAVE these cells

–> Cancer relapse

84
Q

What are the new strategies for treating cancer cells?

A

1) Making the cells differentiate
- -> depleting the cancer stem cell pool

2) Targeting the cancer stem cell

85
Q

What are the challenges for evaluating the cancer stem cell model?

A
  • Identifying cancer stem cell models/obtaining pure populations of cancer stem cells
  • Which/how many cells contribute to tumour growth and progression
  • What is the link between genetic heterogeneity and tumour potential?
86
Q

What changing in the niche can occur during ageing?

What causes these changes?

A

Cell-intrinsic changes in the niche cells

Indirect changes to the function of the cells in the niche

Induced by:
- Changes to the secreted factors (cytokines, growth factors, adhesion molecules)

  • Changes to the structural components of the ECM
  • Inflammatory cytokines?
87
Q

What is the epigenome a major regulator of?

A

Developmental pathways and genes

A Stem cell biology (16 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions