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Stem cells, Ageing and Cancer > Tissue/adult stem cells > Flashcards

Tissue/adult stem cells Flashcards

1
Q

what results in the loss of pluripotency?

A

development and tissue formation results in the loss of pluripotency
- tissue development is accompanied by a progressive loss of pluripotency
- Differentiation rises whilst pluripotency falls – inverse correlation
- Slow acquisition of new characteristics leading to specialised cell types

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2
Q

what is Conrad Waddington’s epigenetic landscape?

A

It illustrates the progressive nature of differentiation and loss of pluripotency:
- Marbles (cells) rolling down a valley and meeting bifurcations
- The bifurcations represent cell fates that the cells may undergo

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3
Q

what are the 2 mechanisms by which you can alter cell fate?

A
  1. reprogramming
  2. trans-differentiation
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4
Q

what is reprogramming of cell fate?

A
  • Reprogramming – process where fully differentiated cell reverts back to an earlier undifferentiated progenitor state, so the cell can readopt the possibility to form different cell types
  • Change TFs to self-renewing, and then to a new cell fate TF
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5
Q

what is the process of trans-differentiation in altering cell fate?

A
  • Trans-differentiation – process where a cell has the ability to completely stop the differentiation programme they were undergoing, and switch to a new differentiation fate without needed to revert to a progenitor state
  • Occurs by forced expression of a limiting number of TFs
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6
Q

what makes cells specialised?

A

All cells in our body have the genes required to change cell fate, but specialised cells have specific gene expression

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7
Q

how does acquisition of specialised cell function occur?

A

the acquisition of specialised function results from the expression of a subset of genes
- Fully differentiated cells have no/limiting capacity to divide
- Limited reversibility and plasticity to go back to progenitor state

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8
Q

what are differentiated adult tissues restricted by?

A

A differentiated tissue has restricted capacity to cope with minor insults, injuries or normal wear and tear

Cells constituting in adult tissues have lost pluripotency and are differentiated, have limited capacity to divide and will not be able to deal with injuries

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9
Q

what organs in the body have regenerative capacity?

A

organs can repair when there are lots of cells:
- Bone marrow-derived cells can reconstitute blood cells
- Epithelial cells of the gut or skin have a high regenerative capacity
- Some areas of the brain can regenerate

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10
Q

how can fully differentiated cells/tissues with no capacity to divide be able to regenerate?

A

due to the presence of adult stem cells

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11
Q

what are adult stem cells?

A

Adult stem cells: a stem cell present in adult tissues/organs that retain the characteristics of stem cells such as self-renewal and potency, except adult stem cells are usually unipotent or multipotent

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12
Q

what is self-renewal?

A

Self-renewal: the ability of a cell to produce a replica of itself (to divide to maintain stem cells)
- Important to maintain regenerative capacity

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13
Q

what is uni/multipotency?

A

Uni/multipotency: unlike embryonic stem cells, which are pluripotent, adult stem cells have limited cell fate decision and usually differentiate into one or several cell types that compose the organ
- E.g. HSC can give rise to lymphocytes, macrophages, red blood cells

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14
Q

what is cellular homeostasis?

A

Cellular homeostasis is the constant or periodic generation of new cells to replace old, damaged or dying cells or add new cells as needed.
-Adult stem cells can fulfil this role through the process of regeneration/replacement

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15
Q

why is it important to balance and regulate cellular homeostasis?

A
  • Must maintain a balance between number of cells maintained as a pool of stem cells that self-renew and number of cells that divide to replenish damaged tissue
  • If balance isn’t controlled, cancer can form if division rates are too high, too few divisions cause ageing and neurodegenerative diseases
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16
Q

what is the classical model of asymmetric stem cell dividion?

A

Adult stem cell divides into 2 fates:
1. One adult stem cell via self-renewal to maintain stem cell pool

  1. The other divides into a progenitor cell which can divide further to generate a pool of cells called transit-amplifying cells (progenitor cells). - —- These cells are highly proliferative and when there are a high number of them, they can differentiate into a specialised cell
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17
Q

what is stem cell asymmetry?

A

Asymmetry at the cellular level – one cell divides asymmetrically to produce one stem cell and one progenitor cell

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18
Q

what is population asymmetry?

A
  • Can have a mixture of symmetric divisions to produce stem cells or progenitor cells, and asymmetric division
  • Overall percentage of these events at the level of the population ensure maintenance of stem cells needed, as well as the generation of progenitors to repair tissue
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19
Q

how do adult stem cells ensure that cellular homeostasis is balanced?

A
  • Adult stem cells tightly regulate this process by residing in a very specialised environment called the stem cell niche
  • Stem cell niche is essential to maintain activity of stem cells, determining whether those cells self-renew or differentiate
  • Maintaining a balance between self-renewal and differentiation is critical to cellular homeostasis
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20
Q

what is the stem cell niche?

A

Stem cell niche: specialised, tissue-specific microenvironment regulating activity of adult stem cells
- it has an essential regulatory role

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21
Q

what are the external components of the stem cell niche?

A

Physical control of stem cells:
- Cell adhesion between stem cells
- Extracellular matrix – structure and stiffness of ECM is important and controlled - If stiffness is too high, cells lose self-renewal capacity
- Physical support to the cells

Chemical control of stem cells:
- Secreted proteins (paracrine, juxtracrine, endocrine signalling, neurotransmitters)
- Cells around the stem cells will produce these secreted molecules which are essential in controlling activity of stem cells
- Metabolic molecules (calcium, ROS) - Oxidative stress is important to control stem cells activity

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22
Q

what are da 3 intracellular mechanisms regulate adult stem cells?

A
  1. Epigenetic regulation: histone modifications and methylation influence the expression of stem cell genes
    - Marks genome for global changes in cell regulation
  2. Transcriptional regulation: networks of transcription factors regulate stem cell quiescence, proliferation, differentiation and self-renewal
  3. Cytoplasmic determinants: asymmetric distribution of proteins in stem cells govern the mode of cell division
    - This ensures that cell division will occur in a symmetric or asymmetric manner
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23
Q

what is an example of an invertebrate adult stem cell?

A

the Drosophila ovarian germline stem cell

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24
Q

what are the components that regulate the Drosophila ovarian germline stem cell?

A
  • Fruitfly ovary contains 16-20 ovarioles
  • Ovarioles contain germline stem cells sitting in a niche called a germarium
  • In each germarium is exactly 2 germline stem cells
  • The 2 germline stem cells are tightly associated with 2 support cells called cap cells
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25
Q

how do the Drosophila germline stem cells divide?

A
  • The germline stem cells divide asymmetrically to maintain one germline stem cell and generate one cystoblast cell
  • The cystoblast cell undergoes 4 rounds of cell divisions to form 16 cells, and any one of these cells can undergo further differentiation to become an oocyte

the asymmetric division must be tightly controlled for this process to occur

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26
Q

what signalling controls germline stem cell differentiation?

A

BMP signalling

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27
Q

what is the process of germline stem cell differentiation?

A
  1. Cap cells are tightly associated with the germline stem cells via cell adhesions
  2. The cap cells produce TGF-beta ligands which diffuse into environment and bind to germline stem cells via BMP receptors to activate BMP signalling - The signalling is via MAD and MED
  3. BMP MAD/MED signalling represses bam gene which is required for differentiation - therefore close association between cap cells and the GSCs will maintain the GSC population
  4. ECM molecules restrict TGF-beta ligand diffusion
  5. Asymmetric division of GSCs enables one of the daughter cells to move away from the cap cells and therefore be under less BMP signalling, and this drives differentiation
    - Loss of Dpp (or overexpression of bam) causes GSC differentiation
    - Overexpression of Dpp (or loss of bam) causes germline tumours
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28
Q

what does loss of Dpp/overexpression of bam lead to in GSCs?

A

Loss of Dpp (or overexpression of bam) causes GSC differentiation

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29
Q

what does overexpression of Dpp/loss of bam lead to in GSCs?

A

Overexpression of Dpp (or loss of bam) causes germline tumours

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30
Q

what determines whether the GSCs self-renew or differentiate?

A

Proximity of GSCs to cap cells determines whether they self-renew or differentiate

31
Q

what is an example of a vertebrate adult stem cell?

A

skeletal muscle stem cells, also known as satellite cells

32
Q

how are skeletal muscle stem cells formed in embryonic development?

A
  • When skeletal muscle cells are generated in embryonic development, some cells of the same origin do not fuse with each other to form myofibres, and are instead set aside during foetal development
  • These cells remain in adult muscle tissues and are responsible for repairing muscle injury
  • These cells are known as satellite cells or skeletal muscle stem cells
33
Q

what is the structure of the satellite cell niche?

A

Satellite cells reside in a niche where they are sandwiched between a muscle fibre and a specialised ECM called a basal lamina

34
Q

what is the activity of the satellite cells when they are in their niche?

A
  • Satellite cells are often quiescent and do not divide, residing in G0 for long periods
  • If there is an injury/wear and tear to the muscle fibre, the satellite cells exit G0 and enter the cell cycle to generate progenitor cells which differentiate as well as regenerate a pool of satellite stem cells for future need
35
Q

how does satellite cell division occur?

A

Asymmetric cell division in stem cell maintenance:
- Cell division occurs in an apical basal plan
- Apical forms the muscle fibre
- Basal is the cell in contact with the basal lamina
- Can use symmetric cell division to form more satellite cells or progenitor cells exclusively if needed
- Asymmetric cell division is regulated by Par proteins – allocation of cytoplasmic determinants to specific poles of the cell

36
Q

how are Par proteins involved in the asymmetric division of satellite cells?

A

Asymmetric cell division is regulated by Par proteins – allocation of cytoplasmic determinants to specific poles of the cell, Par3 and Par1 in particular
- Par1 is polarised to the basal side – leads to self-renewal and formation of satellite cell in contact with basal lamina
- Par3 is highly abundant in apical side – leads to generation of a myogenic progenitor cell near the muscle fibre
- Cell polarity Par proteins can induce p38 MAP-kinase which can trigger transcription of MyoD - MyoD is a TF which drives differentiation
- Par1 prevents accumulation of Par3 in basal side, ensuring that the basal side undergoes self-renewal and apical side undergoes differentiation

37
Q

what is the key component of the satellite cell niche?

A

The basal lamina is a component of the niche:
-The satellite cells are encased between the myofibre and the basal lamina
- Basal lamina has a key protein called laminin which resides in ECM, but has 2 receptors at its surface which interact with the satellite cells
- These 2 receptors are integrin and dystroglycan
- The laminin receptors enables transfer of information to the satellite stem cells

38
Q

how does remodelling of the basal laminal support asymmetric cell division?

A
  • In normal situations, satellite cell is quiescent in G0 and resides between the fibre and the basal lamina
  • Basal lamina has a specific laminin isoform called laminin-alpha2 which is present at the surface of muscle cells
  • When muscle is injured, the satellite cells secrete metalloproteinase proteins (MMP2/9) which can digest the local ECM
  • At the same time, satellite cells start synthesising a new form of laminin called laminin-alpha1
  • Laminin-alpha1 can bind to a different integrin receptor (integrin-alpha6-beta1) than laminin-alpha2
  • Local remodelling of the ECM to incorporate the new laminin isoform provides the satellite cells with a new capacity for new cell signalling via the integrin receptor
39
Q

why is basal lamina remodelling so important?

A

This process is important for setting up the asymmetric distribution of the Par proteins
- If we mutate laminin-alpha1, we no longer see asymmetric distribution of Par proteins, and we lose asymmetric cell division and capacity of self-renewal

40
Q

what are the therapeutic advantages of adult stem cells?

A
  • already specialised: induction of differentiation into specific cell types will be easier
  • plasticity: recent evidence suggests they can differentiate to ranges of tissue types
  • no immune rejection: if used in autologous transplantations
  • no teratomas unlike ESCs
  • no ethical controversy as they are sourced from adult tissues
41
Q

what are the therapeutic disadvantages of adult stem cells?

A
  • minimal quantity: number of isolatable cells may be small
  • finite lifespan: may have limited lifespan in culture
  • ageing: stem cells from aged individuals may have higher chance of genetic damage due to ageing
  • immunogenic: potential immune rejection if donor cells are derived from another indivdual
42
Q

how is stem cell behaviour determined in the Drosophila ovary?

A
  • Cap cells next to terminal filament
  • Cap cell contains multiple signalling pathways e.g. TGF-beta pathway, notch signalling
  • These drosophila pathways are also seen in mammalian stem cells
  • GSCs respond to the signalling from cap cells
43
Q

what are the 4 different types of stem cell niche adhesion?

A
  1. classical cadherin-mediated adhesion
  2. integrin-mediated adhesion
  3. integrin- and cadherin-mediated adhesion together
  4. other molecules/gap junction components
44
Q

what is classical cadherin-mediated cell adhesion?

A

Classical cadherin-mediated physical cell-cell adhesion helps anchor stem cells to their niche:
- a-catenin and b-catenin, which associate with the intracellular domain of cadherins, help to cluster cadherin molecules and form adherens junctions (AJs)
- if cadherins are broken, stem cells move out of niche and can differentiate

45
Q

what is integrin-mediated stem cell adhesion?

A

Integrin-mediated cell-extracellular matrix (ECM) interactions help anchor stem cells to the niche, which often contains a number of ECM components
- The intracellular domains of integrins interact with the actin cytoskeleton network through talin proteins to cluster integrin molecules together
- Integrins contact ECM and stem cell, supported by talin molecules

46
Q

how can cadherins and integrins work together in stem cell adhesion?

A

Cadherin-mediated cell interactions and integrin-mediated cell-ECM interactions can work together to anchor stem cells to the niche
- Cadherin and integrins from stem cell can interact with ECM and niche

47
Q

what other molecules can be involved in stem cell adhesion?

A

In addition to cadherins and integrins, other molecules, such as Delta/Notch, SCF/c-Kit, CD44/hyaluronic acid (HA) and gap junction components, are also involved in stem cell-niche adhesion

48
Q

what other roles do adhesion molecules provide for stem cells, as well as anchorage?

A
  1. signalling
  2. regulate cell division and polarity
  3. regulate competitiveness for niche occupancy
  4. ageing
49
Q

how do adhesion molecules provide signalling for stem cells?

A

Cadherin and integrin complexes can signal directly downstream or facilitate receptor-mediated niche signalling to regulate stem cell self-renewal, proliferation and survival.
- Loss of these signals can result in premature ageing

50
Q

how do adhesion molecules regulate cell division and polarity?

A

Cadherin and integrin molecules are required to regulate asymmetric cell division and possibly to maintain cell polarity;
- the actin cytoskeleton network associated with cadherins or integrins helps anchor one centrosome to the apical side of the cell to ensure that its mitotic spindle is always orientated perpendicular to the niche surface
- the cell that divides to the niche will maintain stem cell population, cell that divides in direction away from niche will differentiate

51
Q

how do adhesion molecules regulate niche competitiveness?

A

Stem cells utilize the strength with which they are anchored to the niche to regulate their relative competitiveness for niche occupancy.
- The expression levels or functions of adhesion molecules are often regulated by self-renewal and differentiation factors.
- Stem cell-niche adhesion thus serves as a quality control mechanism that ensures that stem cells are retained in the niche whereas differentiating cells are lost.
- Stem cell with high cadherin/integrin signalling will self-renew
- If the cadherin/integrin signalling is lost, differentiation is induced

52
Q

how are adhesion molecules implicated in ageing?

A

The expression levels or functions of adhesion molecules in stem cells and niche cells are affected by aging.
- The adhesion between stem cells and their niche is, therefore, also affected by aging
- Old stem cells lose adhesion to the niche as they lose cadherin

53
Q

give an example of a well-defined adult stem cell niche:

A

the mammalian gut crypt

54
Q

what is the mammalian gut crypt?

A
  • in the GI tract, there are a no. of crypts which increase SA
  • crypts use microbiome as fuel to maintain gut epithelia
  • the crypt is a tube of cells arrayed on a basement membrane
  • stem cells are at the basal/distal end of the crypt
  • differentiated cells are at the apical/proximal end of the crypt
55
Q

what does the mammalian gut crypt comprise of?

A
  • single cell epithelium
  • crypt base columnar stem cells (CBCs) are surrounded by Paneth cells
  • Stem cells and Paneth cells exist at basal/distal end of crypt
  • stem cell progeny (transit amplifying cells) move upwards to the apical/proximal end and differentiate as they leave the niche
  • mesenchymal cells send signals that regulate stem cell activity
56
Q

how were crypt base columnar stem cells (CBCs) identified?

A

via the expression of Wnt target genes
- Cells identified that respond to Wnt signals and express Wnt target genes - these cells called CBC (crypt base columnar) cells
- They end up being the ‘stem cell’

57
Q

what factors regulate stem cell proliferation and differentiation in the crypt?

A

Wnt, Notch, BMP, Hedgehog, EGF
- Wnt and Notch are expressed at high levels ventrally

58
Q

what is the role of enterocytes in the gut crypt?

A

Enterocytes role is to uptake ions, water, nutrients, vitamins and absorption of unconjugated bile salts

59
Q

what is the role of enteroendocrine cells in the gut crypt?

A

Enteroendocrine cells secrete hormones, such as GLP-1 and GLP-2, PYY, CCK, and serotonin

60
Q

what is the role of goblet cells in the gut crypt?

A

goblet cells secrete mucin and create a protective mucus layer

61
Q

what is the role of tuft cells in the mammalian gut crypt?

A

tuft cells monitor the intestinal content using succinate and sweet/bitter taste receptors

62
Q

what is the role of Paneth cells in the mammalian gut crypt?

A

Paneth cells are highly specialized secretory functions to regulate the composition of the intestinal flora and cell populations
- They produce EGF, Notch, and Wnt, α-defensins
- Paneth cells are important in providing growth factors to maintain the stem cell population

63
Q

how do CBCs interact with Wnt?

A

CBC stem cells contain receptor called Lgr5 which responds to Wnt, and can be used as a marker of the crypt
- Wnt localised at the base of the crypt

64
Q

how can the human gut be recapitulated in vitro?

A

Can take gut stem cell populations and recreate human gut in culture using signalling molecules such as Wnt and Notch
- scientists recapitulated a crypt growing in culture
- crypt contained basement membrane, mesenchymal support so had some characteristics of human gut but not all

65
Q

how was the interaction between CBC and Wnt analysed?

A

Lgr5-EGFP transgenic mouse
- Paneth cells labelled with a lysozyme antibody (purple)
- Lgr5-EGFP gene was knocked into the mouse
- Everytime Lgr5 was expressed in the mouse, could visibly track the CBC cells in the mouse gut
- Could see purple paneth cells and green CBC stem cells
- Stem cell population at base, and lose GFP expression as they move upward through the crypt
- Wnt pathway located at the at crypt

66
Q

what happens to the CBCs and Wnt in mice with adenomas?

A
  • When mice form adenomas, there is disorganisation of paneth cells and CBCs as they are found at all points in the crypt, not just at the bottom
  • In colorectal cancer, Wnt is no longer restricted to just the crypt
67
Q

how can miniguts be made from stem cells?

A
  1. derived from reprogramming of adult stem cells into a pluripotent state (iPSCs)
    - Skin fibroblasts can be reprogrammed to iPSCs
    - Can add growth factors to iPSCs, embed them and push them towards a gut cell fate to develop organoids
    - Crypts can then form
  2. derived from embryonic stem cells
    - apply gut transcription factors to the pluripotent stem cells
68
Q

why are miniguts useful?

A
  • can help to study a functioning gut in vitro
  • could use these as screening tools to test drug toxicology
69
Q

what are the limitations of miniguts?

A

expensive to grow organoids

70
Q

how do minigut organoids develop?

A

Fluorescent Activated Cell Sorting (FACS):
- As CBC grows, it forms a ring like structure, and some stem cells differentiate to form Paneth cells, while others maintain CBC population
- Where there are more stem cells, the structure begins to bud and loop out
- Forms organoid with epithelial structures trying to bud out
- Centre is kept empty for lumen of the gut

71
Q

what is the mechanism of the self-organising minigut architecture?

A
  1. An organoid derived from Axin2-LacZ knock-in mice.
    - Axin2-LacZ (blue) expression recapitulates Wnt activation
    - Axin2 in Wnt pathway is where budding of crypt occurs
  2. Wnt activation induces local proliferation and EphB expression.
    - Local cell expansion and Eph-Ephrin repulsive force generate bud formation and curvature
72
Q

how physiologically normal are epithelial miniguts?

A
  • The engrafted epithelial mini-guts regenerated indiscernible epithelial patches from surrounding recipient epithelium.
  • The patches persisted for at least 6 months without changing their histologic appearance.
  • Can inject organoids into mouse and they become integrated into the gut epithelium and organise themselves in the gut- can be used for repair of gut epithelia
73
Q

what are the possible uses of miniguts?

A
  1. Understanding human biology e.g. mutation detection
  2. Testing patient samples e.g. testing disease samples, drug discovery, diagnosis
  3. Regenerative medicine e.g. transplants, repair, therapeutics
  4. Identify new genes that regulate the gut
  5. Toxicology applications
  6. Replacement in surgery
74
Q

how can miniguts be used to study inflammatory bowel disease?

A
  • gut stem cells from patients were taken and induced to form miniguts
  • could compare the bowel disease miniguts with wildtype miniguts to see causes
  • could also apply steroids to the induced miniguts to see if they could reduce the effects of the disease

Stem cells, Ageing and Cancer (8 decks)

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