Lecture 9: Adult stem cells

Question 1

How often do cells turnover?

Answer 1

Vary massively! There must be cells within these tissue that contribute to repair

Question 2

tissue specific stem cells:

Answer 2

• called ‘adult’ or tissue-specific stem cells
• can also be derived from foetal tissue
• build & repair tissue
• difficult to isolate & maintain in vitro

Question 3

to repair tissue, stem cells have to:

Answer 3

• supply large numbers of DIFFERENTIATED cells
• BUT protect themselves from accumulating mutations
• AND stop themselves raging
• Adult stem cells have no telomerase
• -therefore telomeres will shorten until cells senesce

Question 4

Telomeres:

Answer 4

• ends of linear chromosomes
• Repetitive DNA sequences (TTAGGG)
• Specialised proteins
• form a ‘capped’ end structure

Question 5

DNA replication is

Answer 5

..bidirectional.

• Polymerase moves 5’ to 3’
• requires a labile primer
• each round of DNA replication leaves 50-200bp DNA unreplicated at the 3’ end

Question 6

Generic Adult stem cell model:

Answer 6

Quiescent stem cell –Damage Physiological Stress–> Transit stem cell –Cell cycle entry –> Active Stem cell [back to beginning or] –> Progenitors -= expand

Question 7

How are adult stem cells protected from mutations whilst still being able to repair tissue

Answer 7

by only dividing a few times and letting the progenitor expand

Question 8

quiescent stem cells divide ____

Answer 8

asymmetrically to give progenitors, progenitors expand

Question 9

Conventional ASC model: IMPLICATIONS

Answer 9

• cells flow through in unidirectional manner

- differentiation becomes restricted, through ORDERED, IRREVERSIBLE fate decisions i.e the stem cells are multipotent

Question 10

why doesnt the generic model apply to all adult stem cell systems?

Answer 10

1) Not all Adult Stem cells are multipotent
2) Not all adult stem cells are quiescent
3) Flow through hierarchy is not always unidirectional

Question 11

Not all adult stem cells are multipotent :

Answer 11

Some examples of UNIPOTENT set cells: Epidermal basal cells only make keratinocytes

Question 12

Not all adult stem cells are quiescent:

Answer 12

e. g. intestinal crypt
- stem cells are continuously dividing
- give rise to more differentiated cells
- which then lead to transit amplifying cells

Question 13

Each different tissue is likely to have evolved _____ strategy(s) to maintain the tissue normally & during repair

Answer 13

SLIGHTLY DIFFERENTLY

Question 14

The fastest self-renewal tissue in a mammal:

Answer 14

Small Intestinal Crypt - Villus Unit

• Continous proliferation from base
• Crypt Base Columnar (CBC) cells are the long term stem cells
• CBCs divide to compete for niche space= those at base most likely to survive

Question 15

Crypt Base Columnar (CBC’s) give rise to :

Answer 15

Enterocytes, Goblet cells, Paneth, Enteroendocrine cells.

-BUT there is another stem cell population = +4 LRC’s

Question 16

Small Intestinal Crypt-Villus Unit CBCs r responsible for:

Answer 16

day-to-day regeneration.

- +4 LRC can revert to Lgr5+ stem cell, therefore NO ‘professional’ G0 stem cells exist

Question 17

mammary gland: MaSC = multipoint give rise to:

Answer 17

• UNIPOTENT Myo-SC

- BIPOTENT Lum-SC

Question 18

MasC are

Answer 18

SLOW cycling or G0
- MaSC are SLOW cycling or G0 –
[Normally - low hormonally drive tissue turnover.
Puberty = increase in ductal morphogenesis]
May be interconversion between Ductal and alveolar progenitors

Question 19

Skeletal muscle: what are the stem cells?

Answer 19

• satellite cell
• Contribute minimally to myofibre maintenance.
• Damage – cells re-enter cell cycle- and under go either:
• Symmetric divisions to remake Stem cell pool
• Asymmetric divisions : myogenesis.
• satellite cells are the professional G0 stem cells BUT unipotent cf blood

Question 20

‘NICHE’ in ecology:

Answer 20

Role and position a species has in its environment

Question 21

“NICHE” in stem cell biology

Answer 21

a local tissue microenvironment that hosts and influence the behaviour and characteristics of stem cells

Question 22

how did concept of niche emerge and the basic idea

Answer 22

• Scofield 1978
• Has a defined anatomical location.
• Regulates self-renewal and
• Removal from niche results in cellular differentiation

Question 23

Niche example:

Answer 23

signals from Distal tip Cell (DTC) triggers the self renewal program in the gremlin stem cells
-as the cells divide some end up away from the DTC - lose niche signal and diff (mitosis)

Question 24

Niches- concepts: OCCUPANCY

Answer 24

cell-cell adhesion between stem cell and niche locates SC’s niche, near to self-renewing signals

Question 25

niche - concepts: FATE

Answer 25

Signals from the NICHE regulate stem cell self-renewal, survival & maintenance

Question 26

Niche- concepts: ASSYMETRIC DIVISION

Answer 26

the physiological organisation of niche can polarise the stem cells, this ensures an asymmetric division

Question 27

mammalian niches provide

Answer 27

-PHYSICAL support
-SOLUBLE FACTORS
-cell-mediated interactions
To MAINTAIN and REGULATE the functions of stem cells

Question 28

mammalian niches contain what type of cells

Answer 28

stem cells & Stromal support cells

Question 29

mammalian niches interact with each other by

Answer 29

• cell-surface receptors
• gap junctions
• soluble factors

Question 30

Cell: soluble factor interactions:

Answer 30

• AUTOCRINE & PARACRINE factors
• secreted factors may: 1) acto locally -1-2 cell diameters
  2) diffuse throughout the niche
• Factors include FGFs, BMPs, & WNTs

Question 31

cell: ECM interactions

Answer 31

ECM / Cell adhesion molecules.
(i) Provide an anchor for stem cells to the niche. (ii) a polarity cue for Stem cell mitotsis.
(iii) a platform for signalling –
SPATIAL CUES
MECHANICAL INPUTS

Question 32

intestine: stem cell location & niche component

Answer 32

• Fast cycling: CBC at crypt base
• Slow cycling: +4 position

niche component: Paneth cells