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Cell Biology > Lecture 15 - Totipotent, Pluripotent and Multipotent Stem cells > Flashcards

Lecture 15 - Totipotent, Pluripotent and Multipotent Stem cells Flashcards

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1
Q

What are the two defining criteria of stem cells?

A
  • Self renewal (have the ability to divide for indefinate periods [although adult stem cells have a shorter life])
  • Differentiate into different specialised cell types (e.g. blood cells, skin cells, bone cells)
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2
Q

What is the intermediate cell called between a fully differentiated cell and a stem cell?

A

A progenitor cell

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3
Q

What is a progenitor cell?

A

A cell that has commited to a certain cell lineage and will further differentiate into a cell of that lineage

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4
Q

How is a population of stem cells maintained?

A

By asymmetrical division of stem cells to form a differentiated daughter cell that is committed to a particular cell lineage and a stem cell to renew the population

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5
Q

Why is asymmetrical division by stem cells important?

A

To ensure the pool of stem cells is not depleted

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6
Q

What are the three possible mechanisms that may control the asymmetric division of stem cells?

A

Segregated cell polarity regulators
Segregated cell fate determinants
Niche Elements

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7
Q

How do Segregated cell polarity regulators control the asymmetric division of stem cells?

A

-asymmetric localisation of cell polarity regulators (localisation determines the cell that will become a stem cell) initiates cells division e.g. PAR-aPKC complex

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8
Q

How do Segregated cell fate determinants control the asymmetric division of stem cells?

A

cell fate determinants are segregated to the cytoplasm of one daughter cell, or associated with the membrane, centrosomes or another cellular constituent that is differently distributed to daughter cells

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9
Q

How do Niche elements control the asymmetric division of stem cells?

A

Stem cells are surrounded by niche microenvironments

  • Regulation of the orientation of the mitotic spindle retains only 1 daughter in the SC niche, so that only one daughter has access to the extrinsic signals necessary for maintaining SC identity
  • other daughter cell is exposed to signals away from the niche that induces differentiation
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10
Q

When is the blastocyst formed?

A

From day 5

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11
Q

What is the blastocyst?

A

-fluid filled ball with an inner cell mass, surrounded by trophectoderm (made of trophoblasts)

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12
Q

What is implantation of the blastoderm guided by?

A

The trophectoderm

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13
Q

What do the inner cell mass and the trophectoderm develop into?

A

ICM
-embryo
Trophectoderm
-extra embryonic tissues e.g. placenta

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14
Q

When are the embryonic stem cells totipotent, pluripotent and what does this mean?

A

Totipotent
-before blastocyst formation
-very brief and early stage
-can develop into entire organism including the placenta
Pluripotent
-after blastocyst formation the cells of the ICM are pluripotent
-can develop into any cell other than the placenta

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15
Q

How does the division of the cells in the embryo occur initially?

A

The size of the embryo remains the same, cells divide but do not get bigger

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16
Q

What do the markers of the ES cells allow experimentally?

A

Allow identification and isolation

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17
Q

What are the common markers of the Mouse ES cells and the human ES cells?

A

Mouse ES cells
-SSEA1

Human ES cells
-SSEA3/4

Shared

  • CD133
  • Oct-4
  • Nanog
  • Sox2
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18
Q

How can you experimentally determine pluripotency (i.e. stem cell functionality)

A

In vivo method - Teratoma assay
Termatoma (cancer tumours that make cells of all three germ layers)
-inject SC and observe the tissues formed
-if pluripotent then will form all 3 germ layers
-this shows differentiation (1 features of SC) but not self renewal

Prove Self renewal

  • using markers, remove cells that are identified as stem cells
  • implant the extracted cells and if forms a whole new teratoma then the cells can do self renewal
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19
Q

How is pluripotency maintained?

A
  • the prevention of differentiation

- the promotion of proliferation and self renewal

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20
Q

What is pluripotency regulated by?

A

several signalling pathways and TFs

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21
Q

What are the signalling factors involved in regulating pluripotency and what are their features?

A

Leukemia inhibiting factor

  • members of the interleukin-6 type cytokine family
  • LIF prevent differentiation of mouse embryonic stem cells and promote self renewal to maintain pluipotency
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22
Q

What occurs without LIF in mouse ESC?

A

ESC spontaenously differentiate

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23
Q

What is the pathway through which LIF acts?

A
  • acts through the LIF receptor (LIFRβ) in association with the signalling component gpi30
  • STAT3 is activated by LIF (downstream of LIF) and acts as a transcription factor
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24
Q

What proteins are involved in inputting cues via LIF and the LIFRβ into the mouse ESC?

A

JAK - janus kinase
SHP2 - SHP2-domain-containing protein tyrosine kinase 2
MEK - nitrogen activated protein kinase (MAPK) and extracellular signal related kinase (ERK) protein kinase

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25
Q

What type of cell can an embryonic stem cell be based upon determined by its signalling?

A

Trophectoderm - totipotent
ES - pluripotent
Primitive ectoderm - differentiation

26
Q

What is the action of Sox2-Oct4?

A
  • Inhibit trophectoderm

- promote ES and primitive ectoderm

27
Q

What is the action of Nanog?

A
  • inhibits primitive ectoderm

- promotes ES

28
Q

What is the action of STAT3?

A
  • inhibits or promote primitive ectoderm

- promotes ES differentiation

29
Q

What are the three TFs that regulate the pluripotent state of the ESC?

A

The interaction of:

  • Sox2-Oct4
  • Nanog
  • STAT3
30
Q

What are the features of Oct4 (aka Oct3)?

A
  • ‘gate keeper’ TF, expressed by pluripotent ESC
  • prevents differentiation
  • present at the 4 cell stage of embryo
  • at blastocyst stage only expressed in the ICM
  • down regulated once cells are committed to a lineage
31
Q

What experiments showed the action of Oct4? And what were the conclusions from these experiments?

A

Knockout in mice

  • inner cell mass fails to develop
  • ES cells differentiate inappropriately into trophectoderm

Overexpression
-ESC differentiation into primitive ectoderm and mesoderm

Conclusions
-specific levels of Oct-4 are required to maintain ES cells in a primitive, pluripotent state

32
Q

What is the structure and action of Oct4?

A

TF so associates with DNA via 2 DNA binding domains

-binds and regulates down stream genes that code for factors involved in the pluripotency of ESC: FGF4, Rex1, Sox2

33
Q

What are the two main roles of Oct 4?

A

Maintain self renewal and pluripotency

Promote differentation

34
Q

What are the features of Oct4 in maintaining self renewal and pluripotency?

A

modulates genes that promote:

  • permissive chromatin
  • DNA repair
  • anti-apoptosis
  • anti-differentiation
  • inactivate pRb (which is cell cycle linked - more of it stops the cell cycle)
35
Q

What are the features of Oct4 in promoting differentiation?

A 
modulates genes that promote:
-repressive chromatin
-DNA checkpoint control
-apoptosis
-active pRB
All this facilitates cellular commitment
36
Q

What are the features of Sox2?

A
  • cooperative with Oct4, forms a complex
  • expression pattern similar to Oct-4
  • cooperatively bind DNA
37
Q

What is the action of the Sox2-Oct4 complex?

A
  • regulate Nanog expression

- cooperate with Nanog to control ES cell pluripotency

38
Q

What is Nanog?

A
  • TF expressed specifically by ESC in the ICM
  • slightly later expression than Oct-4
  • induces longevity
39
Q

What is the action of Nanog?

A
  • Acts as a repressor to prevent transcription of genes required for differentiation
  • activates genes that are required for ESC self renewal e.g. Rex1, which is also a target for Oct-4
40
Q

What are the main factors involved in determining ESC pluripotency?

A

Oct4/Sox2, Nanog and Rex1 have interrelated roles in determining ESC pluripotency, determined by their relative levels

41
Q

How do Oct4, Nanog and Sox2 prevent and control differentiation down the germ layer lineages?

A

Promote self renewal via modulating the action of two groups of genes:

  • Activate promoters of self-renewal genes (OCT4, SOX2, NANOG)
  • Silence promoters of developmental genes (NEUROG1, PAX6, GATA4)
42
Q

How are the activating and silencing of genes by Oct4, Sox2 and Nanog acheived?

A

Through epigenetics

  • specifically chromatin packaging
  • ESC have open chromatin (permissive and transcriptionally active
43
Q

What is the state of chromatin as differentiation progresses?

A

Initially ESC have open chromatin (permissive and transcriptionally active
-as differentiation progresses get closed chromatin (transcriptionally repressive)

44
Q

What are the changes in chromatin for the transcriptional control of differentiation based on?

A
  • stage of the cell

- what genes are needed/not

45
Q

What does stopping pluripotency require?

A

Interacting factors

  • specifically LIN1,2,3 (lineage transcription factor)
  • Sox2/Oct4/Nanog influence is reduced as lineage is commited to
  • LIN’s activated so Sox2/Oct4/Nanog cannot reach DNA
  • the specific factor determines which lineage the cell goes down
46
Q

What happens to telomeres with cell division?

A

In the adult cell, telomeres shortern with every division, meaning there is a limited no of adult cell division

47
Q

What occurs to cells without telomerase?

A

Reach quiescene

48
Q

What are the features of telomerase in ESM and cancers?

A
  • have more telomerase
  • lose telomeres but repeating DNA sequence (TTAGGG) lengths are added back on (5-15 times) so that there is no telomere shortening overall
49
Q

What type of metabolism is present in ESCs/adults?

A

ESC
-tend to have glycolytic metabolism
Adults
-phosphorylation based metabolism

50
Q

What are the features of adult stem cells?

A

-involved in post natal patterning e.g. remodelling and wound repair
-mainly in bone marrow, skin and colon
-multipotent (differentation potential more limited than the ESC)
-can self renew and differentiate in the cell type of the host tissue in which they reside
-

51
Q

What is the primary function of adult stem cells?

A

Maintain steady state of activity of a cell and its resident tissue
-may also help replace cells lost through injury or disease

52
Q

Why might adult stem cells have reduced self renewal ability compared to ES cells?

A

Reduced telomerase

-not as much risk of teratomas forming if used in therapy compared to ESC

53
Q

How can you test the properties of adult stem cells?

A

Destroy the bone marrow of an animal
Inject stem cells and should completely replenish
-observe markers

54
Q

What are 5 examples of adult stem cells?

A
  • Haematopoietic
  • Epidermal (basal layer of skin)
  • Mesenchymal (bone marrow stem cells)
  • Neural
  • Limbal
55
Q

What are the features of Neural stem cells?

A
  • in the adult brain (as well as progenitor cells)
  • capable of generating neurons and glial cells
  • many located in the subventricular zone which lines the walls of lateral ventricles
  • self renewing
56
Q

What is the subventricular zone?

A
  • very inaccessible part of the brain in terms of therapy

- the niche environment for neural stem cells

57
Q

What is the general differentiation process of neural stem cells?

A

Neural stem cells
Rapidly dividing daughter cells
Migratory precursors (located near vascularture, increasing possibility for transportation)
Migratory precursors travel to other bits of the brain

58
Q

What is the specific differentiation process of neural stem cells into glia and neurons?

A

Glia
-NSC differentiate into Glial restricted precursor cells
-then divide into either oligodendrocyte progenitor cells (then oligodendrocytes) or astrocyte
Neurons
-NSC divide into neuron restricted precursors and then to neurons

59
Q

What are teh features of limbal stem cells?

A
  • in limbus (or eye), an accessible site
  • generate the cornea
  • high proliferative potential
  • migrate out and around cornea to enable function
  • surrounded by niche resident supporting cells
  • all eventually differentiate
  • form transit amplifying cells before fully differentiating
60
Q

What is the purpose of niche resident supporting cells surrounding limbal stem cells?

A

anchor cells and expose future daughter cells to the correct signals for self renewal or differentiation

Cell Biology (15 decks)

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