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A Stem cell biology > Adult stem cells > Flashcards

Adult stem cells Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

Describe the regenerative capacity of humans/mammals?

A

Limited (unable to regenerate limbs)

BUT can regenerate some tissues

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2
Q

What are the fast regenerating tissues of mamals?

A
  • Skin
  • Gut epithelium
  • Blood
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3
Q

What is the lifespan and proliferative ability of the blood cells?

What does this mean?

A

VERY short lifespan (each day lose ~10^11 red blood cells)

BUT they are constantly being replenished

–> MUST be a pool of progenitor cells in the blood that are able to regenerate the different blood cell types

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4
Q

What is the stem cell that gives rise to the blood cells

A

The hematopoietic stem cell

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5
Q

What happens if irradiate a mouse?

What happens if inject an irradiated mouse with bone marrow from a healthy mouse?

A

Irradiated mouse will die as there is no longer the production of blood cells

HOWEVER, if inject bone marrow from healthy mouse –> irradiated mouse will SURVIVE and is able to produce ALL of the blood cell types

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6
Q

What did Till and McCulloch do (1961)?

What did they identify?

A

Investigated the spleens of the RESCUED irradiated mice and noticed COLONIES form on the spleens:

  • The more cells injected from the bone marrow –> the more colonies they get
    1) Due to the discreteness of the colonies, they concluded they are most likely to develop from a SINGLE CELL
    2) Due to the LINEAR relationship between injection of the cells and the amount of colonies –> suggests the cells from the BONE MARROW are forming these colonies
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7
Q

What confirmed the findings of Tim and McCulloch?

A

Genetic markers

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8
Q

What did Tim and McCulloch call the cells forming the colonies?

A

COLONY-FORMING UNITS

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9
Q

Why are the COLONY-FORMING UNITS seen as stem cells?

A

They form colonies on the spleen containing:
1) Differentiated blood cells - showing differentiation

2) New ‘colony forming units’ - showing self-renewal

This is the definition of a stem cell (must be able to self-renew AND differentiate)

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10
Q

How was it seen that the colonies formed by the colony-forming units contain undifferentiated cell types (new colony forming units)?

A

Injection of the colony-forming units from the spleen into the irradiated mouse

–> Mouse survived

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11
Q

What is the CLASSICAL model of the HSC lineage commitment?

A

Hierarchy:

  • Pluripotent stem cells that give rise to the hematopoetic tissue (as well as the 3 germ layers)
  • Multipotent progenitors (HSC)
  • Oligopotent progenitors
  • Lineage restricted progenitor
  • Effector cells
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12
Q

What is the functional capacity of the HSC?

A

Multipotent (only give rise to the cells of the blood)

Give rise to the MESODERM only

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13
Q

What are oligopotent progenitors?

Examples?

A

Able to differentiate into a FEW cell types (less than multipotent)

Eg. Lymphoid and myeloid stem cells

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14
Q

Which lineage-restricted progenitors do the common myeloid progenitor cells give rise to?

A

MEP (megakaryocyte erythrocyte progenitors)

GMP (granulocyte macrophage progenitors)

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15
Q

What are megakaryocytes?

What do the MEPs give rise to?

A

Large bone marrow cell

Give rise to:

  • Erythrocytes
  • Platelets
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16
Q

What are granulocytes?

What do the GMPs give rise to?

A

White blood cells of the immune system

Give rise to:

  • Granulocytes
  • Macrophages
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17
Q

What effector cells do the common lymphoid progenitor cells give rise to?

A

T cells

B cells

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18
Q

What are the ‘effector cells’ of the blood?

A

The functional DIFFERENTIATED cells of the blood system

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19
Q

How do we prove that a cell is a stem cell?

A

Do functional assays to prove it has stem cell properties (can differentiate and self-renew)

  • In VITRO
  • In VIVO
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20
Q

What is the in vivo functional test for a HSC?

A

Inject into irraditated mice and assess the ability to recapitulate the blood system

SERIALLY

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21
Q

How can stem cells be IDENTIFIED?

A

Looking at surface markers that define a stem cell population:

  • Looking for the PRESENCE and ABSECE of markers
  • Looking at the COMBINATION of markers
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22
Q

How can stem cells be ISOLATED from a heterogenous population of cells?

A

Using FACS (based on the cell surface antigens of the cells):

  • Label the cells with antibodies (against specific markers)
  • Cells with presence/absence of certain markers will be separated
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23
Q

How do cells adopt different cell fates?

A
  • Cells change their gene expression profile as they differentiate
  • Different terminally differentiated effector cell types have different gene expression profiles
  • Gene expression profile is determined by differential expression of TF
24
Q

Why do different terminally differentiated effector cell types have different gene expression profiles?

A

Express genes that are SPECIFIC for THEIR function

Repress genes that are SPECIFIC to OTHER cell types/other cell functions

25
Q

What do TF do?

A

1) Determine gene expression patterns by binding to DNA

2) Recruit ACTIVATORS/ COREPRESSORS to the ares of transcription

26
Q

How are TF often found?

A

As components of multiprotein complexes q

27
Q

What are the TF that influence stem cell fate?

What can these 4 factors do?

A
  • Sox2
  • Oct4
  • Myc
  • Klf4

They can REPROGRAM somatic cells –> ES cell-like fate (iPSC)

28
Q

What is a master regulator?

A

A TF that appers to control most of the regulatory activities of other TF that cause a cell to adopt a particular fate

At the top of the hierarchy of transcriptomic regulation

29
Q

What are the requirements of a TF to be a master regulator of stem cell fate? (3)

A

1) REQUIRED for the development into a specific lineage
2) Can CHANGE the fate of the cells they are introduced to
3) Can ANTAGONISE the opposite lineage programmes

30
Q

What is considered to be the master regulator of the Erythroid cell fate?

Why?

A

GATA-1

Fulfils the 3 requirements:

1) If delete Gata-1 from the MEP progenitors –> no development of the erythroid lineages

–> REQUIRED

2) If introduce Gata-1 into the GMP progenitors –> changes the fate of the cells into MEP and the development of the E lineage

–> can CHANGE the fate

3) Gata-3 up regulates erythroid markers at the same time as down regulating the myeloid markers

–> ANAGONISES the opposite lineage programme

31
Q

What is considered to be the master regulator of the myleoid cell fate?

A

PU.1

32
Q

How does GATA-1 mediate the antagonism of PU.1?

A

Normally:

  • PU.1 binds to DNA
  • Binds to c-Jun (co-factor) through its Ets domain
  • -> Regulate target genes

In the presence of GATA-1:
- Outcompetes c-Jun and binds to the Ets domain of PU.1 (through its carboxyterminal zinc finger domain)

–> PU.1 no longer bound to the c-Jun cofactor and cn no longer drive the expression of PU.1 target genes

33
Q

How does PU.1 mediate the antagonism of GATA-1?

A

Normally:
- GATA1 binds to GATA sequence in the DNA (through its carboxyterminal zinc finger domain)

–> Drives expression of GATA1 target genes

In the presence of PU.1:
- Bind to GATA1 (through its TAD domain to the czf GATA1 domain) and displaces GATA1 from the DNA

–> GATA1 no longer drives expression of GATA1 target genes

34
Q

How can TF A and TF B cross-antagonise? (3)

*Model for GATA1 and PU.1

A

1) Negatively influence each other
2) Auto regulate each other

3) Positively and negatively regulate target genes
(down regulate the expression of opponents through inhibiting the expression of target genes)

35
Q

Describe the levels of TF A and TF B in a undifferentiated/uncommitted cell

What does this mean?

(*Model for GATA1 and PU.1)

A

EQUAL amounts

Meaning:
- NO expression of the target genes (both are inhibiting each other)

36
Q

What happens in undifferentiated cell when there is a stochastic event/signalling cue?

A
  • Get higher expression of either TF A or TF B
  • Through a series of loops –> the TF auto regulates itself (increase expression) and REPRESSES the transcription of the other TF
  • Cell turns into a specific cell type due to having more TF of A or B (can make 2 alternative cells)
37
Q

Why was the classical stem cell models questioned?

A

As it suggests that every time we take a HSC in a transplantation experiment –> should ALWAYS get the SAME functional outcome

HOWEVER, this is not the case - HSCs appear to be heterogeneous (not all equal)

38
Q

In what aspects are HSCs heterogeneous?

A

With regards to:
1) Self-renewal upon transplantation

2) Cell cycle properties
3) Differentiation

39
Q

How are HSCs heterogeneous with regards to self-renewal upon transplantation?

A

If take HSCs and put into irradiated mice - SHOULD be able to SERIALLY transplant them over many generations of mice

BUT, the ability of the HSCs to serially transplant is variable (not all have equal self-renewal capacity)

40
Q

How are HSCs heterogeneous with regards to the cell cycle properties?

A

Some HSCs are dormant/quiescent/not cycling

Whilst others are progressing through the cell cycle

41
Q

How are HSCs heterogeneous with regards to differentiation?

A

IF the classical model is true…

When take HSC - should be balanced in differentiation and should get EQUAL amounts of all the erythroid and myeloid lineages

BUT, there is a LINEAGE BIAST for HSCs to preferentially make more myeloid or erythroid cells

42
Q

How can heterogeneity be masked? (may have been the case in previous experiments that proposed the classical model)

A

Population-based cell studies

Why?
Get the SAME measure of gene expression profile in a population of cells that do not have equal transcript levels (average out) as a population of cells that may have the same number of transcripts per cell (uniform)

43
Q

Why is it advantageous to do SINGLE cell studies of stem cells?

A

To understand properly the properties of the cell

As population-based studies can mask certain properties (Eg. heterogeneity)

44
Q

When looking at the gene expression of single multi potent cell types, what was seen?

What is this idea called?

A

Although found at the LOW gene expression level,
undifferentiated, multipotent cell ALREADY express come genes that are SPECIFIC for their differentiated cell types

LINEAGE PRIMING

45
Q

When are lineage programmes initiated?

How?

A

Initiated in the HSC compartment

  • HSCs express specific lineage markers –> more prone upon the differentiation cue to give rise to that specific lineage
46
Q

What can still occur in the HSC compartment, even though the cells may be lineage primed?

A

They can still inter-covert between different lineages (change the genes they are expressing)

47
Q

What are the 3 different HSC lineage commitment models?

Haas S et al (2018) Cell Stem Cell 22:627-638

A

1) Classical
2) Early split
3) Continuous Waddingotn-like

48
Q

What is the ‘early split’ model of HSC lineage commitment?

A

?

49
Q

What is the ‘continuous Waddingotn-like’ model of HSC lineage commitment?

A
  • HSCs are still at the ‘top’ of the hierarchy but are not a particular entity

HSCs are more like a state
- Cells exist in this state but as go down the epigenetic landscape, they become more restricted

  • Cells progress through a continuum, rather than being discrete entities
50
Q

What are the causes of HSC heterogeneity?

A

1) Niche localisation
2) Genetic heterogeneity
3) Epigenetic heterogeneity
4) Biological processes
5) Segregation of cell fate determinants
6) Stochasticity (randomness)

51
Q

How does niche localisation cause HSC heterogeneity?

A

In VIVO, HSCs exist in different locations in the body –> receive different signalling cues –> different impacts on the cell

52
Q

How does genetic heterogeneity cause HSC heterogeneity?

A

Intrinsic differences of the SC arise due to inherent errors into the genome when the SC divide

(Eg. DNA mutation, chromosome translocation)

53
Q

How does epigenetic heterogeneity cause HSC heterogeneity?

A

Different cells differ in DNA methylation profiles

54
Q

How do biological processes cause HSC heterogeneity?

A

Not all the stem cells are actively cycling –> are in different stages of the cell cycle

  • Cells in early G1 will differentiate into a different cell type to the cells in late G1 if you force them to differentiate
55
Q

How does the segregation of cell fate determinants cause HSC heterogeneity?

A

A dividing cell needs to divide all of its cytoplasmic components:

  • Cytoplasmic components may be not equally distributed when the cells divide
  • -> cells become different
56
Q

How does stochasticity cause HSC heterogeneity?

A

Random encounter of molecules into the cell may occur

Transcription is leaky

57
Q

What are the consequences of HSC heterogeneity?

A

1) Contribution to hematopoiesis - which cells contribute to the cells of the blood system??
2) Emergency hematopoiesis - do lineage primed cells allow this process to occur rapidly when this is needed??(eg. blood loss)
3) Ageing
4) Hematologic malignancies

A Stem cell biology (16 decks)

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