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1
Q

what is a stem cell

A

cells that have the potential to generate specialised tissues (differentiate) as well as copies of themselves (replication)

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2
Q

what can totipotent stem cells differentiate into

A

all cell types of the body

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3
Q

what can pluripotent stem cells differentiate into

A

derivatives of the 3 germ layers (ectoderm, mesoderm and endoderm)

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4
Q

what can multipotent stem cells differentiate into

A

different cell types from a tissue or organ (tissue specific)

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5
Q

what can unipotent stem cells differentiate into

A

only a single cell type

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6
Q

what is an allogenic transplant

A

stem cells are derived from a different donor and are expanded in the lab – eg embryonic stem cells, cord blood cells

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7
Q

what is an autologous transplant

A

stem cells transplanted are derived from same patient – expanded and treated outside the body and re-implanted into same patient eg auto transplant of bone barrow cells or producing iPSCs

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8
Q

what are the pluripotency factors

A

SOX2, OCT4, MYC and KLF4

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9
Q

what can stem cells provide models for?

A
  • models to screen new drugs
  • models to study genetic conditions
  • models for oth
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10
Q

what are embryonic carcinoma cells

A

Embryonal carcinoma (EC) cells are the stem cells of teratocarcinomas, and the malignant counterparts of embryonic stem (ES) cells derived from the inner cell mass of blastocyst-stage embryos

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11
Q

EC and ESCs grow better on a feeder layer T/F

A

T

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12
Q

list properties of ES cells

A
  • derived from ICM of blastocysts
  • indefinite proliferative potential
  • clonogenic
  • pluripotent
  • germline transmission to chimeras
  • permissive to genetic manipulation
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13
Q

what is LIF (leukaemic inhibitory factor) important for?

A

self renewal state

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14
Q

how does LIF work

A

interacts with LIF receptor which combines with gp130. Activates JAK pathway which upregulates STAT3 which is critical to maintain proliferation

also activates ERK1/2 kinase by binding SH2 which has an inhibitory effect on STAT3 and induces differentiation

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15
Q

what determines the balance of self renewal and differentiation

A

balance of STAT3 and ERK1/2

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16
Q

if concentration of LIF is low what happens to cells

A

differentiate

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17
Q

if conc of LIF is high what happens to cells

A

self renew

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18
Q

LIF alone is not sufficient to do what

A

maintain pluripotency

block neural differentiation

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19
Q

what did ying 2003 show that you need BMP4 and LIF for

A

LIF blocks differentiation into mesoderm and endoderm
BMPs induce genes that block differentiation into neurons
overall lead to blocking of differentiation and maintenance of pluripotency

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20
Q

what surface markers do both hES and mES show

A

ALP+, OCT4+ and Nanog +

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21
Q

what surface markers do hES show not including ALP+, OCT4+ and Nanog +

A

SSEA3, SSEA4, TRA-1-60, GCTM2, Thy1, MHC

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22
Q

what surface markers do hES show not including ALP+, OCT4+ and Nanog +

A

SSEA1

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23
Q

what is mouse hES pluripotency maintained by

A

presence of LIF and inhibitors of ERK1/2 and GSK3b

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24
Q

what is human hES pluripotency maintained by

A

FGF2 and activin

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25
Q

what do the mouse and human epiblasts differ in

A

the timing of their formation

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26
Q

what are human escs the equivalent to in mouse

A

mouse epiblast cells

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27
Q

what are the two stages of pluripotency and what cells represent them

A

naive - mES

primed - mEpiESC or hES

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28
Q

what did gaffini do to try and capture a true naive hESC

A

exposed cells to different combinations of factors. Used Oct4-GFP to visualise pluripotency. Oct4 is controlled by different enhancers in naive and primed so can tell what state the cell is by deleting either of the enhancers. Found 8 factors (NHSM) which changed a primed cell into a more naive cell

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29
Q

why are naive HESC important

A
  • give fundamental understanding of pluripotency
  • easier to modify genetically
  • potential application for humanised organs as evidenced by human-mouse chimerism (can’t be done with primed)
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30
Q

what are the intrinsic factors that control pluripotency

A

SOX4
OCT4
NANOG

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31
Q

The Niwa 2000 paper found that relative levels of Oct3/4 influence ES cell fate. T/F

A

T

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32
Q

what does upregulation of Oct4 lead to

A

extraembryonic endoderm and mesoderm

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33
Q

what does downregulation of Oct4 give

A

trophoectoderm

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34
Q

without oct4 was does the embryo fail to acquire

A

the potential for the production of different lineages

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35
Q

the interaction between oct4 and what determines trophoectoderm differentiation (Niwa 200)

A

Cdx2

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36
Q

OCt4 and Cdx2 bind in a complex that inhibits their individual transcriptional activity. When theres low expression of Oct4 there is high expression of Cdx2. What has forced overexpression of cdx2 been found to lead to

A

trophoblast differentiation

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37
Q

embryos where Sox2 is deleted fail to generate what?

A

epiblast

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38
Q

nanog was identified in 2 independent screens by who

A

Mitsui (2003) and chambers (2003)

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39
Q

how did the mitsui in silico screen identify nanog

A

look for genes highly expressed in ES cell population

found that nanog rescued LIF deficiency

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40
Q

how did the chambers functional screen identify nanog

A

transfected cells with ES cell genes
looked for cell displaying more pluripotent properties. Put nanog in cells that were deficient in LIF receptor and showed it could maintain pluripotency

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41
Q

what happens to nanog deficient cells

A

lose pluripotency and differentiate to form the extraembryonic endoderm

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42
Q

using FACs for Nanog GFP+ found what

A

nanog expression is heterogenous in the cell population. it may act as a rheostat to provide variable resistance to differentiation

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43
Q

what are embryoid bodies

A

heterogenous aggregates that resemble an organised embryo

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44
Q

what signalling mediates self organisation and axis formation in embryoid bodies

A

Wnt signalling

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45
Q

what are the pros of using embryoid bodies to produce differentiated cells

A

cheap to produce

generate 3 germ layers

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46
Q

what are the cons of using embryoid bodies to produce differentiated cells

A

difficult to control aggregation in a reproducible way
number of days before differentiated cells can be collected
dont get enrichment of particular lineage

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47
Q

how can you isolate desired cell types

A
  • FACs
  • using density gradients
  • inserting selectable markers (good for research)
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48
Q

summarise the generation of purified neural precursors from ES cell paper Li (1998)

A

used Sox2 to drive ectodermal differentiation
replaced one allele with casette that had LacZ reporter and neomycin resistance
enriched for cells expressing Sox2 (survive on neomycin)
obtained relatively pure population of neurons

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49
Q

summarise the D’Amour et al(2006) Productin of Pancreatic hormone-expressing
endocrine cells from human embryonic stem cells study

A

developed a differentiation protocol that mimicked in vivo formation of pancreatic cells
measured C peptide to measure levels of processing insulin
first derived fetal cells

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50
Q

how did Kroon 2008 follow D’amour 2006

A

adapted the protocol with hope to avoid fetal cells.

tested these cells in vivo in mouse models of diabetes

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51
Q

how did they test if the pancreatic cells worked in vivo

A

implanted into mice.
measured each mouses response to glucose via the production of C peptide (made when insulin is processed)
measured in a mouse diabetes model
The transplanted cells were able to reduce blood glucode

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52
Q

what did kroon 2008 do to confirm that it was the transplanted cells that reduced the blood glucose

A

explanted the cells (removed them) and saw that the blood glucose increased rapidly

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53
Q

although the results from kroon 2008 were promising. What negative results were seen

A

15% of the mice developed cells suggesting that the transplanted cells were contaminated

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54
Q

how did kelly 2011 cause no animals to obtain tumours

A

enriched the cells for endocrine pancreatic progenitors using the cell surface marker CD142
none of the implanted animals formed tumours

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55
Q

what did the osafune paper show

A

that there are differences in the differentiation propensities between different cell lines

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56
Q

what is said to be the future of 3D differentiation

A

organoids - get the formation of an organ with the lineage that you want.

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57
Q

what did the expereiments by john gurdon find

A

found that mature cells could be reprogrammed to become pluripotent.. Found all cells had the same genes. When nucleus for an intestine cell was placed in an enucleated it was able to form progeny that had phenotypic characteristics of the frog that the intestine cell was taken from

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58
Q

what is therapeutic cloning

A

take cells from a patient and do SCNT to create a blastocyst. Stem cells can then be obtained from this blastocyst that can be differentiated into different tissues for therapeutic purposes

59
Q

Hwang 2004/2005 paper about SCNT derived embryonic stem cells proved to be a fabrication why

A

issues with data

60
Q

who reported in 2013 that somatic cell nuclear transfer could be used to produce human embryonic stem cells

A

tachibana

61
Q

what are the main points of the takahashi and yamanaka (2006) paper - induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

A

developed an assay to read pluripotency. Knocked in geomycin resistance gene at fbx15 loci
if cells are pluripotent they will be resistant to the antibiotic
24 genes collectively gave resistance
withdrew factors and found only 4 genes were needed (Oct3/4, Sox2, c-Myc and Klf4)
nanog was indispensible
injected iPSCs created this way in vivo and showed the formation of teratomas
injected into blastocysts and saw the formation of chimeras

62
Q

what are the yamanaka factors to create iPSCs and why did people have problems with them

A

Oct3/4, Sox2, Klf4 and c-Myc

c-Myc is an oncogene so people didnt want to subject cells to it

63
Q

what are the thomson factors to create iPSCs

A

Oct4, Sox2, Nanog, Lin28

lin28 represses inhibitor of Myc, indirectly activating myc

64
Q

what are the preferred ways of generating pluripotent stem cells from somatic cells

A

exposure to transcription factors and small molecules

  • but can be a slower process
65
Q

what is the problem for generation of pluripotent cell from somatic cells by cell fusion

A

not good for therapeutic application as you generate a tetraploid cell

66
Q

what are the 4 different ways of reprogramming a cell

A
  1. somatic cell nuclear transfer
  2. cell fusion with pluripotent stem cell
  3. transcription factor expression
  4. small molecule exposure
67
Q

what are the current methods to make iPSCs by exposing them to factors

A
  • integrating virus
  • non integrating vector
  • Excisable vector
  • protein
  • small molecule replacements
68
Q

you dont want to use integrating virus’ for the reprogramming of cells as this can interfere with the genetic makeup of the cell. What are the best alternatives

A
  • proteins
  • transposons
  • RNA
  • small molecules
69
Q

what are the main points from the Hanna (2007) paper - Treatment of sickle cell anaemia mouse model with iPS cells geenrated from autologous skin

A
  • used mouse models of thalassaemia and harvested tail tip fibroblasts
  • reprogrammed them in vitro and corrected the mutation
  • differentiated to haematopoietic progenitors and implanted back into animal
  • showed its possible to take cells from diseased individuals, reprogram, correct the mutation, differentiate and put back in organism to show functional recovery
70
Q

what are the issues with ES cells

A
  • genomic instability
  • need continual supply of high quality embryos
  • potential for tumour formation
  • questions regarding functional differentiation
  • problem of immune rejection
  • ethical controverst
71
Q

what are the advantages of iPSCs

A
  • no requirement for the administration of immunosupressive drugs
  • opportunity to repair genetic defect by HR
  • opportunity to repeatedly differentiate iPSCs into desired cell type for continued therapy
  • less ethical issues
72
Q

what are the main concerns surrounding iPSCs as evidenced by Zhao 2011

A

reprogramming event may trigger mutations
- cells derived from B6 EiPSCs can be immunogenic in B6 mice. abnormal overexpression of proteins directly contributes to this immunogenicity

73
Q

what is direct differentiation

A

differentiation from one differentiated cell type to another

74
Q

what are the main points fro the vierbuchen 2010 paper regarding direct differentiation

A

able to direct the differentiation of fibroblasts to functional neurons.
Screened factors responsible for this conversion and found: Brn2, Myt1l, Zic1, Olig2 and Ascl1

75
Q

what do we need to do/know before using iPSCs as therapy

A
  • are all iPSCs the same?
  • need to develop robust and reliable differentiation protocols
  • need to know relative efficiency of these different differentiation methods
  • need to devise a way that iPSC can be screened for quality
76
Q

who described mesenchymal cells as “adherent fibroblast-like colonies from monolayer cultures of bone marrow, thymus and spleen”

A

Friedenstein

77
Q

the true identity of mesencymal stem cells (Caplan 1991) was determined as stem cells when what

A

transplants of clonal bone marrow MSCs produced bone in vivo

78
Q

why are mesenchymal stem cells also referred to as mesenchymal stromal cells

A

mounting evidence indicates that cell population isolated from bone marrow are highly heterogenous and consist of several subpopulations all of which do not fulfil the criteria to be considered stem cells

79
Q

what is the minimum criteria to define a MSC

A
  • remain plastic adherent under standard culture conditions
  • express CD105, CD73 and CD90
  • lack expression of markers of endothelial and haematopoietic cells
  • differentiate into osteoblasts, adipocytes and chondrocytes in vitro
80
Q

evidence suggests that MSC may be present virtually in any vascularised tissue throughout the whole body

A

T

81
Q

the Crisan (2008) paper - A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs - contributed to the understanding that MSC came from around blood vessels as a quick source for tissue repair. What were the main findings

A
  • in all tissues detected NG2+ and CD146+ cells surrounding small blood vessels
  • characterised cells expressing CD146 using flow cytometry - selected out ones that were negative for certain markers
  • expanded in vitro - maintined expression of CD146
  • transplanted into SCID mouse - differentiated into muscle and bone
  • isolated cells that showed same markers as MSC confirming their identity
82
Q

MSC are attractive for autologous transplants why

A

can be obtained from bone marrow or fat tissue (becoming more popular)

83
Q

MSC have been used in several clinical trials for cell replacement. what have they particularly shown promise in

A

treating racehorse injuries

84
Q

MSCs secrete factors such as TGF-b, IL-2, prostaglandin and PGE2 which attract what

A

immune cells such as macrophages

85
Q

how do MSCs secrete factors to attract immune cells and what are current therapeutic strategies targetting this

A

vesicles. There are efforts to purify these vesicles so they can be directly administered

86
Q

MSCs have an inherent tropism to tumours why?

A

tumour creates a microenvironment and produces MMPs to digest the ECM. MMP cleaves and activates PAR1

87
Q

what are the main points from the nakamizo 2005 paper “Human bone marrow-Derived MSC in the treatment of gliomas”

A

hMSCs labelled in red were injected into carotid artery
within 7 days they located the tumour
when other cells were transplanted they did not locate the tumour - property is unique to hMSCs

88
Q

how did nakamizo directly test that the migration of MSCs was directly due to the tumour

A

used transwell culture dished
hMSCs were placed in upper well and conditioned medium from U87 gliomas was placed in the lower wells. Exposure to conditioned media from U87 cell produced significant hMSC migration

89
Q

what did nakamizo do as a proof of principle that MSCs were able to deliver antitumour agen

A

genetically modified hMSCs by transfecting with cDNA of IFN-B. These cells were cocultured with gliomal cell line and found to inhibit their growth. also proved in vivo that IFN-B secreted by MSC delivered intercranially increased the survival of mice

90
Q

what are the key point of the paper - “mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer” Loebinger 2009

A

TRAIL is a member of the tumour necrosis factor superfamily. that is able to selectively induce apoptosis in transformed cells but not normal cells.
MSC were tranduced with TRAIL-GFP lentivirus that can be induced with doxycycline
in vivo - early administration of Dox reduces volume of the tumour

91
Q

what was the evidence that stem cells existed in the bone marrow

A

transplantation of bone marrow into an irradiated mouse meant it was able to survive

92
Q

how were haematopoietic stem cells discovered

A

noticed colonies on spleen of mice that had been transplanted with bone marrow. all colonies contained differentiated blood cells and new colony forming units. these colony forming units also lead to rescue of irradiated mice

93
Q

why are HSC multipotent

A

they can only form 2 lineages - myeloid and lymphoid

94
Q

what play a large role in stem cell linage fate

A

transcription factors

95
Q

what are features of master regulators of stem cell fate

A
  1. required for the development into a specific lineage
  2. can change the fate of the cells that theyre introduced to
  3. antagonise the opposite lineage prorams
96
Q

what is the master regulator of the erythroid lineage

A

GATA1

97
Q

what is the master regulator of the myeloid lineage

A

PU.1

98
Q

describe GATA1 mediated antagonism of PU.1

A
  • to regulate the expressio of genes, PU.1 has to bind DNA and bind the cofactor c-Jun
  • GATA1 outcompetes c-Jun meaning PU.1 cant drive the expression of target genes
99
Q

describe PU.1 mediated antagonism of GATA1

A
  • GATA1 is a transcription factor that binds to GATA sequences in DNA
  • PU.1 can bind to GATA1 and stop it binding sites in the DNA
100
Q

when TF are equal the cell remains undifferentiated T/F

A

T

101
Q

HSC are heterogenous with respoect to:

A
  • Self renewal upon transplantation
  • cell cycle properties
  • differentiation
102
Q

what causes HSC heterogeneity

A
  • niche localisation
  • replication errors
  • differing methylation
  • asymmetrical segregation
  • stochasticity
103
Q

what are the consequences of HSC heterogeneity

A

ageing

haematological malignancies

104
Q

what is a niche in stem cell biology

A

a local tissue microenvironment that hosts and influences the behaviours or characteristics of stem cells

105
Q

who first proposed the idea of the stem cell niche

A

Schofield 1978 “The relationship between the spleen colony-forming cell and the haemopoietic stem cell”

106
Q

what were the key points of a stem cell niche when it was first proposed by schofield

A
  • has a defined anatomical location
  • regulates self renewal of stem cell
  • removal from niche results in stem cell differentiation
107
Q

what are the niche producing cells in the drosophilia testes

A

the hub cells (present at the anterior end of the testes)

108
Q

the hub cell (niche producing cell) of the drosophila tetes are in contact with which 2 type of stem cells

A

germline

somatic (cyst)

109
Q

when not in contact with hub cells what do stem cells differentiate into

A

gonialblast

110
Q

what does division of germline stem cells in the drosophila testis lead to

A

the production of 2 cells. One stays in contact with the hub cell and therefore remains undifferentiated. Other moves posterior due to spatial restrictions and differentiates

111
Q

gonialblast undergoes 4 mitotic divisions with incomplete cytokinesis to form ___ spermatogonia which mature into spermatocytes

A

16

112
Q

the hub cell produces which ligand that activates JAK/STAT signalling in the germline and cyst stem cells

A

unpaired

113
Q

JAK/STAT signalling is sufficient for the self renewal of the stem cells in the testis T/F

A

it is sufficient for the self renewal of cyst stem cells

germline stem cells require this and the supression of the expression of Bam through activation of the BMP pathway

114
Q

which ligand produced by the hub cell activates the BMP pathway and supresses the expression of Bam

A

Gbb/Dpp

115
Q

what are the niche producing cells of the ovaries

A

Cap

116
Q

what are the stem cells in the drosophila ovary

A

germline

117
Q

what happens when the germline stem cells in the ovary divide

A

do so asymetrically leading to one losing contact with the cap cells and differentiation into cystoblast

118
Q

what signalling is not required in the ovarian niche to maintain undifferentiated stem cells

A

JAK/STAT

119
Q

what signals does the cap cell provide the germline stem cells with in the ovary

A

Gbb/Dpp activates BMP in the stem cells which activates mad and inhibits Bam leading to no differentiation

120
Q

how were the niche cells of haematopoeitic cells identified

A

ablation experiments

121
Q

what are key components that maintain HSC

A

Stem cell factor

CXCL12 (activates CXCR4)

122
Q

in a simplistic stem cell niche what 3 types of interaction are there

A

cell: cell interaction
cell: ECM interaction
cell: soluble signal interaction

123
Q

what is AMD3100

A

a CXCR4 inhibitor. blocks the binding of CXCL12 so the HSC are mobilised - therapy

124
Q

summarise the walkley 2007 paper

A

“A microenvironment induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency”

healthy bone marrow transplanted into a RAR null environment resulted in increased proliferation seen in myeloproliferative syndromes

125
Q

why is the 2D in vitro culture of cells a simplistic model

A
  • soluble gradients absent
  • force apical basal polarity
  • continuous layer of matrix
  • high stiffness
  • no third dimenstion
    Cells in this form of culture lose some of their in vivo phenotype
126
Q

what are examples of 3D stem cell cultures

A

organoids

127
Q

what is an organoid

A

a stem cell culture that can recapitulate the complexity of a whole organ. They have to have multiple organ specific cell types, be capable of recapitulating some function and are spatially organised similar to the organ

128
Q

what is the differential adhesion hypothesis of the formation of organoids

A

similar cells create more bonds with each other based on their differential adhesion leading to an organised architecture

129
Q

where do the stem cells of the gut reside

A

in the crypts between lumen of the intestine

130
Q

what differentiated cell types are present in the gut (intestine) epithelium

A

enterocytes
paneth
goblet
enteroendocrine

131
Q

what cells secrete factors that are important for the maintenance of intestinal stem cells

A

paneth cells

132
Q

intestinal stem cells express what

A

leucine rich repeat GPCR 5 (Lgr5)

133
Q

what are the key points from the Sato 2009 paper: Single Lgr5 stem cells build crypt-villus structures in vitro without mesenchymal niche

A
  1. Isolated mouse intestinal crypts – labelled LGR5 with GFP – can do FACs
  2. Crypt preparations were suspended in Matrigel (protein mix derived from mouse sarcoma cells – rich in ECM)
  3. Optimisation of culture medium – titration of key signalling molecules (EGF, R-Spondin, Noggin)

were also able to generate similar organoids from single lgr5+ cells following dissociation of crypts

134
Q

what are particular applications of organoids

A

experimental tool
diagnostic tool
therapeutic tool

135
Q

what virus have organoids been successful in increasing the understanding of

A

zika virus

136
Q

organoids can allow personalised medicine T/F

A

T - first application for this was seen in cases of intestinal organoids for cystic fibrosis

137
Q

what have organoids also been produced for

A

snake venom glands

138
Q

what is aging an imbalance favouring

A

favouring differentiation

139
Q

what is cancer an imbalance favouring

A

self renewal

140
Q

what are the effects of ageing on the blood

A

decreased immunity
anaemia
increased incidence of bone marrow failure

141
Q

what happens to populations of HSC upon ageing

A

see an increase in number but a reduction in reconstitution potential. The HSC also have a myeloid lineage bias

142
Q

what are intrinsic factors that drive HSC ageing

A
  • DNA damage
  • ROS
  • polarity shift
  • altered proteostasis
  • impaired autophagy
  • epigenetic drift
143
Q

how does aging increase DNA damage

A

HSC are quiescent (protected from replicative DNA damage)

- upon ageing there is an increased proportion of cycling cells - increase DNA damage and production of ROS

stem cells (1 decks)

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