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BIOM30001 - Frontiers in Biomedicine > Lecture 15 - Stem Cells - Basics > Flashcards

Lecture 15 - Stem Cells - Basics Flashcards

1
Q

What changes when cells become more differentiated?

A

Not a change in genes, but rather a change in gene expression through permanent:
• Chromatin alteration
• Alteration in transcription factor expression

These changes are inherited through many cell divisions

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2
Q

Distinguish between determination and differentiation

A

Determination:
• Occurs prior to overt differentiation
• Operationally defined
• Change in gene expression

Differentiation:
 • Result of changes in gene expression
 • Cell acquires correct:
- Shape polarity
- Orientation
- Organelles and proteins
for given tissue
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3
Q

What is transdifferentiation?

Give some examples

A

Cell normally committed to one lineage is switched to a different lineage pathway

Often occurs between cells in two closely related lineages

Examples:
Often in disease states:
• Intestinal metaplasia of oesophagus
• Squamous metaplasia in respiratory tract

Pancreatic progenitor lineage
• Acinar cell → endocrine cell

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4
Q

Describe intestinal metaplasia

When does it occur?

A

Occurs when there is damage to oesophageal epithelium:
• Acid reflux from stomach
• Conversion of squamous epithelium into intestine

This is a precursor for oesophageal adenocarcinoma

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5
Q

What is the developmental capacity heir achy?

A
  1. Totipotent
    • Can give rise to a new individual given appropriate maternal support (i.e. + extra embryonic tissue)
  2. Pluripotent
    • Can give rise to all types of adult tissue (can’t form extra embryonic tissue)
  3. Multipotent
    • Can give rise to several types of mature cell
  4. Oligopotent
  5. Unipotent
    • Can only give rise to one cell type
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6
Q

What are the various reproductive capacities of adult cells?

A
  1. Labile
    • Constantly renewing
    • e.g. HSCs, skin and gut epithelia
  2. Stable
    • Not actively renewing, but capable of re-entering the cell cycle with the appropriate signals
    • e.g. Kidney, liver
  3. Permanent
    • Can not self-renew
    • e.g. Neurons, cardiac muscle
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7
Q

The lining of the intestine is replaced every …

A

4 days

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8
Q

A new epidermis is generated every …

A

4 weeks

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9
Q

What are the principle features of stem cells?

A
  • Capable of self-renewal
  • Can differentiate into a variety of cell types
  • Capable of indefinite growth
  • Slowly dividing
  • Rare
  • Long lived
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10
Q

List some of the adult tissue stem cells

A

Intestines:
• Crypt cells

Haematopoietic stem cells

Neural stem cells

Cardiac stem cells

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11
Q

What cellular feature allows stem cells to be long lived?

A

Express telomerase at high levels

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12
Q

Describe the location of tissue stem cells

A

Often restricted to specific niches

These niches provide the signals which regulate the growth and proliferation of the stem cells

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13
Q

Describe proof of stem cell isolation

A
  • Single cell can repopulate a tissue and give rise to differentiated progeny as well as more stem cells
  • Identified in transplantation assays with marked cells
  • Critical that descendants of stem cell are shown to be functional
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14
Q

List some markers of specific differentiation stages in cell lineages

A
  • Transcription factors
  • Cell surface molecules (e.g. CDs)
  • Cytostructural molecules (e.g. intermediate filaments)
  • Specific functional gene products
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15
Q

What controls the key decision points in the haematopoietic stem cell hierarchy?

A

Transcription factors

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16
Q

What differentiates the different descendants of the HSC?

A

Different cell surface markers

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17
Q

What is interesting about the heart and CNS in terms of stem cells?

A

Recently shown to have stem cell populations, through formally thought to be stable tissues

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18
Q

Describe the features of neural stem cells

A

Neurons are born constantly throughout life in specific brain regions

Subventricular zone and hippocampus

New neurons from SVZ wind up in the olfactory epithelium

Hippocampal neurogenesis may have a role in learning and memory

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19
Q

What are the four types of differentiated cells in the gut?

Briefly describe the function of each

From what do these arise?

A
  1. Enterocytes
    • Absorb nutrients from the lumen of the gut
  2. Paneth cells
    • Secrete defensins and lysozyme
  3. Goblet cells
    • Secrete mucin
  4. Enteroendocrine cells
    • Produce gut hormones

These all arise from stem cells in the crypts

20
Q

What regulates the differentiation of stem cells in the crypt into the various cell types?

A
  1. Extrinsic signals:
    • Wnt signalling
    • NOTCH signalling
  2. Networks of transcription factors
21
Q

Describe regulation of stem cell growth and differentiation in the hair follicle

A

Extrinsic signals:
•Wnt/B-catenin etc.

There are various signalling pathways that regulate the stem cells through quiescence to proliferation

When there is damage, normally quiescent stem cells are activated

22
Q

Characterise the stem cells of the liver

What are the stem cells in the liver?

A

‘Facultative’ stem cells

Liver stem cells:
• Hepatocytes
• Bipotential stem cells in the biliary tree

23
Q

Describe the signalling that results in proliferation of liver stem cells

A

Many signalling systems control formation of hepatocytes and bile duct from liver stem cells

**

24
Q

What are Yamanaka factors?

A

The four transcriptions factors demonstrated by Yamanaka to be capable of reprogramming cells to become pluripotent

25
Q

What are the two ‘types’ of human pluripotent stem cells?

A

Embryonic SCs

iPSCs

26
Q

What is the definition of a pluripotent stem cell?

List the important properties

A

A cell capable of differentiating into any cell in the body

Properties:
 • Grow indefinitely in vitro
 • Maintain normal genetic makeup
 • Cloned lines capable of differentiation into a wide range of somatic and extra-embryonic tissues in vivo
 • Capable of colonising all tissues
27
Q

SCNT is capable of the generation of …

A

Embryos

28
Q

Describe the process of SCNT

What is the potential application of SCNT?

A
  1. Nucleus of somatic cell from individual introduced into enucleated oocyte from donor
  2. Oocyte stimulated to form an embryo
Application:
3. Any cell type may be generated from these ESCs:
 • HSCs
 • Hepatocytes
 • Neurons
 • Cardiomyocytes
  1. Cells transplanted back into individual depending on their disease

(The cells produced from the embryo will be genetically identical to the individual who donated the nucleus)

29
Q

Describe the early stages of human development

A

Speratozoa fertilise ova

  1. Zygote
    - - cleavage –
  2. 2 cell stage
  3. 4 cell stage
  4. 8 cell stage
  5. Blastocyte:
    • Trophectoderm
    • Inner cell mass
30
Q

Describe the blastocyte

A
  • Body plan not yet apparent
  • Many cells will not form new human
  • Trophectoderm gives rise to extra-embryonic tissue
  • Inner cell mass forms embryo
31
Q

Up until which point can twins form?

A

Up to 14 days

32
Q

When is the blastocyst stage?

A

Around the 5 day mark

33
Q

Describe some biological proofs of pluripotence

A

– Generation of a chimaeric mouse –

  1. ES cells from pigmented strain of mouse introduced into ICM of blastocyt of an albino mouse
  2. Injected cells become incorporated into the ICM
  3. Blastocyst develops in foster mother
  4. Healthy, chimaeric mouse is born:
    • Patches of pigmented skin etc.

– Human teratoma generation –
Human ES cells can form teratomas containing:
• Tissues representative of all three embryonic germ layers
• Structures resembling early embryos

34
Q

Describe spontaneous ES cell differentiation in vitro

A

*

35
Q

List the seven signalling systems that control animal development

A
  1. Hedgehog
  2. Wnt
  3. TGF-beta
  4. Notch
  5. JAK-STAT
  6. TYR KIN
  7. NUCLEAR REC
36
Q

List the germ layers derived from ES cells

List some adult tissues that are derived from each

A 
Endoderm
 • Endothelium (lining of organs)
 • Pneumocytes
 • Pancreatic cells
 • Respiratory tract
 • GIT
Mesoderm
 • Muscle (cardiac, smooth, skeletal)
 • Bone
 • HSCs
 • Dermis

Ectoderm
• CNS
• Epidermis

37
Q

Describe the derivation of cardiac myocytes

A
  1. Mesodermal precursors
  2. MICP:
    • Multipotent cardiovascular progenitors
  3. …
  4. Cardiac myocytes
38
Q

What is the beauty of SCNT?

A

The ES that are generated are genetically identical to the individual who donated the somatic cell

39
Q

Describe how iPSCs are generated

A
  1. Somatic cells transfected with virus
2. Virus contains genes for Yamanaki factors:
 • Oct-4
 • Sox2
 • Klf-4
 • c-Myc
  1. iPS cells are generated
40
Q

What is the beauty of iPSCs?

A

Avoids use of human embryos

Can be genetically identical to individual

41
Q

What are the potential applications of iPSCs?

A

Research:
• Disease modelling
• Modelling of early human development
• Functional genomics
• Doscovery of novel factors controlling tissue regeneration and repair
• In vitro models for drug discovery and toxicology

Therapeutic:
• Tissue matching

42
Q

Describe how iPSCs have been used to model a human disease

A

Long Q-T syndrome

*

43
Q

Describe how iPSCs can be used for human functional genomics

A

There are genomic differences between mice and humans

Using iPSCs instead of mouse cells means that we can more accurately study diseases

*

eg. Diabetes
Generation of:
• B islet cells
• Fat / muscle

Transplantation of B islet cells into a diabetic host (mouse)

In vitro assay of fat / muscle cells
• Glucose uptake / insulin sensitivity assay

44
Q

Describe how stem cells can be used to study CNS development

A

Human cortical development differs significantly from other mammals

iPSCs can be used to model human cortical development to better understand disorders of brain dev.:
• Schizophrenia
• Autism
• Epilepsy

iPSCs from individuals with the disease can be used to recapitulate key events in pathogenesis

45
Q

Describe potential therapeutic use of iPSCs for brain repair

A

Neural progenitors from human ESCs have been shown to be integrated into mouse cerebral cortex

This has implications for repair of neural tissue

46
Q

Which restraints are placed on adult tissue stem cells?

A

Restricted to form certain cells

e.g. Skin stem cell in basal layer only gives rise to cells of the skin tissue

This is through restraints on gene expression

47
Q

What is adult neurogenesis?

A

Generation of new neurons in the adult brain from stem cells in hippocampus and SVZ

BIOM30001 - Frontiers in Biomedicine (35 decks)

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