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BIOM30001 - Frontiers in Biomedicine > Lecture 16 - Stem Cells - Therapies for Respiratory Diseases > Flashcards

Lecture 16 - Stem Cells - Therapies for Respiratory Diseases Flashcards

1
Q

What is the gastrula?

A

The embryo after gastrulation has occurred; i.e. the three germ layers are present

The foetus is embedded in the endometrium

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2
Q

What is the germ layer derivation of the lung

A

Endoderm:
• Lung epithelium

Mesoderm:
• Lung mesenchyme

Ectoderm:
• Lung innervation

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3
Q

List some of the various cells in the lungs

A

The lung comprises over 50 cell types

Vasculature:
• Endothelium

Alveoli:
• Type I and II pneumocytes

Lung mesenchyme:
• Fibroblasts
• Myofibroblasts
• Smooth muscle cells

Airways:
• Ciliated cells
• Goblet cells
• Clara cells

Bronchioles:
 • Neuroendocrine cells
 • Clara cells
 • Ciliated cells
 • Basal cells

Haematopoietic cells:
• DCs
• Macrophages
• Lymphocytes

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4
Q

Describe the development of the lung

A
  1. Embryonic phase:
    Outpouchings form from the foregut endoderm
  2. Pseudoglandular:
    Epithelial lung buds form, surrounded by loosely packed mesenchyme
  3. Canalicular
    Branching morphogenesis form the conducting and respiratory airways
  4. Sacular
    Alveolar ducts form
  5. Alveolar
    Alveolar sacs form
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5
Q

Where are the lung epithelial stem cells during development?

A

At the distal tips of the growing lung buds

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6
Q

What is Id2?

Describe how it has been used to investigate lung development

A

All lung epithelial cells are progeny of Id2(pos) stem cells

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7
Q

Outline the lung endodermal heirarchy

A 
Endoderm:
→ Lung epithelium
→ Thyroid
→ Thymus
etc.

Lung epithelium → lung embryonic stem cells

Lung embryonic stem cells:
→ Alveolar progenitor
→ Bronchiolar progenitor

Alveolar progenitor → Type II pneumocytes → Type I pneumocytes

Bronchiolar progenitor
→ Neuroendocrine cells
→ Basal cells

Basal cells → club cells

Club cells
→ Clara cells
→ Ciliated cells

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8
Q

What is the ‘potency’ of lung epithelial stem cells?

A

Multipotent

Can form all epithelial cells in the lung:
 • Type I and II pneumocytes
 • Ciliated cells
 • Clara cells
 • Basal cells
 • Neuroendocrine cells
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9
Q

What is the origin of the lung mesenchyme?

A

The lung mesenchymal cells (fibroblasts, smooth muscle cells) are derived from:

Splanchnic mesoderm

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10
Q

Where is smooth muscle present in the lungs?

A

In the airways

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11
Q

Where are the mesenchymal stem cells in the developing lungs

A

Distal tip of the developing lung buds

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12
Q

What is the importance of FGF-10?

A

Marker of mesenchymal stem cells present in the distal tip of the developing lung buds

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13
Q

What controls the proliferation and differentiation of the stem cells in the lung?

A

The mesenchyme releases signals that control the stem cell differentiation into the various cell types

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14
Q

Describe the development of innervation in the lungs

A

Neural crest cells (ectodermal origin) migrate down into the lungs

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15
Q

Describe the development of vasculature in the lungs

A

Endothelial progenitor cells derived from the mesoderm form the vasculature

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16
Q

Describe the co-development of the heart an lung

A

New evidence that the mesenchymal of the heart and lung develop from a shared progenitor:

Multipotent cardiopulmonary progenitor

17
Q

What are the defining features of stem cells?

A
  • Self-renewal
  • Differentiation into many cell types
  • Immortal
18
Q

Describe how flow cytometry is used to investigate the lung

A

Single cell types can be isolated based on cell markers

This allows the isolation of rare stem cells (expressing certain markers)

19
Q

Describe, in general, cell surface markers of stem cells

A

In general, stem cells express cell surface markers associated with the stem cell state, whilst having low expression of markers associated with differentiated cell lineages

20
Q

Describe the importance of the lung epithelial stem cell niche

A

*
The factors present in the niche are specific and very important for the tissue structure

When the niche is disrupted, there are histological changes (possibly disease)

Epithelial stem cell fate and lineage is determined by this microenvironment

21
Q

Describe the importance of lung mesenchymal cells for the lung epithelial cells

A

Lung mesenchymal cells interact directly with the epithelial cells:
• Direct their differentiation

e.g.
• Release of FGF-10

22
Q

How is the lung epithelium maintained in the adult lung?

A
  1. Multi-lineage stem cells
    These can differentiate into all the epithelial cell types
  2. Lineage-restricted stem cells
    Can differentiate into only alveoli or airway epithelial cells
23
Q

What is the significance of EpCAM and CD24?

A

Lung epithelial cell progenitors are:
CD45(neg) CD31 (neg) EpCAM(pos) CD24 (lo)

This can be determined by clonogenic assay

24
Q

Which techniques are useful in studying lung stem cells

A

Clonogenic assays

Lineage-tracing techniques

25
Q

What is the stem cell implication of the tissue origin heterogeneity of the lung?

A

The lung is made up of cells from many different lineages:
• Endoderm, mesoderm, ectoderm

These different cell types must be maintained by different stem cells

26
Q

What is the importance of lung disease?

What is the success with current therapies?

A

By 2020 > 1 in 6 deaths will be attributed to lung disease
COPD ranked 3rd in Global Burden of Disease

300 million people worldwide with asthma

Current therapies:
 • Largely palliate
 • Treat the symptoms
 • Largely unable to reverse the disease
 • Most diseases are dependent on lung transplant

→ This is why stem cells could be so beneficial

27
Q

How could stem cells be used for therapy of lung disease?

Give some examples of the different approaches

A

Depends on the features of the particular disease
e.g. Acute / chronic injury, extent of damage etc.

Different stem cells would be needed for different diseases

Approaches:
• Cystic fibrosis: replacement of CFTR
• Adult RDS: regeneration of epithelia and endothelium
• Asthma: inhibition of airway remodelling, SMC hypertrophy

28
Q

Describe normal endogenous stem cell responses to injury in the lung

How could this be therapeutically modulated?

What are the challenges of this approach?

A

Either:
1. Endogenous stem cells react to the injury too much, leading to hyperplasia, loss of architecture and cancer

  1. Lack of repair

Therapeutic approach:
• Switch off / on the endogenous stem cells for a better repair process

Challenges:
• In disease states, the intrinsic potential of the endogenous stem cells may be altered
• In other cases, the microenvironment may be altered

29
Q

What is the benefit of stem cell transplants?

What are the challenges of this approach?

A

Stem cells have the intrinsic capacity to self renew, proliferate and differentiate

This is an alternative to whole tissue transplants

Challenges:
• Source of stem cells? (iPSCs, Adult SCs or ESCs?)
• The microenvironment in disease states may not be able to provide adequate signals to drive the differentiation of the stem cells

30
Q

Describe the use of stem cells in gene therapy

What are the challenges of this approach?

A

e.g. Cystic fibrosis

Stem cells w/ a functional CFTR gene could be expanded in vitro and then transplanted back into the patient

Challenges:
• Engraftment is very difficult
• Requires depletion of the airway epithelium without harming the microenvironment

31
Q

Describe how stem cells could be used in bioengineering

A

Decellularisation
• Lung is depleted of cells through treatment (detergents, enzymes etc.)
• Matrix scaffold is re-seeded with stem cells (matching the individual)
• This new organ can be transplanted back into the individual (without rejection)

So far this has been done with a trachea

32
Q

Describe the generalised stem cell heirarchy

A

Stem cell → Progenitor cells → Differentiated cells

33
Q

Why can’t ESCs be directly used for therapy?

A

They can form teratomas, as they are pluripotent

Must first direct them to differentiate into the tissue of interest

BIOM30001 - Frontiers in Biomedicine (35 decks)

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