Lecture 16 - Stem cell therapies for resp. disease Flashcards
The lung epithelium is derived from _________
endoderm
But there are cells from all 3 germ layers - innervation from ectoderm for instance
There are over __ different cell types in the adult lung
50
lots of different mesenchymal, epitheliual, bood, nerve cells
The lung epitthelium is formed by proliferaion of an ________ progenitor cell in the ____ ________
The lung epitthelium is formed by proliferaion of an endodermal progenitor cell in the foregut endoderm
The structure of the lung is then formed by formation of an epithelial lung bud, surrounded by loosely packed ________ ____
mesenchymal cells
What are the 5 stages f lung develpoment
embryonic
pseudoglandular - bit more branching
canalicular - more complex branching
saccular - alveolar start to form
alveolar - seperation of aleolar for better gas exchange (continues beyond birth)
The stem cells that give rise to all the epithelial branching is a small bunch that reside ..
at the tips of the lung stem - the fetal lung epithelial stem cells
The Mesenchymal cells derived from splanchnic mesoderm give rise to what in the developing lung
fibroblasts and smooth muscle
The proliferation and differentiation of lung embryonic stem cells is ergulated by signals emanating from …
the surrounding mesenchyme
The innervation of the developing lung is derived from…
neural crest progenitor cells in the ectoderm
The vascularisation of the developing lung is derived from…
endothelial progenitor cells of the mesoderm
New evidenece shows that lung mesemchyme and endothelium shares a common ancestor with…
the cv system
Flow cytometry
Enzymes can be used to break down the lung tissue to singe cells, then can select cells and look at whether they can proliferate and differentiate - what the advantages of this for stem cell research?
The ‘single cell’ measuring principle: each and every cell is analysed as a single event; rare populations can be detected
in the adult lung there are stem cells with multi-linage potential, meaning…
what else is there?
They can differentiate into airway and alveoli epithelial lineages
There are also progenitors that are lineage restricted (generate only alveoli or airway cells)
There is definitely a progenitor cell hierarchy in which part of the lung?
epithelium
(cHECK out the scematic diagram)
.
Epithelial stem cell fate and lineage preference is determined by..
Microenvironment
Lung mesenchymal stromal cells interact directly with epithelial cells and create…
a niche for epithelial stem cells in culture
Adult lung progenitor cells can be isolated on the basis of the differential expression of..
EpCAM and CD24
What is a powerful tool for the analysis of lung stem/progenitor cell organisation and regulation?
In vitro clonogenic assays
In vivo-lineage tracing techniques enable the identification of…
lineage hierarchies
True or False
Different stem cells are required to maintain each of the different germ layers
True
Stem cells are defined in context. The deregulation of the micro-environment can effect…
the homeostasis of epithelial stem cells and contribute to lung disease
lung disease is ranked what for mortality, incidence, prevalence and cost?
2nd
COPD is ranked what in global burden of disease
3rd
Different diseases are going to take different approaches and possibly different stem cells depends on the …
nature, severity and timing
What is a common therapeutic objective for differnet lung diseases?
regeneration of epithelia
reduce inflammatory milleu
inhibit mesemchymal/smooth muscle
Congenital lung hypoplasia is what?
lung is underdeveloped
need to regenerate everything
Inchronic respiratory diseases the injury repair process goes wrong lead to ..
A) lack of repair
B) too much proliferation of endogenous stem cells which can lead to hyperplasia and cancer.
Development of drugs which switch on/off adult lung stem cells will offer the ability to correct the endogenous regeneration and repair process
In some cases the intrinsic potential of stem cells may be affected by the disease, while in other cases ..
the microenvironment may be damaged.
What are the challenges of stem cell transplants for lung regeneration?
What source of stemc ells to use
Lung epithelial stem cells delivered to a ‘diseased’ lung may not receive adequate signals for ‘healthy’ lung regeneration. If the microenvironment is also damaged, the fate and specificity of the exogenous stem cells may be altered.
How can the micro-environment be reconditioned to make it suitable for SC transplantation?
good question… don’t think there’s’ an answer
What are some sources of SCs for therapy?
benefits and drawbacks for each
Embryonic stem cells
induced pluripotent SCs (iPS) - autologous, but have modified cell so need to make sure it’s still safe
Safest - Adult stem cells, proliferative potential is less than the others
Stem cells can be used as a vehicle for gene therapy
Expansion of stem cells in vitro provides an opportinity to correct what?
the genotype of patients with CF.
Lung stem cells could be engineered with a correct copy of the CFTR gene and transplanted back into patients to replace the “diseased” epithelium with “normal” epithelial cells
What are the challenges for Stem cells being used as a vehicle for gene therapy
engraftment of stem cells in the lung epithelium is often very poor
Seeding stem cells onto decellularised trachea scaffolds has been successful in the clinic for replacement of ..
injured trachea - formed a viable piece which was transplanted
easy because its a single layer of epithelial cells.
need to check the cilia are beating the right way though!
What are the key questions for lung stem cells therapies?
What are the endogenous lung stem cells that maintain the lung throughout adult life
How do we isolate adult lung SCs
What are the regualtors of proliferation and differentiation in adult lung SCs
How do we drive embryonic SCs or iPS cells to differentiate into lung cells
In summary what are the potential clinical uses of stem cells for respiratory diseases?
Regenerative medicine - cellular therapy and regulation of endogenous stem cells
Bioengineering - breathing now life into old lungs
Gene therapy - cystic fibrosis
Immunimodulation - mesenchymal stem cells
