2017 Group Project 5: Difference between revisions

From Embryology
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- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium  
- Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium  
- Results showed a diminution of branching airways and alveoli bronchiolization
- Results showed a diminution of branching airways and alveoli bronchiolization
- Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)


==Abnormal development==
==Abnormal development==

Revision as of 11:00, 13 September 2017

2017 Student Projects 
Student Projects: 1 Cerebral Cortex | 2 Kidney | 3 Heart | 4 Eye | 5 Lung | 6 Cerebellum
Student Page - here is the sample page I demonstrated with in the first labs.I remind all students that you have your own Group Forum on Moodle for your discussions, it is only accessible by members of your group.
Editing Links: Editing Basics | Images | Tables | Referencing | Journal Searches | Copyright | Font Colours | Virtual Slide Permalink | My Preferences | One Page Wiki Card | Printing | Movies | Language Translation | Student Movies | Using OpenOffice | Internet Browsers | Moodle | Navigation/Contribution | Term Link | Short URLs | 2018 Test Student

Lungs

An introduction to the lungs...

On this page, we will be exploring the development of the lungs through the stages of embryonic growth.

Lung Anatomy

Lung Histology

Developmental origin overview

Brief overview of development of lung

More detailed overview in lung development stages

The Respiratory Zone

The Terminal Bronchioles

Alveolar ducts

Alveoli

The Conducting Zone

The Lung Development Stages

Stage
Description
Embryonic (weeks 4-5)
About
Pseudoglandular (weeks 5-17)
About
Canalicular (weeks 16-25)
About
Saccular (weeks 24-40)
About
Alveolar (week 36-8 years)
About

Developmental timeline

Stage
Development
"'Historical Discoveries'"
Embryonic (weeks 4-5)
The Embryonic stage is the first stage of lung development. It is identified by the emergence of lung buds in the ventral wall of the foregut; these lung buds will later divide to form lobar divisions. The endoderm is responsible for the epithelium of the lung buds which will later differentiate into specialised respiratory epithelium. The mesoderm is responsible for the mesenchyme surrounding the lung buds.
Christian Pander, Karl Ernst von Baer, and Heinrich Rathke were among the first to use a new wave of technology in embryology; involving the use of new staining techniques and improved microscopy. Their findings together identified the presence of primary germ layers (ectoderm, endoderm and mesoderm) and the development of early organs. [1]
Pseudoglandular (weeks 5-17)
about
history
Canalicular (weeks 16-25)
about
history
Saccular (weeks 24-40)
about
history
Alveolar (week 36-8 years)
about
history

Structure of respiratory network

Physiologically, the organ can be divided into two parts:

The Conducting system – consists of all tubular structures including the larynx, trachea and bronchi. (image)

The Functional unit – An alveolus containing specialised epithelial cells where gas exchange occurs.

By week 8 of development, the lungs are in the development of the pseudoglandular stage (refer to developmental timeline). The three germ layers formed in gastrulation all contribute to the development of the lung, including signalling for a cascade of events as well as branching of the bronchiole.

3D model of the air way tree.jpg

A three-dimensional fractal model of an airway tree with 54 611 branches; branches distal to different segmental bronchi are shown in same colour as segmental bronchus. (a) Anterior view and (b) right lateral view

Developmental signalling processes

The development of a mammalian lung is a multi-step and highly complex process involving signalling pathways. This hierarchy process, referred to as branching morphogenesis is essential to generate numerous airways and gas-exchanging units, and is critically regulated by interactions of signalling pathways in the epithelium and mesenchyme.

Several growth factors and chemical signals have been identified to influence lung development. The main signalling molecules include:

1. Fibroblast Growth Factor (FGF10) - serves as a signalling cue for epithelium outgrowth in the mesenchyme.

2. Sonic Hedgehog (SHH) - produced in the epitheliumand is involved in regulating FGF10 expression, leading to the intertubular mesenchyme to facilitate growth and formation of epithelial buds.

3. Heparan Sulfate Glycosaminoglycans (HS-GAG) - interacts with SHH in order to produce epthelial cells and lung morphogenesis. There is still a lack of understanding in the role that HS plays in mammalian lung development.

Early buds formation is dependent on reciprocal interactions between the lung epithelium and mesenchyme mediated by distinct signalling.

Distal signalling centre is marked by the expression of fibroblast growth factor FGF10 in the mesenchyme. FGF10 signalling serves as cue for epithelium outgrowth.

The Conducting System

Branching morphogenesis is observed in many organ systems, including the lungs. It has been of great interest and has been studied in great detail. The bronchial tree arises from the sequential use of three simple modes of branching.

These modes include:

1. Domain branching

2. Planar bifurcation

3. Orthogonal bifurcation

Trifurcations have also been observed, however it is not as prevalent.

These branching structures involve are regulated by a network of signalling factors. To form a branched structure, signalling molecules have to form a pattern in space that precedes bud outgrowth. This is assisted with the molecule FGF10 and will be further explored. For direct elongation, FGF10 has a higher concentration at the distal tip of the lung bud allowing direct elongation of the structure. In terminal branching, there is a split localisation of FGF10 and results in a terminally branched structure. For lateral branching, FGF10 is restricted to being a single spots on the side allowing the structure to grow laterally. FGF10 appears to drive outgrowth of lung buds, as well as other organs.

With regards to early lung development, transitions from one mode of branching to the other occur to ultimately build the lung tree. In the domain branching mode, the lung bud elongates and new buds first appear on one side of the stalk, perpendicular to the main axis on either sides of the stalk. Domain branching is used to build the backbone of the respiratory tree.

Planar and orthogonal bifurcations represent two consecutive rounds of branching, however they differ in the second round as they branch in the same plane as planar bifurcations. Planar and orthogonal bifurcations create lobes surfaces and fill the interior. The branching process is controlled by genetic information and is tightly regulated. In the lung, dichotomous branching gives rise to two daughter branches with a smaller diameter than the mother branch.

In earlier studies, lung branching has been proposed to be influenced by the viscosity of amniotic fluid and the mesenchyme, separated by a ‘skin’ of surface tension, the epithelium. However, more recently this has been negated as branching can occur without a mesenchyme, without growth and the robustness of the branching process suggests that it is a highly controlled process. Signalling factors play a key role in branching morphogenesis. A recent study has shown that branching can still occur in the absence of mesenchyme, only if the appropriate signalling factors are added.

  • Add image of branching patterns

Alveolus: the functional unit

How the alveoli work. Cell types Maturation and development Surfactant - where cells are derived from (macrophages, type 1 and type 2 pneumocytes) Lungs become fully developed within the mother, however they do not function until birth.

At the end of the conducting system, are sac-like structures known as alveoli, which are assist in gas in exchange.

Current understandings and areas of research

include any relevant articles

Review and research articles

Movies

Animal models

Mouse models

Key pathways that maintain the mesenchymal-epithelial interactions that allow normal embryological lung development: VEGF, Bmp, Shh, and Wnt.... Sox 2

Wnt signaling pathway involves the binding of the Wnt ligand to the Frizzled family receptor that can elicit different effects depending on the type of Wnt pathway. (noncanonical/calcium, canonical, noncanonical planar cell polarity)

Wnt7b signaling role in embryonic lung development? (body axis patterning ... cell fate specification, cell proliferataion, cell migration) ... "regulates tube shape and branch-point formation in the lung through control of epithelial cell shape" - Wnt 7b actions have a widespread effect in tissue development & regulation of mesenchymal differentiation as seen in mouse lung development models - Wnt pathway: interaction of the Wnt protein to LRP coreceptor complex to cause the stabilisation and nuclear translocation of beta catenin

Sox 2 - branching morphogenesis and epithelial cell differentiation. - Sox 2 is a Sry related HMG - There is an increased expression of Sox 2 in unbranched lung epithelium and is absent in branching regions - Development of a transgenic mice with doxycycline inducible Sox2 continuously expressed in their lung epithelium - Results showed a diminution of branching airways and alveoli bronchiolization - Driving precursor-like cells to a committed state (cGRP positive neuroendocrine cells and ΔNp63 isoform expressing (pre-) basal cells)

Abnormal development

Premature Birth

Lobar Emphysema

Congenital Diaphragmatic Hernia

Azygos lobe

Meconium Aspiration Syndrome

Newborn Respiratory Distress Syndrome

Surfactant Metabolism

Bronchopulmonary Dysplasia

Lung Agenesis

Cystic Fibrosis

CHAOS (Congenital High Airway Obstruction Syndrome)

CPAM (Congenital Pulmonary Airway Malformation)

Lung Cardiovasculature

Future questions

Glossary

References

  1. Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Comparative Embryology. Available from: https://www.ncbi.nlm.nih.gov/books/NBK9974/