How to build human airways, a lesson from frogs

Associate professor Jakub Sedzinski from the Novo Nordisk Foundation for Stem Cell Medicine, reNEW

Researchers have succeeded in building a comprehensive model that explains how different cell types in the airways follow a specific path of development by expressing certain genes.

Crucial research to tackle a global public health problem
Research on the development of human airways is crucial, as respiratory diseases are a major global public health problem. Nearly 545 million people, equivalent to 7,4% of the world’s population, are currently living with a chronic respiratory illness. The number of patients suffering from these conditions is significantly increasing due to environmental pollution. However, the development of airways, which are responsible for transporting air to and from the lungs, is a complex process that has puzzled scientists for many years. To get a better understanding, researchers are now turning to the study of frog embryonic skin to gain valuable insights into how airways are formed and developed.

Why are frogs such interesting creatures?
Frog embryonic skin shares similarities with respiratory tissue in mammals, including humans, such as the presence of cilia and the production of mucus that help protect against pathogens. The accessibility of the frog and its embryonic skin model make it valuable for respiratory biology research, allowing for investigations into cell division, migration, and tissue differentiation. By dissecting the complex interactions between the mucus, cilia, and epithelial cells in the airways, researchers can gain insights into how the airways and respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) develop, the two most common chronic respiratory diseases worldwide. With this knowledge, researchers can work towards the development of stem cell therapies aimed at restoring airway function.

Frog embryonic skin recapitulates human respiratory epithelium. It consists of multiple cell types that work in concert to prevent infection of pathogens. Green: actin signal, Yellow: cilia of multiciliated cells. Credit: Raghavan Thiagarajan.

About the study
The study, led by Associate Professor Jakub Sedzinski, principal investigator at the Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW at Copenhagen University, and Kedar Natarajan from the Technical University of Denmark and published in Science Advances, combined developmental biology, and advanced bioinformatics to sequence the developing frog skin.

They discovered that cells could follow different paths of development, and these paths happen at different speeds. This is necessary to maintain the proper balance of cells in the body and to ensure that respiratory tissue can protect itself from harmful pathogens and dust particles, which can potentially lead to the development of serious respiratory diseases.  By using computer models and imaging techniques, they were able to track the development of different cell types and see how they matured over time.

During development, cells go through a process where genes are turned on and off in a seemingly random way. This can lead to cells taking on different roles and functions within the body. However, as development progresses, cells become more specialised, and their gene expression becomes more specific to their role. We found that this process happens during the neurula stage, which is a critical time for establishing the diversity and frequency of cell fate switching.

‘This knowledge is crucial for developing regenerative therapies that can restore the function of damaged airways, which is important for treating respiratory diseases such as asthma and COPD’, says Associate Professor Sedzinski.

Associate Professor Kedar Natarajan adds “To understand what happens when chronic respiratory diseases occur, we need to have a better picture of all the cells, their states, especially during the early stages of cell type formation. Understanding how individual cells make decisions can enable us to influence cellular decisions making in disease. This knowledge can help open a new door to how we treat diseases like asthma or COPD.”

What are the benefits that this study offers compared to previous studies?
Previous studies of the respiratory epithelium have primarily focused on regeneration and repair after injury rather than on the developmental aspect of the tissue. This study provides new insights into the process of cell type specification during the development of the mucociliary epithelium (MCE). This model can be used to study the effects of genetic and environmental factors on cellular dynamics during development.

Moreover, our research allows us to understand the development of these cells without the prerequisite of lung formation, which can be useful for studying respiratory biology across different species.

What are the next steps?
The next step in our research is to understand how we can manipulate the frog embryonic skin model to drive the development of specific cell types and regulate the cellular composition. This requires manipulation of various transcription factors that we have identified in our study. By modulating the expression of these factors, we can promote the development of specific cell types.

Additionally, we aim to understand the spatial distribution of the identified genes so that we can determine when and where they are active during development. This will provide us with important insights into the signalling pathways and molecular mechanisms that drive cellular differentiation and tissue patterning.

Find the study here:

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