Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research

Why did we fund this project?

This award aims to develop a human 3D lung organoid model replacing the use of mice in some developmental studies.

Premature births are associated with high rates of mortality, predominantly due to the lungs being underdeveloped so they cannot provide enough oxygen. Characterising the mechanisms underlying lung development can help develop therapeutics that mature the lungs. Current in vitro models typically use early human foetal tissue, which does not reflect the clinical situation for underdeveloped lungs. Instead, therapeutics are screened by isolating murine embryos by culling pregnant mice. Dr Marko Nicolić has established new collaborations with the Foetal Medicine Unit at University College London Hospitals and the Histopathology Department at Great Ormond Street Hospital to access donated foetal lung tissue from the third trimester of pregnancy. The student, with Marko, will use genomic and transcriptomics to characterise the later stages of foetal lung development. They will also isolate alveolar stem cells to produce an organoid model suitable for drug screening studies enabling researchers without access to foetal lung tissue to replace the use of animal models.

We aim to develop a human late fetal 3D organoid model to reduce and replace the use of animals in lung developmental studies. Currently, lung research is primary based on mouse models, due to the highly conserved molecular pathways between mice and humans. Through combining data collected from Pubmed and our collaborators, approximately 20,000 and 171,933 pregnant mice are sacrificed yearly on a national and international level respectively for lung research. Despite the invaluable contribution of mouse models to our current understanding of lung development, there are differences between these organisms that have functional consequences.

Currently, end-stage respiratory diseases are the third-leading cause of death among non-infectious diseases. In addition, premature birth is still associated with high mortality due to lung immaturity. Characterisation of lung development using models that better resemble the human lung is of vital importance to improve translational outcomes. A current limitation is that late fetal lungs are significantly under-characterised due to ethical reasons that limit access to fetal tissue. To address this problem, in collaboration with the Fetal Medicine Unit at University College London Hospitals and the Histopathology Department at Great Ormond Street Hospital, we have gained ethical approval for the use of fetal lung tissue from the third trimester of pregnancy. 

We will develop a 3D late fetal organoid culture which will provide a unique model that can be used by other research groups to replace animals used for disease modelling and drug screening. In particular, our model will replace mice used by our collaborators and other research groups to study alveolar maturation/development, replacing 2000 pregnant mice that are sacrificed annually for these studies in the UK. Furthermore, based on a Pubmed search, our model can replace 9% of mouse models used in lung research globally, leading to a further reduction of 15,552 pregnant mice that are sacrificed annually for alveolar maturation/development studies. Our findings will also benefit other groups conducting studies on comparable organs and support the development of protocols for creating lung tissue from human-induced pluripotent stem cells for adult lung disease modelling and identification of lung regeneration therapies. We will ensure maximum 3Rs impact is reached by introducing and promoting this model to the research community for uptake through various platforms and activities, as well as setting up a tissue resource to provide human fetal lung cells, as well as cells from other organs to various groups nationally and internationally.