lung epithelial maturation

The third most prevalent cause of death worldwide amongst non-infectious diseases is end-stage pulmonary disease
(Organization 2011). There are currently no treatments that reverse lung function decline for diseases that are
characterised by epithelial damage and failed epithelial regeneration, such as chronic obstructive pulmonary disease
(COPD) and idiopathic pulmonary fibrosis (Liang et al. 2016; Ng-Blichfeldt et al. 2019). In addition, premature birth
still results in significant mortality and health problems, which mostly occur due to lung immaturity. However,
current interventions to promote alveolar maturation do not treat the impact of premature birth on adult lung function,
which manifests itself as obstructive COPD-like features (Bolton et al. 2012). Understanding the various epithelial
and stromal cell populations on a molecular and functional level in healthy lungs during development and adulthood
is an essential requirement to develop translational solutions for lung repair and regeneration.
Currently, mouse embryonic lungs are widely used as a model to study human lung development. However, my
prospective supervisor, Dr Marko Nikolic, has shown that although 96% of orthologous genes are shared in mouse
and human embryonic tip stem cells (the primary epithelial stem cell population in the developing lung), there are
significant differences that most likely result in functional variabilities (Nikolic et. al, 2017). Furthermore, Dr Nikolic
has developed for the first time, a 3D organoid model system derived from lung tip stem cells obtained from human
foetal lung tissue, which can undergo long term self-renewal and differentiation towards bronchiolar and alveolar
fates using human-specific growth factors and signalling inhibitors (Nikolic et al. 2017a).
In addition, while prematurity and associated conditions are significant health problems, cellular and molecular
studies of foetal lung development remain unexplored during its late stages (20-40 post-conceptional weeks (pcw))
due to operational and ethical reasons (Nikolic et al. 2018). Dr Nikolic has gained ethical approval (REC 20/PR/0542)
to use normal lung tissue obtained from medically-indicated terminations of pregnancies between this time period.
Both the novel 3D organoid expertise and fresh lung tissue resource, will be invaluable resources that we aim to use
to study critical, previously unexplored phases of lung development.

I will study late foetal human lung development both from a functional perspective through the use of organoids as
well as through transcriptomics using state of the art scRNAseq technology. Unmasking the various cell types and
cell-cell interactions spatially and temporally during lung maturation, will allow me to propose and investigate
potentially effective therapies for premature lung maturation, as well as suggest novel regenerative therapies for endstage lung diseases in adults. This project has the potential to have a wide impact on developmental biology and
regenerative medicine.