Research

1) Understanding epigenetic mechanisms underlying alveolar differentiation from early lung progenitor cells

Advances in single cell technology have allowed us to create detailed maps of cell populations in human organs, including the lungs. By combining various types of data, such as transcriptome and chromatic accessibility assays, we previously gained a deeper understanding of human lung development (Peng, Lim, Sun et al. 2022). However, there is still much to learn about the epigenetic mechanisms that go beyond transcription. Our goal is to investigate these mechanisms in alveolar differentiation and maturation, starting from early lung progenitor cells. We will use a lung organoid system that models diverse lung developmental stages in human, with cutting edge technologies, e.g. 3D genomics, DamID-seq, and/or in situ hybridization and spatial transcriptomics.

2) Defining alveolar differentiation and maturation using human lung organoid system 

Human alveolar type 2 (AT2) cells are cuboidal and polygonal in shape, making up approximately 5% of the alveoli's surface area. Their primary function is to synthesize and secrete surfactant proteins, which help reduce surface tension in the alveoli during homeostasis. It is essential to investigate the production and assembly of surfactant proteins in human AT2 cells because these processes may differ from those in rodents. Moreover, AT2 cells serve as 'bifunctional' stem cells. They have the ability to self-renew and regenerate AT1 cells in response to alveolar injury. Additionally, these cells are highly associated with various lung diseases, including COPD, fibrosis, lung tumors like adenocarcinomas, as well as diverse pathogenes. Therefore, here we aim to revisit human AT2 cells to clarify the definition of alveolar differentiation and maturation, and it physiological roles relevant to lung diseases.

3) Exploring congenital pulmonary disease mechanism in human

Human fetal tip/AT2 cells are highly proliferative and plastic in their cell fate decisions, depending on surrounding environmental cues. We previously describe that the tip cells at 19-23 pcw maintain the progenitor/AT2 cell features and differentiate to airway or AT1 cell lineages by modulation of Wnt and/or FGF signaling, as well as by mechanical cues (Li et al. 2021; Brownfield et al. 2022; Lim et al. 2023). However, in diseased condition such as congenital pulmonary airway malformation, there are multiple numbers of epithelial cysts formed in different sizes, that comprised of diverse spectrum of differentiating airway-like cells in a distal area that presumes to develop alveolar cell types. In this project, we will explore the unkwown cellular and molecular mechanisms controlling the cell fate of lung progenitor cells, using single cell and spatial transcriptomics and lung organoid modelling technology .

1) Unravelling saccular & alveolar stage development using non-human lung models

Human lung structures start to develop around 24 weeks of pregnancy, during the saccular and alveolar stages. However, studying how these alveolar structures organize during these stages is challenging because it's difficult to access human tissues. After 24 weeks, premature babies can survive with medical breathing support, making it hard to gather data directly from human lungs. As an alternative, researchers consider using non-human lung models like marmosets and mini-pigs, as their lung architecture is highly similar to humans, with alveolarized respiratory bronchioles and branching patterns. Here we aim to investigate the developmental mechanism of human alveoli using these non-human lung models.

2) Modelling functional alveoli structures in vitro in 3D comprised of alveolar type 1 and 2 cells as well as non-epithelial cell types

From the knowledge gained from non-human lung models, we are aiming to develop modelling technology to generate alveoli structures in vitro in 3D condition. To get closer to this goal, we are going to adopt tissue engineering technology in collaboration with material science teams in Korea. In the end, this model can be utilized to simulate lung diseases associated with the alveolar functions, such as COPD.