Our research

Our lungs are complex organs which consist of intricately interconnected tubes carrying air or blood (Rawlins, 2011). They provide a large internal surface area to allow gas exchange between the air and the blood whilst also maintaining a barrier which protects our body from inhaled pathogens and pollutants. The Rawlins lab studies lung development and maintenance (homeostasis) with the long-term aim of inducing regeneration, including restoration of the gas exchange surface, in people with diseased lungs (Lee and Rawlins, 2018).

Lung embryonic development

During embryonic development the lung forms by branching morphogenesis to initially make the bronchioles (conducting airways through which air is transported in and out of the body) and then the alveoli (gas exchange surface). Experiments in mice have shown that the most important epithelial progenitor cell is found at the branching tip of the epithelium where it self-renews throughout embryonic development. Descendants of the tip progenitor sequentially differentiate to conducting airway and then to alveolar fates as they exit the tip domain (Rawlins et al., 2009a). We have used ex vivo grafting experiments in mouse lungs to demonstrate that differentiation of the tip progenitor population is controlled by extrinsic signalling from the local environment (Laresgoiti et al., 2016). Interestingly, mouse genetics has shown us that environmental influences on the tip cells include circulating hormones, suggesting a that there is a global control of organ maturation in the developing embryo (Laresgoiti et al., 2016).

We routinely use mouse as a model system for studying human lung development because many of the cellular and molecular mechanisms are conserved between the two species. However, recent work shows that not all aspects of human lung development can be modelled in the mouse (Nikolic et al, 2018). We have shown that, similar to the mouse, the distal tip epithelium of the human embryonic lung contains a multipotent progenitor population (Nikolic et al., 2017). Moreover, the human and mouse tip cells are >95% identical at the transcriptional level, although with interesting differences in specific signalling molecules and transcription factors. This information allowed us to develop culture conditions for organoid culture of human embryonic lung tips (Nikolic et al., 2017). We are now using these organoids and “humanised” mouse lungs to study the cellular and molecular mechanisms of human lung development.

Adult airway homeostasis

Once the overall structure of the lung has been laid down by the embryonic tip progenitors, postnatal growth and adult maintenance relies on adult stem cell populations. In the mouse trachea the dividing cells are the basal cells and the secretory cells (Rawlins and Hogan, 2008; Rawlins et al., 2009b; Rawlins et al., 2007; Rock et al., 2009). We have collaborated with physicists to determine the quantitative contribution of basal and secretory cells to airway homeostasis. This work defined the homeostatic airway lineage, showing that basal cells are the long-term self-renewing stem cell population, whereas during homeostasis turn-over of the secretory cells is sufficient to account for production of new ciliated cells (Watson et al., 2015). This study also demonstrated the presence of a wide-spread luminal precursor cell located in the basal layer which we hypothesize is an adaptation to allow rapid airway repair following damage caused by influenza infection, or other insults.

Another significant question is how molecular cues control the steady-state maintenance of the airway epithelium. We have focused on the proliferation and self-renewal of the basal cells, as well as mechanisms regulating differentiation. We have used mouse genetics to show that FGFR2 (Fibroblast Growth Factor Receptor 2) signalling is necessary for tracheal basal cell self-renewal (Balasooriya et al., 2017). By contrast, we found that FGFR1 signalling activity unexpectedly limited the proliferation of steady-state basal cells by post-translationally activating the signalling inhibitor Sprouty2 (Balasooriya et al., 2016). FGFR1 is also necessary for ciliated cell differentiation in the mouse trachea (Balasooriya et al., 2016). Similarly, we have identified two transcription factors, Fank1 and Jazf1, that play a crucial role in the gene regulatory network controlling ciliated cell differentiation (Johnson et al., 2018). Further work focuses on determining how these pathways interact in homeostasis and repair settings.

Balasooriya, G., Goschorska, M., Piddini, E., Rawlins, E.L., 2017. FGFR2 is required for airway basal cell self-renewal and terminal differentiation. Development.

Balasooriya, G.I., Johnson, J.A., Basson, M.A., Rawlins, E.L., 2016. An FGFR1-SPRY2 Signaling Axis Limits Basal Cell Proliferation in the Steady-State Airway Epithelium. Dev Cell 37, 85-97.

Johnson, J.A., Watson, J.K., Nikolic, M.Z., Rawlins, E.L., 2018. Fank1 and Jazf1 promote multiciliated cell differentiation in the mouse airway epithelium. Biol Open 7.

Laresgoiti, U., Nikolic, M.Z., Rao, C., Brady, J.L., Richardson, R.V., Batchen, E.J., Chapman, K.E., Rawlins, E.L., 2016. Lung epithelial tip progenitors integrate glucocorticoid- and STAT3-mediated signals to control progeny fate. Development 143, 3686-3699.

Lee, J.H., Rawlins, E.L., 2018. Developmental mechanisms and adult stem cells for therapeutic lung regeneration. Dev Biol 433, 166-176.

Nikolic, M.Z., Caritg, O., Jeng, Q., Johnson, J.A., Sun, D., Howell, K.J., Brady, J.L., Laresgoiti, U., Allen, G., Butler, R., Zilbauer, M., Giangreco, A., Rawlins, E.L., 2017. Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids. Elife 6.

Nikolic, M.Z., Sun, D., Rawlins, E.L., 2018. lung development: recent progress and new challenges. Development 145.

Rawlins, E.L., 2011. The building blocks of mammalian lung development. Dev Dyn 240, 463-476.

Rawlins, E.L., Clark, C.P., Xue, Y., Hogan, B.L., 2009a. The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741-3745.

Rawlins, E.L., Hogan, B.L., 2008. Ciliated epithelial cell lifespan in the mouse trachea and lung. Am J Physiol Lung Cell Mol Physiol 295, L231-234.

Rawlins, E.L., Okubo, T., Xue, Y., Brass, D.M., Auten, R.L., Hasegawa, H., Wang, F., Hogan, B.L., 2009b. The role of Scgb1a1+ Clara cells in the long-term maintenance and repair of lung airway, but not alveolar, epithelium. Cell Stem Cell 4, 525-534.

Rawlins, E.L., Ostrowski, L.E., Randell, S.H., Hogan, B.L., 2007. Lung development and repair: Contribution of the ciliated lineage. Proc Natl Acad Sci U S A 104, 410-417.

Rock, J.R., Onaitis, M.W., Rawlins, E.L., Lu, Y., Clark, C.P., Xue, Y., Randell, S.H., Hogan, B.L., 2009. Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A 106, 12771-12775.

Watson, J.K., Rulands, S., Wilkinson, A.C., Wuidart, A., Ousset, M., Van Keymeulen, A., Gottgens, B., Blanpain, C., Simons, B.D., Rawlins, E.L., 2015. Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium. Cell Rep 12, 90-101.