Emma Rawlins PhD, MRC Research Fellow, Member of the Department of Pathology.
Stem and progenitor cells in the mammalian lung
Our lungs have a complex three-dimensional structure which facilitates respiration and host defence. Building this structure requires that lung embryonic progenitor cells produce the correct types and numbers of cells in the correct sequence. How is this controlled? And how is the final structure maintained in the adult? Our lab investigates the cellular and molecular mechanisms which control stem and progenitor cell fate decisions in the developing and adult lungs. Key unanswered questions include what mechanisms control the decision of lung progenitors to self-renew or to differentiate? Which pathways are required for cell lineage specification in the lung? Our approach is to use the power of mouse genetics to understand the control of lung progenitor cell behaviour at the single cell level.This allows individual cells to be analysed quantitatively in vivo, or by live-imaging in organ culture systems.
We have previously shown that in the embryonic lung there is a population of Id2+ multipotent epithelial progenitor cells located at the distal tips of the budding epithelium.The developmental potential, or competence, of these cells changes during embryogenesis.At the same time the cells undergo a change in gene expression pattern.We are currently exploring the cellular and molecular basis of this change in competence.
The identity of the epithelial stem and progenitor cells in the postnatal lung remains controversial. Our previous work has shown that each anatomical region (trachea, bronchioles, alveoli) has its own progenitor cell population and that the behaviour of these progenitors can change in response to local conditions. Our current postnatal work focuses on:
• Better characterising the adult lung progenitor cells. This includes testing whether progenitor cell behaviour is widespread or there are stem cells. • Understanding the genetic regulation of the progenitors under several different physiologically-relevant conditions. In particular, we are focusing on genes that are hypothesised to control the decision to self-renew or differentiate.
Our long-term vision is to combine the developmental and homeostatic aspects of our work to develop new approaches to ameliorate human pulmonary disease. In particular, we are working towards being able specifically to direct endogenous lung stem cells to generate any lung epithelial cell type.
• Rawlins EL, Okubo T, Xue Y, Brass DM, Auten RL, Hasegawa H,Wang F and Hogan BLM (2009)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 EL, Clark CP, Xue Y and Hogan BLM (2009) The Id2 distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development136 3741-3745
• Rawlins EL (2011) The building blocks of mammalian lung development. Developmental Dynamics 240 463-76
• Watson JK, Rulands S, Wilkinson AC, Wuidart A, Ousset M, Van Keymeulen A, Gottgens B, Blanpain C, Simons BD and Rawlins EL (2015) Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow Turnover Airway Epithelium. Cell Reports 12, 1-12
EuroStemCell Factsheet: Lung stem cells in health, repair and disease