Mobilising epithelial stem cells for human lung regeneration

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Chronic lung disease is responsible for 6 million inpatient bed days a year in the UK. Chronic obstructive pulmonary disease (COPD; including emphysema) and idiopathic pulmonary fibrosis (IPF) are increasingly recognised as diseases of epithelial damage and failed epithelial regeneration, with no treatments that reverse lung function decline. Epithelial cells and tissue line the outer surfaces of organs and blood vessels throughout the body. Unfortunately, a limited amount is known about adult stem cell populations that maintain adult human lung and in particular, strategies to support or enhance epithelial regeneration do not exist. During my prior research, I worked with Dr Emma Rawlins at Cambridge University on human lung developmental biology. Together, we developed a novel cell culture system which allowed the expansion of lung stem cells for the first time. Over the coming years, I hope to establish myself as a clinical academic group leader and the opportunity to work within the UKRMP network under Profs. Janes and Watt is an ideal opportunity to turn my basic research towards translational end points for my patients. A Fellowship at UCL Respiratory would allow me the opportunity to develop my independent work with access to adult human clinical specimens and a multitude of murine models available between the two main centres.Aim1: I intend to develop methods to expand adult stem cells from the human lung. I will systematically evaluate the importance of individual factors within the culture medium for the expansion of adult lung stem cells. This work will be greatly facilitated by collaboration with CSCRM as the Kings Stem Cell Hotel has partnership arrangements with several companies that provide high-content imaging platforms which is ideally suited for tracking stem cell self-renewal and differentiation. These experiments will define specific factors and pathways that orchestrate epithelial stem cell self-renewal and differentiation during homeostasis.Aim 2: Using the factors identified as controlling lung stem cell behaviour, I will examine their role in living organisms such as mice. Aim 3: Finally, I will focus on whether manipulation of basal stem cells can be protective against injury. To test this hypothesis, I will use tracheal injury models as these are most relevant to human airway regeneration. These findings will be of broad relevance given that the pathogenesis of many chronic lung diseases, including COPD, idiopathic pulmonary fibrosis and interstitial lung disease are thought to involve repetitive epithelial injury resulting in a loss of epithelial stem cells.