Mobilising epithelial stem cells for human lung regeneration

在英国，慢性肺病每年造成600万天的住院日。慢性阻塞性肺疾病(COPD；包括肺气肿)和特发性肺纤维化(IPF)越来越被认为是上皮损伤和上皮再生失败的疾病，没有任何治疗方法可以逆转肺功能下降。上皮细胞和组织排列在全身器官和血管的外表面。不幸的是，人们对维持成人肺的成体干细胞群体知之甚少，尤其是不存在支持或增强上皮再生的策略。在我之前的研究中，我与剑桥大学的Emma Rawlins博士合作研究人类肺发育生物学。我们共同开发了一种新的细胞培养系统，首次允许肺干细胞的扩增。在接下来的几年里，我希望确立自己作为临床学术小组组长的地位，并有机会在UKRMP网络中工作，在教授的领导下工作。Janes和Watt是一个理想的机会，可以将我的基础研究转向我的患者的翻译终点。在伦敦大学学院呼吸学院的奖学金将使我有机会发展我的独立工作，接触成人临床标本和两个主要中心之间可用的大量小鼠模型。目的1：我打算开发从人类肺中扩增成人干细胞的方法。我将系统地评估培养基内个别因素对成人肺干细胞扩增的重要性。与CSCRM的合作将极大地促进这项工作，因为国王干细胞酒店与几家公司有合作关系，这些公司提供高内容成像平台，非常适合追踪干细胞的自我更新和分化。这些实验将确定在稳态期间协调上皮干细胞自我更新和分化的特定因素和途径。目标2：使用被确定为控制肺干细胞行为的因素，我将检查它们在活体(如小鼠)中的作用。目的3：最后，我将重点讨论基底干细胞的操作是否能起到保护作用。为了验证这一假设，我将使用气管损伤模型，因为这些模型与人类呼吸道再生最相关。这些发现将具有广泛的相关性，因为包括COPD、特发性肺纤维化和间质性肺疾病在内的许多慢性肺部疾病的发病机制被认为涉及重复的上皮损伤，导致上皮干细胞的损失。

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.