IPF患者气道基底细胞的干性特征、定向分化及其调控机制研究

Idiopathic pulmonary fibrosis is now generally regarded as a consequence of multiple interacting genetic and environmental risk factors， with repetitive local micro-injuries to ageing alveolar epithelium playing a central role. These micro-injuries initiate aberrant epithelial– fibroblast communication，the induction of matrix-producing myofibroblasts，and considerable extracellular matrix accumulation and remodelling of lung interstitium. The epithelial cells lining the mammalian lung are subjected to constant interaction with the external environment，necessitating robust regeneration strategies to deal with cell loss due to natural turnover or damage arising from inhaled agents or disease. Although steady-state turnover of the epithelium appears to be relatively low in ideal situations， the vital role of the lung requires stem and progenitor cell populations that can promptly respond to the loss or damage of epithelial tissues.. Basal cells (BCs) lie adjacent to the epithelial basal lamina and constitute a pulmonary stem cell population. In humans，BCs are found throughout the pseudostratified epithelium of conducting airways and up to the terminal bronchioles. BCs display characteristic expression of TP63， KRT5，and the cell surface markers NGFR and ITGA6. Airway BCs are crucial for lung health and resilience，because of their ability to response to injury by virtue of their abilities to self-renew and to differentiate into alveolar epithelial cells，secretory cells，and ciliated cells. These capacities of basal progenitor cells to restore the airway to normal structure and function makes them indispensible for lung health and resilience.. BCs depletion or dysfunction has been proposed as one mechanism of fibrogenesis in idiopathic pulmonary fibrosis. In this study, we reveal the contribution of airway basal cells numbers，multipotentiality，and self-renewal function in regulating lung repair and fibrosis of IPF， as well as its modulation by signal pathway in differentiation， transdifferentiation，and dedifferentiation between lung stem cells and functional respiratory cell populations. This study presents the specific understanding of the stem cell populations within the pulmonary epithelium and use these stem cell populations to generate models for exploring lung function and disease. Although such approaches will take years to translate into clinical treatments，the current trajectory of pulmonary stem cell research provides a solid platform for future advances that will improve IPF patient prospects.

老化肺泡上皮局部由危险环境因子引发的反复微损伤新近被认为是特发性肺纤维化（IPF）的初始环节，继而上皮细胞与成纤维细胞间异常互动，诱导肌成纤维细胞产生基质并大量沉积于胞外，重构肺间质。上皮细胞静态更新与损伤后快速修复是气道上皮稳态维持的关键机制，可有效阻抑气道上皮老化或损伤的发生。近来，我们以及同行发现广泛分布于人气道的基底细胞（BCs）具有自我更新、多向分化与组织修复等干细胞功能特征，且是维护气道上皮稳态的绝对主力。故推测BCs功能异常极可能与IPF的发病关系密切。为此，课题组结合正在进行中的IPF临床研究，以BCs为切入点，探究BCs的干性功能对IPF发生、发展与转归的影响。重点围绕IPF患者：①气道上皮区域组织干细胞的分布与功能特点、②BCs向肺泡细胞定向分化的能力及其信号机制、③修复性BCs分子标识的筛选与初步鉴定等内容展开系列研究，为寻找IPF发病新机制与治疗新举措提供实验依据。

特发性肺纤维化（Idiopathic Pulmonary Fibrosis, IPF）是一种病因不明、慢性进行性、纤维化性间质性肺炎，发病机制不详。近年来，气道基底细胞（basal cells，BCs）的功能及其在IPF进展中的作用受到越来越多的关注。本项目围绕IPF患者气道上皮区域BCs的干性特征、功能特点及其对IPF 疾病进程的调控机制展开了系列研究。结果显示不同严重程度IPF患者Krt5+ /p63+ /ITGA6+ BCs具有与正常对照相似的增殖、分化能力及转录组学特征，可通过细胞互作等模式发挥促进组织修复及抗纤维化作用，有望成为治疗IPF的新一代“种子”细胞，具有良好的临床应用前景。本课题组据此开展了自体修复性气道上皮细胞经支气管镜下输注治疗特发性肺纤维化的临床研究，入组的两例患者显著获益，为IPF的控制和治疗带来了新思路。