Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
EMBO J. 2019 Jun 17;38(12). doi: 10.15252/embj.2019102099. Epub 2019 Apr 26.
Bronchioalveolar stem cells (BASCs) are a potential source for lung regeneration, but direct evidence for a multipotential lineage contribution during homeostasis and disease is critically missing, since specific genetic labeling of BASCs has not been possible. We developed a novel cell tracing approach based on intein-mediated assembly of newly engineered split-effectors, allowing selective targeting of dual-marker expressing BASCs in the mouse lung. RNA sequencing of isolated BASCs demonstrates that BASCs show a distinct transcriptional profile, characterized by co-expression of bronchiolar and alveolar epithelial genes. We found that BASCs generate the majority of distal lung airway cells after bronchiolar damage but only moderately contribute to cellular turnover under homeostatic conditions. Importantly, DTA-mediated ablation of BASCs compromised proper regeneration of distal airways. The study defines BASCs as crucial components of the lung repair machinery and provides a paradigmatic example for the detection and manipulation of stem cells that cannot be recognized by a single marker alone.
肺内气道干细胞（BASCs）是肺再生的潜在来源，但在稳态和疾病过程中，缺乏直接的多能谱系贡献证据，因为无法对 BASCs 进行特异性遗传标记。我们开发了一种新的细胞示踪方法，基于内含子介导的新型分裂效应子的组装，允许在小鼠肺中选择性靶向双标记表达的 BASCs。分离的 BASCs 的 RNA 测序表明，BASCs 表现出独特的转录谱，特征是支气管和肺泡上皮基因的共表达。我们发现，BASCs 在支气管损伤后产生大多数远端肺气道细胞，但在稳态条件下对细胞更新的贡献适中。重要的是，DTA 介导的 BASCs 消融会损害远端气道的正常再生。该研究将 BASCs 定义为肺修复机制的关键组成部分，并为检测和操纵不能仅用单个标记识别的干细胞提供了一个典范示例。
