Maurat Elise, Raasch Katharina, Leipold Alexander M, Henrot Pauline, Zysman Maeva, Prevel Renaud, Trian Thomas, Krammer Tobias, Bergeron Vanessa, Thumerel Matthieu, Nassoy Pierre, Berger Patrick, Saliba Antoine-Emmanuel, Andrique Laetitia, Recher Gaëlle, Dupin Isabelle
Univ-Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, CIC1401, Pessac, France.
INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, CIC1401, Pessac, France.
Eur Respir J. 2024 Dec 5;64(6). doi: 10.1183/13993003.00562-2024. Print 2024 Dec.
Airflow limitation is the hallmark of obstructive pulmonary diseases, with the distal airways representing a major site of obstruction. Although numerous models of bronchi already exist, there is currently no culture system for obstructive diseases that reproduces the architecture and function of small airways. Here, we aimed to engineer a model of distal airways to overcome the limitations of current culture systems.
We developed a so-called bronchioid model by encapsulating human bronchial adult stem cells derived from clinical samples in a tubular scaffold made of alginate gel.
This template drives the spontaneous self-organisation of epithelial cells into a tubular structure. Fine control of the level of contraction is required to establish a model of the bronchiole, which has a physiologically relevant shape and size. Three-dimensional imaging, gene expression and single-cell RNA-sequencing analysis of bronchioids made of bronchial epithelial cells revealed tubular organisation, epithelial junction formation and differentiation into ciliated and goblet cells. Ciliary beating was observed, at a decreased frequency in bronchioids made of cells from COPD patients. The bronchioid could be infected by rhinovirus. An air-liquid interface was introduced that modulated gene expression.
Here, we provide a proof of concept of a perfusable bronchioid with proper mucociliary and contractile functions. The key advantages of our approach, such as the air‒liquid interface, lumen accessibility, recapitulation of pathological features and possible assessment of clinically relevant end-points, will make our pulmonary organoid-like model a powerful tool for preclinical studies.
气流受限是阻塞性肺疾病的标志，远端气道是主要阻塞部位。尽管已经存在众多支气管模型，但目前尚无用于阻塞性疾病的培养系统能够重现小气道的结构和功能。在此，我们旨在构建一种远端气道模型，以克服当前培养系统的局限性。
我们通过将源自临床样本的人支气管成体干细胞封装在由藻酸盐凝胶制成的管状支架中，开发了一种所谓的类支气管模型。
该模板驱动上皮细胞自发自组织形成管状结构。需要精确控制收缩水平以建立具有生理相关形状和大小的细支气管模型。对由支气管上皮细胞制成的类支气管进行三维成像、基因表达和单细胞RNA测序分析，揭示了管状组织、上皮连接形成以及向纤毛细胞和杯状细胞的分化。观察到纤毛摆动，在慢性阻塞性肺疾病（COPD）患者细胞制成的类支气管中频率降低。类支气管可被鼻病毒感染。引入气液界面可调节基因表达。
在此，我们提供了一种具有适当黏液纤毛和收缩功能的可灌注类支气管的概念验证。我们方法的关键优势，如气液界面、管腔可及性、病理特征的重现以及对临床相关终点的可能评估，将使我们的类肺器官模型成为临床前研究的有力工具。
