Abstract：
Patients with cystic fibrosis (CF) experience severe lung disease, including persistent infections, inflammation, and irreversible fibrotic remodeling of the airways. Although therapy with transmembrane conductance regulator (CFTR) protein modulators reached optimal results in terms of CFTR rescue, lung transplant remains the best line of care for patients in an advanced stage of CF. Indeed, chronic inflammation and tissue remodeling still represent stumbling blocks during treatment, and underlying mechanisms are still unclear. Nowadays, animal models are not able to fully replicate clinical features of the human disease and the conventional in vitro models lack a stromal compartment undergoing fibrotic remodeling. To address this gap, we show the development of a 3D full-thickness model of CF with a human bronchial epithelium differentiated on a connective airway tissue. We demonstrated that the epithelial cells not only underwent mucociliary differentiation but also migrated in the connective tissue and formed gland-like structures. The presence of the connective tissue stimulated the pro-inflammatory behaviour of the epithelium, which activated the fibroblasts embedded into their own extracellular matrix (ECM). By varying the composition of the model with CF epithelial cells and a CF or healthy connective tissue, it was possible to replicate different moments of CF disease, as demonstrated by the differences in the transcriptome of the CF epithelium in the different conditions. The possibility to faithfully represent the crosstalk between epithelial and connective in CF through the full thickness model, along with inflammation and stromal activation, makes the model suitable to better understand mechanisms of disease genesis, progression, and response to therapy.
摘要：
囊性纤维化（CF）患者经历严重的肺部疾病，包括持续性感染,炎症,和气道的不可逆纤维化重塑。尽管使用跨膜传导调节剂（CFTR）蛋白调节剂的治疗在CFTR挽救方面达到最佳效果，肺移植仍然是CF晚期患者的最佳治疗方法。的确,慢性炎症和组织重塑仍然是治疗过程中的绊脚石，和潜在的机制仍不清楚。如今,动物模型不能完全复制人类疾病的临床特征,并且常规体外模型缺乏经历纤维化重塑的基质区室。为了解决这个差距，我们显示了CF的3D全厚度模型的开发，该模型具有在结缔组织上分化的人支气管上皮。我们证明，上皮细胞不仅经历了粘膜纤毛分化，而且在结缔组织中迁移并形成腺样结构。结缔组织的存在刺激了上皮的促炎行为，它激活了嵌入到自己的细胞外基质（ECM）中的成纤维细胞。通过改变CF上皮细胞和CF或健康结缔组织的模型组成，有可能复制CF疾病的不同时刻，如在不同条件下CF上皮转录组的差异所证明的。通过全厚度模型忠实地表示CF中上皮和结缔组织之间的串扰的可能性，伴随着炎症和基质激活，使模型适合更好地理解疾病发生的机制，programming,和对治疗的反应。
