Basal Cell-derived WNT7A Promotes Fibrogenesis at the Fibrotic Niche in Idiopathic Pulmonary Fibrosis.
Basal Cell-derived WNT7A Promotes Fibrogenesis at the Fibrotic Niche in Idiopathic Pulmonary Fibrosis.
复制标题
基底细胞源性 WNT7A 促进特发性肺纤维化纤维化微环境的纤维形成。
DOI：
10.1165/rcmb.2022-0074oc
复制
发表时间：
2023
影响因子：
6.4
通讯作者：
Jiang,Dianhua
中科院分区：
文献类型：
--
作者：
Huang,Guanling;Liang,Jiurong;Huang,Kevin;Liu,Xue;Taghavifar,Forough;Yao,Changfu;Parimon,Tanyalak;Liu,Ningshan;Dai,Kristy;Aziz,Adam;Wang,Yizhou;Waldron,RichardT;Mou,Hongmei;Stripp,Barry;Noble,PaulW;Jiang,Dianhua
上皮完整性丧失、细支气管化和成纤维细胞活化是特发性肺纤维化（IPF）的关键特征。IPF中基底细胞样细胞的长期积累可能影响纤维化生态位，从而促进纤维形成。为了研究它们在IPF中的作用，从IPF外植体和健康供体肺组织中分离基底细胞。单细胞RNA测序用于评估基底细胞中差异表达的基因。用sLP-mCherry生态位标记系统证明了基底细胞和生态位的相互作用。使用Luminex测定来评估由基底细胞分泌的细胞因子。研究了基底细胞在成纤维细胞活化中的作用。使用三维类器官培养测定来询问基底细胞对AEC 2（2型肺泡上皮细胞）更新能力的影响。微扰用于研究WNT 7A在体外和在体内重复博来霉素模型中的功能。我们发现WNT 7A在基底样细胞中高度特异性表达。基底细胞分泌的蛋白质可以被邻近的成纤维细胞和AEC 2捕获。基底细胞或基底细胞条件培养基通过WNT 7A激活成纤维细胞。基底细胞衍生的WNT 7A抑制三维类器官培养物中的AEC 2祖细胞更新。针对WNT 7A的中和抗体或Frizzled信号传导的小分子抑制剂在小鼠中消除基底细胞诱导的成纤维细胞活化并减弱肺纤维化。总之，基底细胞和基底细胞衍生的WNT 7A是纤维化小生境的关键组分，在IPF进展中提供了基底细胞的独特非干细胞功能和IPF的新靶向策略。
Loss of epithelial integrity, bronchiolarization, and fibroblast activation are key characteristics of idiopathic pulmonary fibrosis (IPF). Prolonged accumulation of basal-like cells in IPF may impact the fibrotic niche to promote fibrogenesis. To investigate their role in IPF, basal cells were isolated from IPF explant and healthy donor lung tissues. Single-cell RNA sequencing was used to assess differentially expressed genes in basal cells. Basal cell and niche interaction was demonstrated with the sLP-mCherry niche labeling system. Luminex assays were used to assess cytokines secreted by basal cells. The role of basal cells in fibroblast activation was studied. Three-dimensional organoid culture assays were used to interrogate basal cell effects on AEC2 (type 2 alveolar epithelial cell) renewal capacity. Perturbation was used to investigate WNT7A functionin vitroand in a repetitive bleomycin modelin vivo. We found that WNT7A is highly and specifically expressed in basal-like cells. Proteins secreted by basal cells can be captured by neighboring fibroblasts and AEC2s. Basal cells or basal cell-conditioned media activate fibroblasts through WNT7A. Basal cell–derived WNT7A inhibits AEC2 progenitor cell renewal in three-dimensional organoid cultures. Neutralizing antibodies against WNT7A or a small molecule inhibitor of Frizzled signaling abolished basal cell-induced fibroblast activation and attenuated lung fibrosis in mice. In summary, basal cells and basal cell–derived WNT7A are key components of the fibrotic niche, providing a unique non-stem cell function of basal cells in IPF progression and a novel targeting strategy for IPF.