Division of Neonatology, Departments of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Los Angeles, CA 90033, USA.
Hastings Center for Pulmonary Research and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA 90033, USA.
Cells. 2020 Feb 7;9(2):384. doi: 10.3390/cells9020384.
WNT5a is a mainly "non-canonical" WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of Wnt5a disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (Wnt5a) and examined the specific role of Wnt5a during the saccular and alveolar phases of lung development. The lack of Wnt5a in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal Wnt5a inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of Wnt5a inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors Ror1 and Ror2 in alveolar myofibroblasts recapitulated the Wnt5a phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in Wnt5a lungs. Finally, we show that WNT5a is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.
WNT5a 是一种主要的“非经典”WNT 配体，其失调在特发性肺纤维化 (IPF)、慢性阻塞性肺疾病 (COPD) 和哮喘等肺部疾病中观察到。Wnt5a 的种系缺失会破坏胚胎肺发育。然而，WNT5a 的时间特异性功能仍不清楚。在这项研究中，我们生成了一个条件性缺失功能的小鼠模型 (Wnt5a)，并研究了 WNT5a 在肺囊泡和肺泡发育阶段的特定作用。囊泡期 Wnt5a 的缺失阻止了远端气道的扩张，并减弱了内皮细胞和肺泡上皮 I 型 (AT1) 细胞和肌成纤维细胞的分化。出生后 Wnt5a 的失活破坏了肺泡发生，产生类似于人类支气管肺发育不良 (BPD) 的表型。突变肺显示出低肺泡化，但内皮和上皮分化不受影响。Wnt5a 失活对肺泡发生的主要影响是肌成纤维细胞的分化和迁移，关键调节基因的表达减少。这些发现通过分离的肺成纤维细胞在体外得到了验证。肺泡肌成纤维细胞中 WNT5a 受体 Ror1 和 Ror2 的条件性失活再现了 Wnt5a 表型，表明肌成纤维细胞缺陷是 Wnt5a 肺中肺泡发生停止的主要原因。最后，我们表明 WNT5a 在人 BPD 肺样本中减少，表明 WNT5a 在 BPD 发病机制中的临床相关性和潜在作用。
