Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado, United States.
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States.
Am J Physiol Lung Cell Mol Physiol. 2023 Jun 1;324(6):L771-L782. doi: 10.1152/ajplung.00382.2022. Epub 2023 Apr 11.
Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the γ-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation toward the multiciliated lineage. Thus, γ-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here, we demonstrate the therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In summary, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases. Our findings show that low-dose, short-term topical or systemic γ-secretase inhibitor treatment may lead to restoration of multiciliated cells without toxicity and potentially improve epithelial function in a wide range of chronic lung diseases.
纤毛细胞缺失是包括囊性纤维化（CF）、哮喘和慢性阻塞性肺疾病（COPD）在内的慢性炎症性气道疾病中气道上皮重塑的标志。它破坏了黏液纤毛清除功能，从而促进了疾病的进展。有效的清除需要有一个最佳比例的纤毛细胞和分泌细胞。这是由 Notch 信号控制的，使得在两个相邻的细胞中，激活 Notch 的那个细胞成为分泌细胞，而避免 Notch 激活的那个细胞成为纤毛细胞。因此，通过抑制 Notch 信号传导的小分子 γ-分泌酶抑制剂（GSI），可以将 Notch 受体切割为信号激活的抑制剂，从而促使分化为纤毛细胞谱系。因此，GSI 治疗可能会减轻肺部疾病中的纤毛细胞缺失。在这里，我们通过 GSI LY450139（semagacestat）证明了对纤毛细胞的治疗性恢复。LY450139 在健康的原代人鼻上皮细胞（HNECs）分化过程中和成熟培养物中以剂量依赖性方式增加了纤毛细胞的数量，但在祖细胞早期上皮化时应用则没有影响。LY450139 不影响干细胞的增殖。基底和顶端给药同样有效。在健康成年小鼠中，LY450139 增加了纤毛细胞数量，且没有检测到毒性。LY450139 还增加了 CF HNECs 中的纤毛细胞数量并减少了异常的黏液分泌细胞，以及 IL-13 重塑的健康 HNECs 中的纤毛细胞数量。LY450139 在不干扰 CFTR 调节剂化合物活性的情况下，使 CF HNECs 中的纤毛细胞数量正常化。总之，我们证明 GSI 给药是一种有前途的治疗方法，可以恢复纤毛细胞并有可能改善广泛的慢性肺部疾病中的上皮功能。我们的研究结果表明，低剂量、短期局部或全身 GSI 治疗可能会导致纤毛细胞的恢复，而不会产生毒性，并有可能改善广泛的慢性肺部疾病中的上皮功能。
