Tabasi Mohsen, Chen Nathaniel, Sajjan Umadevi
Center for Inflammation and Lung Research, Lewis-Katz Medical School, Temple University, Philadelphia, PA 19140, USA.
Department of Microbiology, Immunology and Inflammation, Lewis-Katz Medical School, Temple University, Philadelphia, PA 19140, USA.
Cells. 2025 Apr 5;14(7):549. doi: 10.3390/cells14070549.
Airway basal cells from chronic obstructive pulmonary disease patients show a reduction in expression and generate an abnormal airway epithelium. Because the specific role of HOXA1 in airway basal cells is not known, we investigated the contribution of HOXA1 in the generation of the airway epithelium, which depends on basal cell proliferation, polarization, and differentiation. Airway stem cells were transduced with an inducible shRNA lentivector to knock down in either proliferating cells or100% confluent cells. The bronchial epithelium expresses HOXA1 near the basement membrane, likely representing basal cells. knockdown in proliferating basal cells attenuated cell proliferation. knockdown in confluent monolayers of basal cells generated an abnormal airway epithelium characterized by goblet cell hyperplasia and an inflammatory phenotype. Compared to the control, HOXA1 knockdown cells showed a decrease in transepithelial resistance, localization of occludin and E-cadherin to the intercellular junctions, reduced expression of occludin but not E-cadherin, and increased expression of TNF-α. Blocking TNF-α increased the expression of occludin in HOXA1 K/D cells. Based on these results, we conclude that HOXA1 plays an important role in cell proliferation, polarization, and differentiation, which are essential steps in airway epithelial generation. Additionally, HOXA1 may regulate occludin expression by inhibiting TNF-α expression.
慢性阻塞性肺疾病患者的气道基底细胞表达降低，并产生异常的气道上皮。由于HOXA1在气道基底细胞中的具体作用尚不清楚，我们研究了HOXA1在气道上皮生成中的作用，气道上皮生成依赖于基底细胞的增殖、极化和分化。用可诱导的短发夹RNA慢病毒载体转导气道干细胞，以敲除增殖细胞或100%汇合细胞中的HOXA1。支气管上皮在基底膜附近表达HOXA1，可能代表基底细胞。在增殖的基底细胞中敲除HOXA1会减弱细胞增殖。在汇合的基底细胞单层中敲除HOXA1会产生异常的气道上皮，其特征为杯状细胞增生和炎症表型。与对照组相比，敲除HOXA1的细胞跨上皮电阻降低，闭合蛋白和E-钙黏蛋白定位于细胞间连接，闭合蛋白表达减少但E-钙黏蛋白未减少，且肿瘤坏死因子-α（TNF-α）表达增加。阻断TNF-α可增加敲除HOXA1细胞中闭合蛋白的表达。基于这些结果，我们得出结论，HOXA1在细胞增殖、极化和分化中起重要作用，而这些是气道上皮生成的关键步骤。此外，HOXA1可能通过抑制TNF-α表达来调节闭合蛋白的表达。
