Wang Di, Liu Hongbo, Bai Shuang, Zheng Xuejian, Zhao Li
Department of Pulmonary and Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China.
Stem Cell Res Ther. 2025 Feb 25;16(1):97. doi: 10.1186/s13287-025-04189-6.
Chronic obstructive pulmonary disease (COPD) is gaining increasing attention, with different subtypes being distinguished for separate research and treatment. The emphysema subtype is characterized by widespread alveolar destruction, which may be associated with aggravated alveolar damage and abnormal repair. Type II alveolar epithelial cells (AEC2s), known for their stem cell potential, have recently emerged as a promising target for COPD treatment. However, to date, few studies have elucidated the specific mechanisms by which AEC2s induce alveolar regeneration.
Lung tissue samples from COPD patients were collected, and bioinformatics analysis was used to identify expression profiles affecting the emphysema phenotype and target genes regulating AEC2 proliferation. In vitro models of smoke-induced injury and viral transfection were established to clarify the role of the target gene PARD6B in regulating AEC2s proliferation and transdifferentiation potential. Co-immunoprecipitation and mass spectrometry were employed to elucidate the specific regulatory mechanisms. Primary mouse AEC2s were isolated for 3D spheroid formation experiments to further validate the role of the target gene.
We observed impaired self-proliferation and enhanced transdifferentiation of AEC2s into AEC1s in lung tissues from COPD patients with emphysema subtype, which was associated with reduced expression of PARD6B. Interestingly, PARD6B primarily functioned as part of a complex in AEC2s. Mechanistically, we found that reduced levels of the PAR3-PARD6B-PRKCI complex could arrest the cell cycle of AEC2s in the G0-G1 phase, thereby impairing their self-proliferation.
Our findings reveal a novel regulatory mechanism for alveolar regeneration, highlighting a potential therapeutic target for managing the emphysema subtype of COPD.
慢性阻塞性肺疾病（COPD）日益受到关注，其不同亚型被区分开来用于单独的研究和治疗。肺气肿亚型的特征是广泛的肺泡破坏，这可能与肺泡损伤加重和异常修复有关。II型肺泡上皮细胞（AEC2s）以其干细胞潜能而闻名，最近已成为COPD治疗的一个有前景的靶点。然而，迄今为止，很少有研究阐明AEC2s诱导肺泡再生的具体机制。
收集COPD患者的肺组织样本，利用生物信息学分析确定影响肺气肿表型的表达谱和调节AEC2增殖的靶基因。建立烟雾诱导损伤和病毒转染的体外模型，以阐明靶基因PARD6B在调节AEC2s增殖和转分化潜能中的作用。采用免疫共沉淀和质谱法阐明具体的调控机制。分离原代小鼠AEC2s进行三维球体形成实验，以进一步验证靶基因的作用。
我们观察到，在患有肺气肿亚型的COPD患者的肺组织中，AEC2s的自我增殖受损，向AEC1s的转分化增强，这与PARD6B表达降低有关。有趣的是，PARD6B主要作为AEC2s中一个复合物的一部分发挥作用。从机制上讲，我们发现PAR3-PARD6B-PRKCI复合物水平降低会使AEC2s的细胞周期停滞在G0-G1期，从而损害其自我增殖。
我们的研究结果揭示了一种新的肺泡再生调控机制，突出了一个治疗COPD肺气肿亚型的潜在靶点。
