Morrow Jarrett D, El-Husseini Zaid W, Yun Jeong H, Hersh Craig P
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA.
Harvard Medical School, Boston, MA.
medRxiv. 2025 Apr 3:2025.04.01.25325047. doi: 10.1101/2025.04.01.25325047.
Cigarette smoking has a significant impact on global health. Although cessation has positive health benefits, some molecular changes to intercellular communications may persist in the lung. In this study we created a framework to generate hypotheses by predicting altered cell-cell communication in smoker lungs using single-cell and spatial transcriptomic data.
We integrated publicly available lung single-cell transcriptomic data with spatial transcriptomic data from never-smoker and current-smoker lung tissue samples to create spatial transcriptomic data at virtual single-cell resolution by mapping individual cells from our lung scRNA-seq atlas to spots in the spatial transcriptomic data. Cell-cell communications altered in smoking were identified using the virtual single-cell transcriptomic data.
We identified pathways altered in the three current-smoker samples compared with the three never-smoker samples, including the up-regulated collagen pathway. We observed increased collagen pathway activity involving the ligands COL1A1 and COL1A2 in adventitial fibroblasts and decreased activity involving COL1A2 and COL6A3 in pericytes and myofibroblasts, respectively. We also identified other pathways with structural (e.g. Fibronectin-1), immune-related (e.g. MHC-II), growth factor (e.g. Pleiotrophin) and immunophilin (e.g. Cyclophilin A) roles.
In this study we inferred spatially proximal cell-cell communication between interacting cell types from spatial transcriptomics at virtual single-cell resolution to identify lung intercellular signaling altered in smoking. Our findings further implicate several pathways previously identified, and provide additional molecular context to inform future functional experiments and therapeutic avenues to mitigate pathogenic effects of smoking.
吸烟对全球健康有重大影响。尽管戒烟对健康有益，但肺内细胞间通讯的一些分子变化可能会持续存在。在本研究中，我们创建了一个框架，通过使用单细胞和空间转录组数据预测吸烟者肺部改变的细胞间通讯来生成假设。
我们将公开可用的肺单细胞转录组数据与来自从不吸烟者和当前吸烟者肺组织样本的空间转录组数据相结合，通过将我们的肺scRNA-seq图谱中的单个细胞映射到空间转录组数据中的斑点，以虚拟单细胞分辨率创建空间转录组数据。使用虚拟单细胞转录组数据识别吸烟中改变的细胞间通讯。
与三个从不吸烟者样本相比，我们在三个当前吸烟者样本中鉴定出改变的通路，包括上调的胶原蛋白通路。我们观察到外膜成纤维细胞中涉及配体COL1A1和COL1A2的胶原蛋白通路活性增加，而周细胞和成肌纤维细胞中分别涉及COL1A2和COL6A3的活性降低。我们还鉴定出其他具有结构（如纤连蛋白-1）、免疫相关（如MHC-II）、生长因子（如多效生长因子）和亲免蛋白（如亲环素A）作用的通路。
在本研究中，我们从虚拟单细胞分辨率的空间转录组学推断相互作用细胞类型之间的空间近端细胞间通讯，以识别吸烟中改变的肺细胞间信号传导。我们的发现进一步牵连了先前鉴定的几条通路，并提供了额外的分子背景，以为未来的功能实验和治疗途径提供信息，以减轻吸烟的致病影响。
