Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis.
Reciprocal interactions between alveolar progenitor dysfunction and aging promote lung fibrosis.
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DOI：
10.7554/elife.85415
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发表时间：
2023-06-14
期刊：
影响因子：
7.7
通讯作者：
Jiang D
中科院分区：
文献类型：
--
作者：
Liang J;Huang G;Liu X;Liu N;Taghavifar F;Dai K;Yao C;Deng N;Wang Y;Chen P;Hogaboam C;Stripp BR;Parks WC;Noble PW;Jiang D
衰老是特发性肺纤维化（IPF）的关键风险因素。2型肺泡上皮细胞（AEC 2）的功能障碍和丧失伴再生失败是IPF发病机制中的重要因果事件，尽管其再生失败和死亡的确切机制仍不清楚。为了系统地检查AEC 2在衰老和肺损伤后的基因组程序变化，我们对来自未受伤或博来霉素损伤的年轻和年老小鼠以及IPF患者和健康供体的肺的肺上皮细胞进行了无偏倚的单细胞RNA-seq分析。我们根据它们的基因特征鉴定了三个AEC 2亚群。AEC 2 -1亚群主要存在于未损伤肺中，而AEC 2 -2和AEC 2 -3亚群则出现于损伤肺中，并随增龄而增加。在功能上，AEC 2亚群与祖细胞更新相关。衰老增强了炎症、应激反应、衰老和凋亡相关基因的表达。有趣的是，即使在年轻小鼠中，肺损伤也增加了AEC 2中与衰老相关的基因表达。衰老和损伤的协同作用导致损伤后老年小鼠肺中AEC 2恢复受损。此外，我们还从人肺中鉴定了三个AEC 2亚群，它们与小鼠AEC 2形成了三个相似的亚群。IPF AEC 2显示出与博来霉素损伤的老年小鼠肺的AEC 2亚群相似的基因组特征。总而言之，我们在转录组和功能分析中发现了衰老和AEC 2损伤的协同作用，从而促进了纤维化。这项研究为衰老和肺损伤之间的相互作用提供了新的见解，与患病的IPF AEC 2细胞有有趣的重叠。
Aging is a critical risk factor in idiopathic pulmonary fibrosis (IPF). Dysfunction and loss of type 2 alveolar epithelial cells (AEC2s) with failed regeneration is a seminal causal event in the pathogenesis of IPF, although the precise mechanisms for their regenerative failure and demise remain unclear. To systematically examine the genomic program changes of AEC2s in aging and after lung injury, we performed unbiased single-cell RNA-seq analyses of lung epithelial cells from uninjured or bleomycin-injured young and old mice, as well as from lungs of IPF patients and healthy donors. We identified three AEC2 subsets based on their gene signatures. Subset AEC2-1 mainly exist in uninjured lungs, while subsets AEC2-2 and AEC2-3 emerged in injured lungs and increased with aging. Functionally, AEC2 subsets are correlated with progenitor cell renewal. Aging enhanced the expression of the genes related to inflammation, stress responses, senescence, and apoptosis. Interestingly, lung injury increased aging-related gene expression in AEC2s even in young mice. The synergistic effects of aging and injury contributed to impaired AEC2 recovery in aged mouse lungs after injury. In addition, we also identified three subsets of AEC2s from human lungs that formed three similar subsets to mouse AEC2s. IPF AEC2s showed a similar genomic signature to AEC2 subsets from bleomycin-injured old mouse lungs. Taken together, we identified synergistic effects of aging and AEC2 injury in transcriptomic and functional analyses that promoted fibrosis. This study provides new insights into the interactions between aging and lung injury with interesting overlap with diseased IPF AEC2 cells.