Hypoxia-inducible factor 2 regulates alveolar regeneration after repetitive injury in three-dimensional cellular and in vivo models

IF 15.8 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-01-08 DOI:10.1126/scitranslmed.adk8623

A. Scott McCall, Sergey Gutor, Hari Tanjore, Ankita Burman, Taylor Sherrill, Micah Chapman, Carla L. Calvi, David Han, Jane Camarata, Raphael P. Hunt, David Nichols, Nicholas E. Banovich, William E. Lawson, Jason J. Gokey, Jonathan A. Kropski, Timothy S. Blackwell

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional “aberrant” epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER–traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.

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缺氧诱导因子2在三维细胞和体内模型中调控重复损伤后肺泡再生

特发性肺纤维化（IPF）是一种进行性间质性肺疾病，其中重复性上皮损伤和肺泡修复不完全导致纤维化中间/过渡性“异常”上皮细胞状态的积累。导致远端肺异常上皮群体出现和持续存在的机制尚不完全清楚。通过分析来自IPF患者和重复性肺上皮损伤小鼠模型的单细胞RNA测序（scRNA-seq）数据，我们发现这些异常上皮细胞中的缺氧诱导因子（HIF）信号持续激活。使用小鼠遗传谱系追踪策略和scRNA-seq，我们发现这些疾病出现的异常上皮细胞主要来自气道来源（Scgb1a1-CreER追踪）祖细胞，并表现出Hif2a激活的转录程序。在气管内重复使用博莱霉素治疗的小鼠中，从气道来源的祖细胞中删除Epas1 （Hif2a）而不是Hif1a，或使用小分子HIF2抑制剂PT-2385，使用预防和拯救方法，减轻实验性肺纤维化，减少异常上皮细胞的外观，促进肺泡修复。在小鼠肺泡类器官中，基因或药物抑制Hif2可促进气道源性上皮祖细胞的肺泡分化。此外，用PT-2385处理人远端肺类器官可提高集落形成效率，增强肺泡2型上皮细胞成熟的蛋白质和转录标记物，并阻止异常上皮细胞的出现。总之，这些研究表明，HIF2激活驱动重复损伤后异常上皮群体的出现，靶向HIF2抑制可能是促进IPF和其他间质性肺疾病的功能性肺泡修复的有效治疗策略。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.