Evidence map›Paper›PMID 40380180›Full record

ArticleRespiratory research2025

Inhibition of DLK1 regulates AT2 differentiation and alleviates established pulmonary fibrosis by upregulating TTF-1/CLDN6.

Yinzhen Li, Chen Zhou, Jiaxing Sun, Enhao Wang, Chunmei Wang, Xuan Liu, Xiaohui Zhou, Jianwen Bai

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In one paragraph

Article in Respiratory research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1 · What the graph read from it

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3 · Its place in the literature

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1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

8 authors.

Yinzhen Li *Department of Emergency Medicine and Critical Care, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
Chen Zhou *Research Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
Jiaxing SunDepartment of Respiratory and Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, 266071, China.
Enhao WangResearch Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
Chunmei WangDepartment of Emergency Medicine and Critical Care, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
Xuan LiuResearch Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China.
Xiaohui ZhouResearch Center for Translational Medicine, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China. zxh100@tongji.edu.cn.
Jianwen BaiDepartment of Emergency Medicine and Critical Care, School of Medicine, Shanghai East Hospital, Tongji University, Shanghai, 200092, China. baijianwen1019@163.com.

Funding

National Natural Science Foundation of China 82070073, 81670067 and 82003182Shanghai Pudong New Area Summit PWYgf2021-03
6 · The paper itself

Abstract

backgroundIdiopathic pulmonary fibrosis (IPF) is a devastating age-related disease with unknown causes and limited effective treatment. Dysregulation of Alveolar Type 2 (AT2) cells facilitates the initiation of IPF. While differentiation of AT2 into AT1 is necessary for restoring alveolar epithelium. Delta-like non-canonical Notch ligand 1 (DLK1) is a paternally imprinted gene that controls stem cell differentiation. However, the role of DLK1 on AT2 during lung fibrosis remains unclear.

methodsLung specimens from 11 patients with IPF or contemporaneous non-IPF controls were collected to determine DLK1 expression. The murine model of bleomycin (BLM) -induced pulmonary fibrosis and cell models of transforming growth factor-beta (TGF-β)-treated A549, MRC5 or primary lung fibroblasts (PLFs) were established. Epithelial DLK1 knockdown mice were constructed by an alveolar epithelial -specific adeno-associated virus (AAV) 6 vector system. Besides, primary AT2 cells were isolated from SPC-EGFP mice and cultured in 2D and 3D organoids.

resultsIn the present study, we found that DLK1, predominantly expressed in AT2 cells, was upregulated in both IPF lungs and the murine fibrotic lung induced by BLM. AAV-mediated epithelial-specific knockdown of DLK1 promoted the proliferation and differentiation of AT2 into AT1 and alleviated the established lung fibrosis in murine BLM-induced models. In addition, recombinant DLK1 inhibited the renewal of AT2 and aggravated TGF-β-induced fibrosis in vitro, which can be rescued by si-DLK1 intervention. Mechanically, conditional knockdown of DLK1 upregulated TTF-1, a transcriptional factor that controls AT2 differentiation via CLDN6.

conclusionDLK1 inhibition regulates AT2 differentiation and contributes to the mitigation of established fibrosis via TTF-1/CLDN6 pathway, which suggests that DLK1 may be a therapeutic target for IPF.

Indexed as

Alveolar Epithelial CellsCalcium-Binding ProteinsCell DifferentiationIdiopathic Pulmonary FibrosisIntercellular Signaling Peptides and ProteinsMembrane ProteinsThyroid Nuclear Factor 1AnimalsBleomycinCells, CulturedDisease Models, AnimalFemaleHumansMaleMiceMice, Inbred C57BLBleomycinCalcium-Binding ProteinsDLK1 protein, humanDlk1 protein, mouseIntercellular Signaling Peptides and ProteinsMembrane ProteinsThyroid Nuclear Factor 1Alveolar type 2 cellsCell differentiationClaudin 6Delta-like non-canonical Notch ligand 1Idiopathic pulmonary fibrosis

Identifiers

PMID40380180
PMCPMC12085069

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.