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Volume 14
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10.3390/cells14231869
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Reciprocal Paracrine Signaling and Dynamic Coordination of Transitional States in the Alveolar Epithelial Type 2 Cells and Associated Alveolar Lipofibroblasts During Homeostasis, Injury and Repair

by
Georgios-Dimitrios Panagiotidis
1,2,3,4,†,
Mengqing Chen
5,†,
Xiuyue Yang
6,7,
Manuela Marega
1,2,3,4,
Stefano Rivetti
1,2,3,4,
Xuran Chu
6,7 and
Saverio Bellusci
8,9,*
1
Department of Medicine V, Internal Medicine, Infectious Diseases and Infection Control, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen (JLU), 35392 Giessen, Germany
2
Cardio-Pulmonary Institute (CPI), 35392 Giessen, Germany
3
Institute for Lung Health (ILH), 35392 Giessen, Germany
4
Department of Medicine II, Internal Medicine, Pulmonary and Critical Care, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392 Giessen, Germany
5
Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
6
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China
7
Oujiang Laboratory, Zhejiang Lab for Regenerative Medicine, Vision and Brain Health, Wenzhou 325035, China
8
Department of Pulmonary and Critical Care Medicine, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, China
9
Laboratory of Extracellular Matrix and Regeneration, Justus-Liebig University Giessen (JLU), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL) and Institute for Lung Health (ILH), 35392 Giessen, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2025, 14(23), 1869; https://doi.org/10.3390/cells14231869
Submission received: 14 October 2025 / Revised: 18 November 2025 / Accepted: 22 November 2025 / Published: 26 November 2025
(This article belongs to the Special Issue Mechanisms of Lung Growth and Regeneration)
Review Reports Versions Notes

Abstract

Single-cell RNA-sequencing has transformed our understanding of alveolar epithelial type 2 (AT2) cells and alveolar lipofibroblasts (LIFs) during lung injury and repair. Both cell types undergo dynamic transitions through intermediate states that determine whether the lung proceeds toward regeneration or fibrosis. Emerging evidence highlights reciprocal paracrine signaling between AT2/AT1 transitional cells and LIF-derived myofibroblasts (aMYFs) as a key regulatory axis. Among these, amphiregulin (AREG)–EGFR signaling functions as a central profibrotic pathway whose inhibition can restore alveolar differentiation and repair. The human WI-38 fibroblast model provides a practical platform to study the reversible LIF–MYF switch and screen antifibrotic and pro-regenerative compounds. Candidate therapeutics including metformin, haloperidol and FGF10 show promise in reprogramming fibroblast and epithelial states through metabolic and signaling modulation. Integrating WI-38-based assays, alveolosphere co-cultures, and multi-omics profiling offers a translational framework for identifying interventions that halt fibrosis and actively induce lung regeneration. This review highlights a unifying framework in which epithelial and mesenchymal plasticity converge to define repair outcomes and identifies actionable targets for promoting alveolar regeneration in chronic lung disease.
Keywords: alveolar regeneration; AT2/AT1 transitional cells; lipofibroblast–myofibroblast (LIF–MYF) switch; AREG–EGFR signaling; fibrosis resolution; WI-38 fibroblast model alveolar regeneration; AT2/AT1 transitional cells; lipofibroblast–myofibroblast (LIF–MYF) switch; AREG–EGFR signaling; fibrosis resolution; WI-38 fibroblast model

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MDPI and ACS Style

Panagiotidis, G.-D.; Chen, M.; Yang, X.; Marega, M.; Rivetti, S.; Chu, X.; Bellusci, S. Reciprocal Paracrine Signaling and Dynamic Coordination of Transitional States in the Alveolar Epithelial Type 2 Cells and Associated Alveolar Lipofibroblasts During Homeostasis, Injury and Repair. Cells 2025, 14, 1869. https://doi.org/10.3390/cells14231869

AMA Style

Panagiotidis G-D, Chen M, Yang X, Marega M, Rivetti S, Chu X, Bellusci S. Reciprocal Paracrine Signaling and Dynamic Coordination of Transitional States in the Alveolar Epithelial Type 2 Cells and Associated Alveolar Lipofibroblasts During Homeostasis, Injury and Repair. Cells. 2025; 14(23):1869. https://doi.org/10.3390/cells14231869

Chicago/Turabian Style

Panagiotidis, Georgios-Dimitrios, Mengqing Chen, Xiuyue Yang, Manuela Marega, Stefano Rivetti, Xuran Chu, and Saverio Bellusci. 2025. "Reciprocal Paracrine Signaling and Dynamic Coordination of Transitional States in the Alveolar Epithelial Type 2 Cells and Associated Alveolar Lipofibroblasts During Homeostasis, Injury and Repair" Cells 14, no. 23: 1869. https://doi.org/10.3390/cells14231869

APA Style

Panagiotidis, G.-D., Chen, M., Yang, X., Marega, M., Rivetti, S., Chu, X., & Bellusci, S. (2025). Reciprocal Paracrine Signaling and Dynamic Coordination of Transitional States in the Alveolar Epithelial Type 2 Cells and Associated Alveolar Lipofibroblasts During Homeostasis, Injury and Repair. Cells, 14(23), 1869. https://doi.org/10.3390/cells14231869

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