{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:20:02Z","timestamp":1790796002240,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870059"],"award-info":[{"award-number":["81870059"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070068"],"award-info":[{"award-number":["82070068"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62760"],"award-info":[{"award-number":["62760"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Changsha","award":["81870059"],"award-info":[{"award-number":["81870059"]}]},{"name":"Natural Science Foundation of Changsha","award":["82070068"],"award-info":[{"award-number":["82070068"]}]},{"name":"Natural Science Foundation of Changsha","award":["62760"],"award-info":[{"award-number":["62760"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary fibrosis is a chronic, progressive fibrosing interstitial disease. It is characterized by fibroblast proliferation, myofibroblast activation, and massive extracellular matrix deposition. These processes result in loss of lung parenchyma function. The transdifferentiation of alveolar epithelial type II (AEC2) to alveolar epithelial type I cells (AEC1) plays an important role in the epithelial repair after lung injury. Pulmonary fibrosis begins when this transdifferentiation process is blocked. Several recent studies have found that novel transitional state cells (intermediate states in the transdifferentiation of AEC2 to AEC1) can potentially regenerate the alveolar epithelium surface and promote a repair process. During the AEC2 to AEC1 trans-differentiation process after injury, AEC2 lose their specific markers and become transitional state cells. Furthermore, transdifferentiation of transitional state cells into AEC1 is the critical step for lung repair. However, transitional cells stagnate in the intermediate states in which failure of transdifferentiation to AEC1 may induce an inadequate repair process and pulmonary fibrosis. In this review, we focus on the traits, origins, functions, and activation of signaling pathways of the transitional state cell and its communication with other cells. We also provide a new opinion on pulmonary fibrosis pathogenesis mechanisms and novel therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms23126757","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T11:45:44Z","timestamp":1655466344000},"page":"6757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Regeneration-Associated Transitional State Cells in Pulmonary Fibrosis"],"prefix":"10.3390","volume":"23","author":[{"given":"Mengxia","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3808-6159","authenticated-orcid":false,"given":"Ziqiang","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410003, China"},{"name":"Hunan Key Laboratory of Organ Fibrosis, Changsha 410003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-5276","authenticated-orcid":false,"given":"Yan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12989-021-00404-3","article-title":"Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: A potential role in severe COVID-19","volume":"18","author":"Li","year":"2021","journal-title":"Part. Fibre Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109482","DOI":"10.1016\/j.cellsig.2019.109482","article-title":"The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis","volume":"66","author":"Selman","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Parimon, T., Yao, C., Stripp, B.R., Noble, P.W., and Chen, P. (2020). Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072269"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/s12931-018-0906-9","article-title":"Culture of human alveolar epithelial type II cells by sprouting","volume":"19","author":"Khan","year":"2018","journal-title":"Respir. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ruaro, B., Salton, F., Braga, L., Wade, B., Confalonieri, P., Volpe, M.C., Baratella, E., Maiocchi, S., and Confalonieri, M. (2021). The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052566"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/j.stem.2021.04.026","article-title":"Age-dependent alveolar epithelial plasticity orchestrates lung homeostasis and regeneration","volume":"28","author":"Penkala","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/s41556-020-0561-5","article-title":"A transitional stem cell state in the lung","volume":"22","author":"Verheyden","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"595811","DOI":"10.3389\/fimmu.2021.595811","article-title":"Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease","volume":"12","author":"Valenzi","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"573429","DOI":"10.3389\/fgene.2020.573429","article-title":"Reconstructing the Developmental Trajectories of Multiple Subtypes in Pulmonary Parenchymal Epithelial Cells by Single-Cell RNA-seq","volume":"11","author":"Huang","year":"2020","journal-title":"Front. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eaba1983","DOI":"10.1126\/sciadv.aba1983","article-title":"Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis","volume":"6","author":"Adams","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/s41556-020-0542-8","article-title":"Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis","volume":"22","author":"Kobayashi","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eaba1972","DOI":"10.1126\/sciadv.aba1972","article-title":"Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis","volume":"6","author":"Habermann","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"844119","DOI":"10.3389\/fbioe.2022.844119","article-title":"Basal-Like Cell-Conditioned Medium Exerts Anti-Fibrotic Effects In Vitro and In Vivo","volume":"10","author":"Khan","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hostettler, K.E., Gazdhar, A., Khan, P., Savic, S., Tamo, L., Lardinois, D., Roth, M., Tamm, M., and Geiser, T. (2017). Multipotent mesenchymal stem cells in lung fibrosis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181946"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nature14112","article-title":"Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury","volume":"517","author":"Vaughan","year":"2015","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1164\/rccm.201810-1975TR","article-title":"Cellular Senescence as a Mechanism and Target in Chronic Lung Diseases","volume":"200","author":"Barnes","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1038\/nm.4419","article-title":"ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis","volume":"23","author":"Lagares","year":"2017","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.ajpath.2021.11.014","article-title":"Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis","volume":"192","author":"Ting","year":"2022","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"L491","DOI":"10.1152\/ajplung.00594.2020","article-title":"Cross-species integration of single-cell RNA-seq resolved alveolar-epithelial transitional states in idiopathic pulmonary fibrosis","volume":"321","author":"Huang","year":"2021","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41586-021-03570-8","article-title":"COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets","volume":"595","author":"Delorey","year":"2021","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.stemcr.2016.09.010","article-title":"Rare SOX2(+) Airway Progenitor Cells Generate KRT5(+) Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection","volume":"7","author":"Ray","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.stem.2020.06.020","article-title":"Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration","volume":"27","author":"Choi","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"580026","DOI":"10.3389\/fcell.2020.580026","article-title":"New Perspectives on the Aberrant Alveolar Repair of Idiopathic Pulmonary Fibrosis","volume":"8","author":"Wang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.1038\/s41467-020-17358-3","article-title":"Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis","volume":"11","author":"Strunz","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E1475","DOI":"10.1073\/pnas.1117988108","article-title":"Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition","volume":"108","author":"Rock","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1164\/rccm.201909-1726LE","article-title":"Ineffectual Type 2-to-Type 1 Alveolar Epithelial Cell Differentiation in Idiopathic Pulmonary Fibrosis: Persistence of the KRT8(hi) Transitional State","volume":"201","author":"Jiang","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.devcel.2018.03.001","article-title":"Spatial-Temporal Lineage Restrictions of Embryonic p63(+) Progenitors Establish Distinct Stem Cell Pools in Adult Airways","volume":"44","author":"Yang","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.stemcr.2020.09.006","article-title":"Basal-like Progenitor Cells: A Review of Dysplastic Alveolar Regeneration and Remodeling in Lung Repair","volume":"15","author":"Weiner","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Strunz, M., Simon, L.M., Ansari, M., Mattner, L.F., Angelidis, I., Mayr, C.H., Kathiriya, J., Yee, M., Ogar, P., and Sengupta, A. (2019). Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration. bioRxiv.","DOI":"10.1101\/705244"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"41661","DOI":"10.1038\/srep41661","article-title":"Differentiation of Club Cells to Alveolar Epithelial Cells In Vitro","volume":"7","author":"Zheng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.stem.2019.12.014","article-title":"Distinct Airway Epithelial Stem Cells Hide among Club Cells but Mobilize to Promote Alveolar Regeneration","volume":"26","author":"Kathiriya","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Aspal, M., and Zemans, R.L. (2020). Mechanisms of ATII-to-ATI Cell Differentiation during Lung Regeneration. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093188"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.cell.2019.11.027","article-title":"Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells","volume":"180","author":"Wu","year":"2020","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1172\/JCI125014","article-title":"Yap\/Taz regulate alveolar regeneration and resolution of lung inflammation","volume":"129","author":"LaCanna","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e128674","DOI":"10.1172\/jci.insight.128674","article-title":"TAZ is required for lung alveolar epithelial cell differentiation after injury","volume":"4","author":"Sun","year":"2019","journal-title":"JCI Insight"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ncb3580","article-title":"Local lung hypoxia determines epithelial fate decisions during alveolar regeneration","volume":"19","author":"Xi","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"L564","DOI":"10.1152\/ajplung.00408.2021","article-title":"IRE1\u03b1 drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis","volume":"322","author":"Auyeung","year":"2022","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e90558","DOI":"10.1172\/jci.insight.90558","article-title":"Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis","volume":"1","author":"Xu","year":"2016","journal-title":"JCI Insight"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1900646","DOI":"10.1183\/13993003.00646-2019","article-title":"A spatially restricted fibrotic niche in pulmonary fibrosis is sustained by M-CSF\/M-CSFR signalling in monocyte-derived alveolar macrophages","volume":"55","author":"Joshi","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1038\/s41467-020-16466-4","article-title":"Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity","volume":"11","author":"Cui","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eaao2301","DOI":"10.1126\/scitranslmed.aao2301","article-title":"Afatinib restrains K-RAS-driven lung tumorigenesis","volume":"10","author":"Moll","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Maynard, A., McCoach, C.E., Rotow, J.K., Harris, L., Haderk, F., Kerr, L., Yu, E.A., Schenk, E.L., Tan, W., and Zee, A. (2019). Heterogeneity and targeted therapy-induced adaptations in lung cancer revealed by longitudinal single-cell RNA sequencing. bioRxiv.","DOI":"10.1101\/2019.12.08.868828"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6757\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:33:54Z","timestamp":1760139234000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,17]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23126757"],"URL":"https:\/\/doi.org\/10.3390\/ijms23126757","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,17]]}}}