Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome
Abstract Background Delay in type II alveolar epithelial cell (AECII) regeneration has been linked to higher mortality in patients with acute respiratory distress syndrome (ARDS). However, the interaction between Doublecortin-like kinase 1 (DCLK1) and the Hippo signaling pathway in ARDS-associated A...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-11-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-023-00760-0 |
| _version_ | 1797452241084350464 |
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| author | Xiao-Yue Chen Ching Kao Syue-Wei Peng Jer-Hwa Chang Yueh-Lun Lee Vincent Laiman Kian Fan Chung Pankaj K. Bhavsar Didik Setyo Heriyanto Kai-Jen Chuang Hsiao-Chi Chuang |
| author_facet | Xiao-Yue Chen Ching Kao Syue-Wei Peng Jer-Hwa Chang Yueh-Lun Lee Vincent Laiman Kian Fan Chung Pankaj K. Bhavsar Didik Setyo Heriyanto Kai-Jen Chuang Hsiao-Chi Chuang |
| author_sort | Xiao-Yue Chen |
| collection | DOAJ |
| description | Abstract Background Delay in type II alveolar epithelial cell (AECII) regeneration has been linked to higher mortality in patients with acute respiratory distress syndrome (ARDS). However, the interaction between Doublecortin-like kinase 1 (DCLK1) and the Hippo signaling pathway in ARDS-associated AECII differentiation remains unclear. Therefore, the objective of this study was to understand the role of the DCLK1/Hippo pathway in mediating AECII differentiation in ARDS. Materials and methods AECII MLE-12 cells were exposed to 0, 0.1, or 1 μg/mL of lipopolysaccharide (LPS) for 6 and 12 h. In the mouse model, C57BL/6JNarl mice were intratracheally (i.t.) injected with 0 (control) or 5 mg/kg LPS and were euthanized for lung collection on days 3 and 7. Results We found that LPS induced AECII markers of differentiation by reducing surfactant protein C (SPC) and p53 while increasing T1α (podoplanin) and E-cadherin at 12 h. Concurrently, nuclear YAP dynamic regulation and increased TAZ levels were observed in LPS-exposed AECII within 12 h. Inhibition of YAP consistently decreased cell levels of SPC, claudin 4 (CLDN-4), galectin 3 (LGALS-3), and p53 while increasing transepithelial electrical resistance (TEER) at 6 h. Furthermore, DCLK1 expression was reduced in isolated human AECII of ARDS, consistent with the results in LPS-exposed AECII at 6 h and mouse SPC-positive (SPC+) cells after 3-day LPS exposure. We observed that downregulated DCLK1 increased p-YAP/YAP, while DCLK1 overexpression slightly reduced p-YAP/YAP, indicating an association between DCLK1 and Hippo-YAP pathway. Conclusions We conclude that DCLK1-mediated Hippo signaling components of YAP/TAZ regulated markers of AECII-to-AECI differentiation in an LPS-induced ARDS model. Graphical Abstract |
| first_indexed | 2024-03-09T15:05:56Z |
| format | Article |
| id | doaj.art-7108a16224c54a179dfa09cadde03ec6 |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-03-09T15:05:56Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-7108a16224c54a179dfa09cadde03ec62023-11-26T13:39:26ZengBMCMolecular Medicine1528-36582023-11-0129111310.1186/s10020-023-00760-0Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndromeXiao-Yue Chen0Ching Kao1Syue-Wei Peng2Jer-Hwa Chang3Yueh-Lun Lee4Vincent Laiman5Kian Fan Chung6Pankaj K. Bhavsar7Didik Setyo Heriyanto8Kai-Jen Chuang9Hsiao-Chi Chuang10Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversitySchool of Respiratory Therapy, College of Medicine, Taipei Medical UniversitySchool of Respiratory Therapy, College of Medicine, Taipei Medical UniversitySchool of Respiratory Therapy, College of Medicine, Taipei Medical UniversityDepartment of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical UniversityInternational Ph.D. Program in Medicine, College of Medicine, Taipei Medical UniversityNational Heart and Lung Institute, Imperial College LondonNational Heart and Lung Institute, Imperial College LondonDepartment of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Dr. Sardjito HospitalSchool of Public Health, College of Public Health, Taipei Medical UniversityGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical UniversityAbstract Background Delay in type II alveolar epithelial cell (AECII) regeneration has been linked to higher mortality in patients with acute respiratory distress syndrome (ARDS). However, the interaction between Doublecortin-like kinase 1 (DCLK1) and the Hippo signaling pathway in ARDS-associated AECII differentiation remains unclear. Therefore, the objective of this study was to understand the role of the DCLK1/Hippo pathway in mediating AECII differentiation in ARDS. Materials and methods AECII MLE-12 cells were exposed to 0, 0.1, or 1 μg/mL of lipopolysaccharide (LPS) for 6 and 12 h. In the mouse model, C57BL/6JNarl mice were intratracheally (i.t.) injected with 0 (control) or 5 mg/kg LPS and were euthanized for lung collection on days 3 and 7. Results We found that LPS induced AECII markers of differentiation by reducing surfactant protein C (SPC) and p53 while increasing T1α (podoplanin) and E-cadherin at 12 h. Concurrently, nuclear YAP dynamic regulation and increased TAZ levels were observed in LPS-exposed AECII within 12 h. Inhibition of YAP consistently decreased cell levels of SPC, claudin 4 (CLDN-4), galectin 3 (LGALS-3), and p53 while increasing transepithelial electrical resistance (TEER) at 6 h. Furthermore, DCLK1 expression was reduced in isolated human AECII of ARDS, consistent with the results in LPS-exposed AECII at 6 h and mouse SPC-positive (SPC+) cells after 3-day LPS exposure. We observed that downregulated DCLK1 increased p-YAP/YAP, while DCLK1 overexpression slightly reduced p-YAP/YAP, indicating an association between DCLK1 and Hippo-YAP pathway. Conclusions We conclude that DCLK1-mediated Hippo signaling components of YAP/TAZ regulated markers of AECII-to-AECI differentiation in an LPS-induced ARDS model. Graphical Abstracthttps://doi.org/10.1186/s10020-023-00760-0EpitheliumInfectionLung injuryPneumocytesRegeneration |
| spellingShingle | Xiao-Yue Chen Ching Kao Syue-Wei Peng Jer-Hwa Chang Yueh-Lun Lee Vincent Laiman Kian Fan Chung Pankaj K. Bhavsar Didik Setyo Heriyanto Kai-Jen Chuang Hsiao-Chi Chuang Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome Molecular Medicine Epithelium Infection Lung injury Pneumocytes Regeneration |
| title | Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome |
| title_full | Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome |
| title_fullStr | Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome |
| title_full_unstemmed | Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome |
| title_short | Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome |
| title_sort | role of dclk1 hippo pathway in type ii alveolar epithelial cells differentiation in acute respiratory distress syndrome |
| topic | Epithelium Infection Lung injury Pneumocytes Regeneration |
| url | https://doi.org/10.1186/s10020-023-00760-0 |
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