Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome

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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

Highlights

LPS activated AECII-to-AECI markers of differentiation via the Hippo signaling pathway.
DCLK1/YAP was dynamically regulated in AECII of LPS-induced ARDS.
DCLK1 had an association with YAP to increase cell stemness in AECII.
DCLK1/Hippo pathway could be a potential therapeutic target in patients with ARDS.

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Most cited references 72

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Type 2 alveolar cells are stem cells in adult lung.

Christina E Barkauskas, Michael J Cronce, Craig Rackley … (2013)

Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.

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Alveolar progenitor and stem cells in lung development, renewal and cancer.

Mark Krasnow, T. Desai, Erica Brownfield (2014)

Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.

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Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

Maximilian Strunz, Lukas M Simon, Meshal Ansari … (2020)

The cell type specific sequences of transcriptional programs during lung regeneration have remained elusive. Using time-series single cell RNA-seq of the bleomycin lung injury model, we resolved transcriptional dynamics for 28 cell types. Trajectory modeling together with lineage tracing revealed that airway and alveolar stem cells converge on a unique Krt8 + transitional stem cell state during alveolar regeneration. These cells have squamous morphology, feature p53 and NFkB activation and display transcriptional features of cellular senescence. The Krt8+ state appears in several independent models of lung injury and persists in human lung fibrosis, creating a distinct cell–cell communication network with mesenchyme and macrophages during repair. We generated a model of gene regulatory programs leading to Krt8+ transitional cells and their terminal differentiation to alveolar type-1 cells. We propose that in lung fibrosis, perturbed molecular checkpoints on the way to terminal differentiation can cause aberrant persistence of regenerative intermediate stem cell states.

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Author and article information

Contributors

Jer-Hwa Chang: m102094030@tmu.edu.tw , jerhwa@tmu.edu.tw

Yueh-Lun Lee: yllee@tmu.edu.tw

Hsiao-Chi Chuang:

ORCID: http://orcid.org/0000-0003-4651-5192

chuanghc@tmu.edu.tw

Journal

Journal ID (nlm-ta): Mol Med

Journal ID (iso-abbrev): Mol Med

Title: Molecular Medicine

Publisher: BioMed Central (London )

ISSN (Print): 1076-1551

ISSN (Electronic): 1528-3658

Publication date (Electronic): 23 November 2023

Publication date PMC-release: 23 November 2023

Publication date Collection: 2023

Volume: 29

Electronic Location Identifier: 159

Affiliations

[1 ]Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, ( https://ror.org/05031qk94) Taipei, Taiwan

[2 ]School of Respiratory Therapy, College of Medicine, Taipei Medical University, ( https://ror.org/05031qk94) 250 Wuxing Street, Taipei, 11031 Taiwan

[3 ]National Heart and Lung Institute, Imperial College London, ( https://ror.org/041kmwe10) London, UK

[4 ]GRID grid.412896.0, ISNI 0000 0000 9337 0481, Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, , Taipei Medical University, ; Taipei, Taiwan

[5 ]Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, ( https://ror.org/05031qk94) 250 Wuxing Street, Taipei, 11031 Taiwan

[6 ]International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, ( https://ror.org/05031qk94) Taipei, Taiwan

[7 ]Department of Anatomical Pathology, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, ( https://ror.org/03ke6d638) Yogyakarta, Indonesia

[8 ]School of Public Health, College of Public Health, Taipei Medical University, ( https://ror.org/05031qk94) Taipei, Taiwan

[9 ]Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, ( https://ror.org/05031qk94) Taipei, Taiwan

[10 ]Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, ( https://ror.org/05031qk94) New Taipei City, Taiwan

[11 ]GRID grid.412896.0, ISNI 0000 0000 9337 0481, Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, , Taipei Medical University, ; Taipei, Taiwan

[12 ]Inhalation Toxicology Research Lab (ITRL), School of Respiratory Therapy, College of Medicine, Taipei Medical University, ( https://ror.org/05031qk94) 250 Wuxing Street, Taipei, 110 Taiwan

Author information

Hsiao-Chi Chuang http://orcid.org/0000-0003-4651-5192

Article

Publisher ID: 760

DOI: 10.1186/s10020-023-00760-0

PMC ID: 10668445

PubMed ID: 37996782

SO-VID: 846401c1-711e-46f2-8c98-cae0d71b04b4

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 31 May 2023

Date accepted : 16 November 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004663, Ministry of Science and Technology, Taiwan;

Award ID: 108-2314-B-038-093

Award ID: 109-2314-B-038-093-MY3

Funded by: Taipei Medical University-Wan Fang Hospital

Award ID: 111TMU-WFH-08

Custom metadata

Keywords: epithelium,infection,lung injury,pneumocytes,regeneration

Data availability:

Keywords: epithelium, infection, lung injury, pneumocytes, regeneration

Role of DCLK1/Hippo pathway in type II alveolar epithelial cells differentiation in acute respiratory distress syndrome

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Abstract

Background

Materials and methods

Results

Conclusions

Graphical Abstract

Highlights

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Decoding Infection and Transmission

Most cited references 72

Type 2 alveolar cells are stem cells in adult lung.

Alveolar progenitor and stem cells in lung development, renewal and cancer.

Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis

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