Cited by 133Developmental Biology and Gene RegulationNeonatal Respiratory Health ResearchRespiratory Support and Mechanisms

Dlk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair

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Finn, Johanna, Sottoriva, Kilian, Pajcini, Kostandin V., Kitajewski, Jan K., Chen, Chang, Zhang, Wei, Malik, Asrar B., Liu, Yuru·2019·Cell Reports

Abstract

Lung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering ∼95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudomonas aeruginosa-induced acute lung injury in mice, that non-canonical Notch ligand Dlk1 (delta-like 1 homolog) is essential for AT2-to-AT1 differentiation. Notch signaling was activated in AT2 at the onset of repair but later suppressed by Dlk1. Deletion of Dlk1 in AT2 induced persistent Notch activation, resulting in stalled transition to AT1 and accumulation of an intermediate cell population that expressed low levels of both AT1 and AT2 markers. Thus, Dlk1 expression leads to precisely timed inhibition of Notch signaling and activates AT2-to-AT1 differentiation, leading to alveolar repair.

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Crossref · 10.1016/j.celrep.2019.02.046

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  • Signaling via DLK1 toward NOTCH receptors may compete with endothelial DLL4 for receptor occupancy.

    “signaling via the non-canonical NOTCH inhibitor DLK1, expressed by non-endothelial populations, toward NOTCH receptors may compete with endothelial DLL4 for receptor occupancy”

    From Single-Cell Transcriptomics Reveals Early Emergence of Liver Parenchymal and Non-parenchymal Cell Lineages (2020) · cites this paper as Finn et al., 2019

    The Discussion (page unavailable) describes DLK1 as a non-canonical NOTCH ligand that can interact with a receptor and block a trans-ligand. The Introduction identifies DLL4 as a canonical NOTCH ligand. The paper does not identify endothelial DLL4 as the competing ligand or establish competition for receptor occupancy between DLK1 and DLL4. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • DLK1 may contribute to the lateral inhibition of Notch in HSEC progenitors.

    “DLK1 may contribute to the lateral inhibition of Notch in HSEC progenitors, comparable to its role in the differentiation of type I from type II alveolar cells in lung repair”

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Authors
Finn, J., Sottoriva, K., Pajcini, K. V., Kitajewski, J. K., Chen, C., Zhang, W., Malik, A. B., & Liu, Y.
Affiliations
  • University of Illinois Chicago (US)
  • Northwestern University (US)
Corresponding author
Liu, Yuru
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-03
Volume
26
Issue
11
Pages
2942-2954.e5
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2921277580
Cited by
133
References
70
Citations by year
2026: 18 · 2025: 19 · 2024: 23 · 2023: 11 · 2022: 25 · 2021: 18 · 2020: 14 · 2019: 5
FWCI
5.13
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
NIH (HL105947, 7829-23, HL134971, HL090152)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Neonatal Respiratory Health Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
Keywords
DLK1, Notch signaling, alveolar type II cells, alveolar type I cells, alveolar repair, cell differentiation, Pseudomonas aeruginosa, acute lung injury, lung regeneration
MeSH terms
Animals, Calcium-Binding Proteins, Cell Differentiation, Cells, Cultured, Female, Male, Mice, Inbred C57BL, Pseudomonas Infections, Regeneration, Signal Transduction, Pneumonia, Bacterial, Mice, Receptors, Notch, Alveolar Epithelial Cells

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