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Cited by 33Tissue Engineering and Regenerative Medicine3D Printing in Biomedical ResearchCellular Mechanics and Interactions

Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix

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Young, Bethany M., Shankar, Keerthana, Tho, Cindy K., Pellegrino, Amanda R., Heise, Rebecca L.·2019·Acta Biomaterialia
DOI 10.1016/j.actbio.2019.10.009PMC PMC6892605

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Abstract

Decellularized tissues offer a unique tool for developing regenerative biomaterials or in vitro platforms for the study of cell-extracellular matrix (ECM) interactions. One main challenge associated with decellularized lung tissue is that ECM components can be stripped away or altered by the detergents used to remove cellular debris. Without characterizing the composition of lung decellularized ECM (dECM) and the cellular response caused by the altered composition, it is difficult to utilize dECM for regeneration and specifically, engineering the complexities of the alveolar-capillary barrier. This study takes steps towards uncovering if dECM must be enhanced with lost ECM proteins to achieve proper epithelial barrier formation. To achieve this, the epithelial barrier function was assessed on dECM coatings with and without the systematic addition of several key basement membrane proteins. After comparing barrier function on collagen I, fibronectin, laminin, and dECM in varying combinations as an in vitro coating, the alveolar epithelium exhibited superior barrier function when dECM was supplemented with laminin as evidenced by trans-epithelial electrical resistance (TEER) and permeability assays. Increased barrier resistance with laminin addition was associated with upregulation of Claudin-18, E-cadherin, and junction adhesion molecule (JAM)-A, and stabilization of zonula occludens (ZO)-1 at junction complexes. The Epac/Rap1 pathway was observed to play a role in the ECM-mediated barrier function determined by protein expression and Epac inhibition. These findings revealed potential ECM coatings and molecular therapeutic targets for improved regeneration with decellularized scaffolds. STATEMENT OF SIGNIFICANCE: Efforts to produce a transplantable organ-scale biomaterial for lung regeneration has not been entirely successful to date, due to incomplete cell-cell junction formation, ultimately leading to severe edema in vivo. To fully understand the process of alveolar junction formation on ECM-derived biomaterials, this research has characterized and tailored decellularized ECM (dECM) to mitigate reductions in barrier strength or cell attachment caused by abnormal ECM compositions or detergent damage to dECM. These results indicate that laminin-driven Epac signaling plays a vital role in the stabilization of the alveolar barrier. Addition of laminin or Epac agonists during alveolar regeneration can reduce epithelial permeability within bioengineered lungs.

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  • Young et al. augmented dECM with basement membrane proteins such as laminin or fibronectin, resulting in improved barrier function in vitro.

    “Recent advancements by Young et al. have focused on enhancing epithelial and alveolar barriers by augmenting dECM with basement membrane proteins such as laminin or fibronectin, resulting in improved barrier function in vitro.”

    From Bioactive scaffolds for tissue engineering: A review of decellularized extracellular matrix applications and innovations (2025) · cites this paper as [176]

    The Results section reports improved in vitro barrier resistance when dECM was supplemented with laminin. Although the study also tested fibronectin-supplemented dECM, the Discussion says fibronectin increased initial cell attachment but caused a prolonged decrease in barrier function. The claim is therefore unsupported insofar as it implies that fibronectin supplementation improved barrier function. (LLM, conf=0.93)

    Experimental — accuracy not yet measured

  • Improved barrier function was correlated with increased expression of adhesion proteins, notably Claudin-18, which may contribute to alveolar stability.

    “This was correlated with an increased expression of adhesion proteins, notably Claudin‐18, which may contribute to alveolar stability.[ 176 ]”

    From Bioactive scaffolds for tissue engineering: A review of decellularized extracellular matrix applications and innovations (2025) · cites this paper as [176]

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Authors
Young, B. M., Shankar, K., Tho, C. K., Pellegrino, A. R., & Heise, R. L.
Affiliations
  • Virginia Commonwealth University (US)
  • Duquesne University (US)
Corresponding author
Heise, Rebecca L.
ORCID
Venue
Acta Biomaterialia
Publisher
Elsevier BV
Published
2019-12
Volume
100
Pages
223-234
ISSN
  • 1556-5068 (ISSN-L)
  • 1742-7061
DOI
10.1016/j.actbio.2019.10.009
PMC
PMC6892605
OpenAlex
W2977527764
Cited by
33
References
91
Citations by year
2026: 2 · 2025: 5 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 10 · 2020: 5
Type
posted content
Language
en
Open access
Licence
Locations
  • SSRN Electronic Journal (publishedVersion)
  • Acta Biomaterialia (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Science Foundation
Topics
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
laminin, epithelial barrier function, alveolar-capillary barrier, cell-matrix interactions, basement membrane proteins, type I collagen, fibronectin, transepithelial electrical resistance, epithelial permeability, tight junctions, claudin-18, E-cadherin, JAM-A, zonula occludens-1, lung regeneration
MeSH terms
Animals, Cattle, Cell Adhesion, Cell Line, Epithelial Cells, Extracellular Matrix, Female, Laminin, Male, Pulmonary Alveoli, Stem Cells, Swine, Electric Impedance, Tight Junctions, Guanine Nucleotide Exchange Factors, Adherens Junctions, Mice

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