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Wnt5a/β-catenin axis is involved in the downregulation of AT2 lineage by PAI-1

Krishan G Jain1, Runzhen Zhao1, Yang Liu1

  • 1Department of Cellular and Molecular Biology, University of Texas at Tyler, Tyler, Texas.

American Journal of Physiology. Lung Cellular and Molecular Physiology
|September 13, 2022
PubMed

Insights

Elevated plasminogen activator inhibitor-1 (PAI-1) impairs alveolar regeneration after lung injury by disrupting alveolar type 2 (AT2) cell fate. Targeting PAI-1 may promote lung repair.

Area of Science:

  • Pulmonary Medicine
  • Cell Biology
  • Regenerative Medicine

Background:

  • COVID-19 associated lung injury highlights the critical need for prompt alveolar regeneration.
  • The role of plasminogen activator inhibitor-1 (PAI-1) in alveolar type 2 (AT2) cell lineage and re-alveolarization remains largely uncharacterized.

Purpose of the Study:

  • To investigate the regulatory mechanisms of elevated PAI-1 on AT2 cell fate and re-alveolarization.
  • To elucidate the involvement of PAI-1-Wnt5a-β catenin signaling pathways in AT2 cell lineage determination.

Main Methods:

  • Utilized *Serpine1* mice to assess AT2 cell yield in vivo.
  • Employed in vitro organoid models to evaluate the impact of PAI-1 on AT2 cell proliferation, differentiation, and development.
  • Investigated the effects of anti-PAI-1 neutralizing antibody, Wnt family member 5A (Wnt5a), and Box5 on AT2 cell behavior and signaling.

Main Results:

  • A significant reduction in AT2 cell yield was observed in *Serpine1* mice.
  • Elevated PAI-1 levels in vitro suppressed organoid formation, developmental efficiency, and total surface area.
  • Administration of anti-PAI-1 antibody normalized organoid parameters, AT2 cell proliferation, differentiation, and β-catenin levels.
  • Wnt5a and Box5 demonstrated the ability to modulate AT2 cell lineage.

Conclusions:

  • Elevated PAI-1 critically regulates AT2 cell proliferation and differentiation through the Wnt5a/β catenin signaling cascade.
  • PAI-1 may function as an autocrine signaling molecule essential for lung injury repair and re-alveolarization.
Keywords:
Serpine1Wnt5/β-cateninalveolar type 2 epithelial cellsdifferentiationproliferation

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