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

Am J Physiol Lung Cell Mol Physiol. 2022 Nov 1;323(5):L515-L524. doi: 10.1152/ajplung.00202.2022. Epub 2022 Sep 13.

Abstract

Failure to regenerate injured alveoli functionally and promptly causes a high incidence of fatality in coronavirus disease 2019 (COVID-19). How elevated plasminogen activator inhibitor-1 (PAI-1) regulates the lineage of alveolar type 2 (AT2) cells for re-alveolarization has not been studied. This study aimed to examine the role of PAI-1-Wnt5a-β catenin cascades in AT2 fate. Dramatic reduction in AT2 yield was observed in Serpine1Tg mice. Elevated PAI-1 level suppressed organoid number, development efficiency, and total surface area in vitro. Anti-PAI-1 neutralizing antibody restored organoid number, proliferation and differentiation of AT2 cells, and β-catenin level in organoids. Both Wnt family member 5A (Wnt5a) and Wnt5a-derived N-butyloxycarbonyl hexapeptide (Box5) altered the lineage of AT2 cells. This study demonstrates that elevated PAI-1 regulates AT2 proliferation and differentiation via the Wnt5a/β catenin cascades. PAI-1 could serve as autocrine signaling for lung injury repair.

Keywords: Serpine1; Wnt5/β-catenin; alveolar type 2 epithelial cells; differentiation; proliferation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Neutralizing
  • COVID-19*
  • Cell Proliferation
  • Down-Regulation
  • Mice
  • Plasminogen Activator Inhibitor 1* / metabolism
  • Pulmonary Alveoli / cytology
  • Wnt Signaling Pathway / physiology
  • Wnt-5a Protein* / metabolism
  • beta Catenin* / metabolism

Substances

  • Antibodies, Neutralizing
  • beta Catenin
  • Wnt-5a Protein
  • Plasminogen Activator Inhibitor 1