Angiocrine Sphingosine-1-Phosphate Activation of S1PR2-YAP Signaling Axis in Alveolar Type II Cells Is Essential for Lung Repair

Cell Rep. 2020 Jun 30;31(13):107828. doi: 10.1016/j.celrep.2020.107828.

Abstract

Lung alveolar epithelium is composed of alveolar type I (AT1) and type II (AT2) cells. AT1 cells mediate gas exchange, whereas AT2 cells act as progenitor cells to repair injured alveoli. Lung microvascular endothelial cells (LMVECs) play a crucial but still poorly understood role in regulating alveolar repair. Here, we studied the role of the LMVEC-derived bioactive lipid sphingosine-1-phosphate (S1P) in promoting alveolar repair using mice with endothelial-specific deletion of sphingosine kinase 1 (Sphk1), the key enzyme promoting S1P generation. These mutant lungs developed airspace-enlargement lesions and exhibited a reduced number of AT1 cells after Pseudomonas-aeruginosa-induced lung injury. We demonstrated that S1P released by LMVECs acted via its receptor, S1PR2, on AT2 cells and induced nuclear translocation of yes-associated protein (YAP), a regulator of AT2 to AT1 transition. Thus, angiocrine S1P released after injury acts via the S1PR2-YAP signaling axis on AT2 cells to promote AT2 to AT1 differentiation required for alveolar repair.

Keywords: S1P; alveoli; endothelial; lung; niche; repair; type II cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Alveolar Epithelial Cells / drug effects
  • Alveolar Epithelial Cells / metabolism*
  • Animals
  • Cell Count
  • Cell Cycle Proteins / metabolism*
  • Down-Regulation / drug effects
  • Female
  • Lung / drug effects
  • Lung / microbiology
  • Lung / pathology*
  • Lysophospholipids / metabolism*
  • Male
  • Mice
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Pseudomonas aeruginosa / physiology
  • Pulmonary Surfactant-Associated Protein C / metabolism*
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptors, Lysosphingolipid / metabolism*
  • Regeneration* / drug effects
  • Signal Transduction* / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • JTE 013
  • Lysophospholipids
  • Pulmonary Surfactant-Associated Protein C
  • Pyrazoles
  • Pyridines
  • Receptors, Lysosphingolipid
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine