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How iPSC Therapy Reduces Endothelial Leakage in an Acute Lung Injury Model

Review of “Induced Pluripotent Stem Cells Attenuate Endothelial Leakage in Acute Lung Injury via Tissue Inhibitor of Metalloproteinases‐1 to Reduce Focal Adhesion Kinase Activity” from STEM CELLS by Stuart P. Atkinson

Recent studies from the laboratory of Kuang‐Yao Yang (Taipei Veterans General Hospital, Taipei) established how the intravenous injection of induced pluripotent stem cells (iPSCs) reduced endotoxin-induced acute lung injury severity and improved physiologic impairment thanks to the migration and accumulation at the injury site and the reduction in nuclear factor kappa B (NF‐κB) activity and neutrophil accumulation [1]. Their subsequent studies suggested that iPSCs enhanced G-protein-coupled receptor kinase 2 (GRK2) activity and reduced expression of a triggering receptor expressed on myeloid cells to regulate neutrophil chemotaxis after endotoxin exposure [2, 3].

The team return with a new STEM CELLS article that explores the effects of iPSCs on endothelial cell leakage in endotoxin‐induced acute lung injury [4], with a specific focus on focal adhesion kinase (FAK) [5] and the Snail transcription factor [6] given their links to endothelial barrier function and blood–brain barrier permeability, respectively. Now the authors report that iPSC therapy attenuates endothelial cell leakage after endotoxin‐induced acute lung injury through a pathway involving tissue inhibitor of metalloproteinases‐1 (TIMP‐1) and the FAK/Snail pathway.

Su et al. investigated the potential of iPSC therapy in moderating pulmonary endothelial leakage in endotoxin‐induced acute lung injury by intravenously delivering mouse iPSCs into male C57BL/6 mice following intratracheal lipopolysaccharide delivery and analyzing various parameters after 24 hours. Encouragingly, iPSC therapy alleviated histological signs of acute lung injury, reduced levels of protein leakage and proinflammatory cytokine expression in bronchoalveolar lavage fluid, and also restored endothelial cell junctional protein expression (vascular endothelial cadherin, or VE‐cadherin) in acute lung injury mouse lungs, suggesting a reduction in endothelial cell permeability.

Subsequent mechanistic insights came from the analysis of human umbilical vein endothelial cells, which the authors employed as a model of junctional protein‐expressing cells. Interestingly, the addition of human iPSCs following lipopolysaccharide insult led to the restoration of disrupted VE‐cadherin expression, and a reduction in Snail activity and FAK phosphorylation. Subsequent analysis of proteins secreted by iPSCs suggested that TIMP-1 may play an essential role in combating the effects of lipopolysaccharide treatment, a finding which the authors confirmed by demonstrating how TIMP-1 loss diminished the beneficial effects of iPSC in acute lung injury mice by increasing FAK phosphorylation. 

Overall, the authors establish that iPSC therapy can attenuate endotoxin‐induced acute lung injury by inhibiting pulmonary endothelial leakage by secreting TIMP‐1 and inhibiting the activation of the FAK/Snail pathway. However, the authors do note certain limitations to their study, which the authors hope to remedy by analyzing additional effects of iPSCs on endothelial barrier permeability, evaluating TIMP-1 secretion by iPSCs, assessing the role of other paracrine factors from iPSCs that ameliorate acute lung injury by reducing endothelial leakage, and identifying iPSC-secreted factors that regulate neutrophil‐endothelial cell interactions. 

For more on induced pluripotent stem cell-based treatments for acute lung injury, stay tuned to the Stem Cells Portal!


  1. Yang K-Y, Shih H-C, How C-K, et al., IV Delivery of Induced Pluripotent Stem Cells Attenuates Endotoxin-Induced Acute Lung Injury in Mice. Chest 2011;140:1243-1253.
  2. Su VY-F, Chiou S-H, Lin C-S, et al., Induced pluripotent stem cells reduce neutrophil chemotaxis via activating GRK2 in endotoxin-induced acute lung injury. Respirology 2017;22:1156-1164.
  3. Su VY-F, Yang K-Y, Chiou S-H, et al., Induced Pluripotent Stem Cells Regulate Triggering Receptor Expressed on Myeloid Cell-1 Expression and the p38 Mitogen-Activated Protein Kinase Pathway in Endotoxin-Induced Acute Lung Injury. STEM CELLS 2019;37:631-639.
  4. Su VY-F, Chiou S-H, Lin C-S, et al., Induced Pluripotent Stem Cells Attenuate Endothelial Leakage in Acute Lung Injury via Tissue Inhibitor of Metalloproteinases-1 to Reduce Focal Adhesion Kinase Activity. STEM CELLS 2019;37:1516-1527.
  5. Le Boeuf F, Houle F, Sussman M, et al., Phosphorylation of Focal Adhesion Kinase (FAK) on Ser732 Is Induced by Rho-dependent Kinase and Is Essential for Proline-rich Tyrosine Kinase-2–mediated Phosphorylation of FAK on Tyr407 in Response to Vascular Endothelial Growth Factor. Molecular Biology of the Cell 2006;17:3508-3520.
  6. Yang R, Liu W, Miao L, et al., Induction of VEGFA and Snail-1 by meningitic Escherichia coli mediates disruption of the blood-brain barrier. Oncotarget 2016;7:63839-63855.