Connexin 43-Mediated Mitochondrial Transfer of iPSC-MSCs Alleviates Asthma Inflammation

Stem Cell Reports. 2018 Nov 13;11(5):1120-1135. doi: 10.1016/j.stemcr.2018.09.012. Epub 2018 Oct 18.

Abstract

We previously identified an immunomodulatory role of human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) in asthmatic inflammation. Mitochondrial transfer from bone marrow MSCs to epithelial cells can result in the attenuation of acute lung injury in mice. However, the effects of mitochondrial transfer from iPSC-MSCs to epithelial cells in asthma and the mechanisms underlying these effects are unclear. We found that iPSC-MSC transplantation significantly reduced T helper 2 cytokines, attenuated the mitochondrial dysfunction of epithelial cells, and alleviated asthma inflammation in mice. Tunneling nanotubes (TNTs) were formed between iPSC-MSCs and epithelial cells, and mitochondrial transfer from iPSC-MSCs to epithelial cells via TNTs was observed both in vitro and in mice. Overexpression or silencing of connexin 43 (CX43) in iPSC-MSCs demonstrated that CX43 plays a critical role in the regulation of TNT formation by mediating mitochondrial transfer between iPSC-MSCs and epithelial cells. This study provides a therapeutic strategy for targeting asthma inflammation.

Keywords: asthma; connexin 43; epithelial cells; iPSC-MSCs; mitochondrial transfer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Asthma / pathology*
  • Asthma / therapy*
  • Cell Line
  • Cobalt / pharmacology
  • Connexin 43 / metabolism*
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / ultrastructure
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation*
  • Inflammation / pathology*
  • Lung / pathology
  • Lung / physiopathology
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Nanotubes / chemistry
  • Ovalbumin

Substances

  • Connexin 43
  • Cobalt
  • Ovalbumin
  • cobaltous chloride