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

Summary

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.

Graphical Abstract

Highlights

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  iPSC-MSCs attenuate asthma inflammation and protect epithelial cells

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  The protection of iPSC-MSCs is attributable to mitochondrial transfer via TNTs

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  CX43-mediated TNT formation regulates the mitochondrial donation of iPSC-MSCs

Abstract

In this article, Fu, Lian, and colleagues show that mesenchymal stem cells derived from human induced pluripotent stem cells can transfer their mitochondria to rescue the injured bronchial epithelial cells, which attenuates asthma inflammation. Connexin 43, a component of gap junctions, plays a critical role during the process of mitochondrial transfer by regulating intercellular tunneling nanotube formation.