Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage.

Dan Jiang,Qizhou Lian,Fei Gao,Hung-Fat Tse,Qing Li,Goufeng Xu,Zhendong Yu,Yuelin Zhang,David Sai Hung Wong

doi:10.1038/cddis.2016.358

Abstract

Recent studies have demonstrated that mesenchymal stem cells (MSCs) can donate mitochondria to airway epithelial cells and rescue mitochondrial damage in lung injury. We sought to determine whether MSCs could donate mitochondria and protect against oxidative stress-induced mitochondrial dysfunction in the cornea. Co-culturing of MSCs and corneal epithelial cells (CECs) indicated that the efficiency of mitochondrial transfer from MSCs to CECs was enhanced by Rotenone (Rot)-induced oxidative stress. The efficient mitochondrial transfer was associated with increased formation of tunneling nanotubes (TNTs) between MSCs and CECs, tubular connections that allowed direct intercellular communication. Separation of MSCs and CECs by a transwell culture system revealed no mitochiondrial transfer from MSCs to CECs and mitochondrial function was impaired when CECs were exposed to Rot challenge. CECs with or without mitochondrial transfer from MSCs displayed a distinct survival capacity and mitochondrial oxygen consumption rate. Mechanistically, increased filopodia outgrowth in CECs for TNT formation was associated with oxidative inflammation-activated NFκB/TNFαip2 signaling pathways that could be attenuated by reactive oxygen species scavenger N-acetylcysteine (NAC) treatment. Furthermore, MSCs grown on a decellularized porcine corneal scaffold were transplanted onto an alkali-injured eye in a rabbit model. Enhanced corneal wound healing was evident following healthy MSC scaffold transplantation. And transferred mitochondria was detected in corneal epithelium. In conclusion, mitochondrial transfer from MSCs provides novel protection for the cornea against oxidative stress-induced mitochondrial damage. This therapeutic strategy may prove relevant for a broad range of mitochondrial diseases.

Highlights

Chemical burns to the cornea, including alkali injury, are a very common cause of severe corneal damage and vision impairment
To examine the potential of mitochondrial transfer from mesenchymal stem cell (MSC) to corneal epithelial cell (CEC), we genetically labeled MSCs with lentiviral-mediated mitochondrial-specific fragment fused with green florescence protein (LV-Mito-GFP)
LV-MitoGFP-labeled MSCs and Violet-labeled CECs were co-cultured at a ratio of 1 : 1 for 24 h

Summary

Introduction

Chemical burns to the cornea, including alkali injury, are a very common cause of severe corneal damage and vision impairment. MSCs support corneal limbal stem cell growth and suppress alkali-induced oxidative injury in the cornea have been thought mainly to be via paracrine effects.[7,8] Some studies have indicated that cornea or bone marrow-derived MSCs can be induced to express markers of CECs.[1,2,9] apart from paracrine effects, anti-inflammation function and cell replacement, other mechanisms of MSC-modulated therapeutic effects in repair of ocular surface disease remain largely unknown. Cell Death and Disease the efficacy of corneal repair is accompanied by MSC-mediated mitochondrial donation The outcome of these proof-of-concept studies will enable us to develop a novel strategy to manipulate stem cell-based tissue repair by regulating direct mitochondrial transfer

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