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Title: Mitochondrial transfer from induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial and smooth muscle cells attenuates oxidative stress-induced injury
Author: Li, Xiang
ISNI:       0000 0004 7228 7848
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by persistent airflow limitation that is not fully reversible and is usually caused by cigarette smoke (CS). The disease is predicted to be the fourth leading cause of death by 2030, but none of the currently available treatments can alleviate the progressive decline in lung function. Mesenchymal stem cells (MSCs) are fibroblast-like multipotent stem cells that can be isolated from various tissues such as bone marrow (BM-MSCs). Despite numerous reports of their efficacy in COPD-related pre-clinical models, BM-MSCs have not demonstrated efficacy in a clinical trial of COPD, highlighting the need for improved MSC-based therapy. The in vitro derivation of MSCs from induced pluripotent stem cells (iPSCs) has provided a new source of MSCs. Compared to BM-MSCs, iPSC-derived MSCs (iPSC-MSCs) are a more abundant source, have a higher expanding capacity and are possibly not subject to the ageing-associated dysfunction seen in BM-MSCs. In this study I determined the effects of human iPSC-MSCs in a rat COPD model using BM-MSCs as comparison. Rats were exposed to CS for 1 hr/day for 56 days. iPSC-MSCs or BM-MSCs were administrated at days 29 and 43. iPSC-MSCs demonstrated superior effects over BM-MSCs in attenuating CS-induced lung airspace enlargement, fibrosis, inflammation and apoptosis. In a mouse model of ozone-induced lung damage, intravenous administration of iPSC-MSCs 24 hours before ozone exposure for 3 hours alleviated airway hyper-responsiveness, inflammation and apoptosis in the lung. There is increasing evidence demonstrating that mitochondrial dysfunction may play an important role in COPD pathogenesis, indicating mitochondria as a potential therapeutic target. Meanwhile, mitochondrial transfer from MSCs to injured airway cells has been reported as a novel mechanism of action for MSCs. In this study mitochondrial transfer from iPSC-MSCs to the airway epithelium of CS-exposed rats was detected. iPSC-MSCs also transferred mitochondria to bronchial epithelial BEAS-2B cells and primary airway smooth muscle cell (ASMCs) in vitro in a direct co-culture system, an effect that was enhanced by CS medium (CSM). Direct co-culture with iPSC-MSCs alleviated CSM-induced ATP deprivation in BEAS-2B cells, as well as CSM-induced mitochondrial reactive oxygen species (ROS), apoptosis and reduction of mitochondrial membrane potential (ΔΨm) in ASMCs. Administration of iPSC-MSCs also prevented ozone-induced mitochondrial ROS and ΔΨm reduction in mouse lungs. The paracrine effects of iPSC-MSCs were also investigated. iPSC-MSC-derived conditioned medium (iPSC-MSCs-CdM) protected BEAS2-B cells from CSM-induced apoptosis. The effect was reduced by depleting stem cell factor (SCF) from iPSC-MSCs-CdM. However, both iPSC-MSCs-CdM and trans-well inserts containing iPSC-MSCs were only able to alleviate CSM-induced mitochondrial ROS, but not ΔΨm reduction and apoptosis, in ASMCs. I demonstrated the capacity of iPSC-MSCs to alleviate oxidative stress-induced COPD phenotype in vivo. Mitochondrial transfer from iPSC-MSCs was able to alleviate oxidative stress-induced mitochondrial dysfunction and apoptosis in target cells. The full capacity of iPSC-MSCs to achieve these effects may rely on a combination of cell-cell contact and release of paracrine factors. These findings define iPSC-MSCs as a promising candidate for the development of MSCs-based therapy of COPD.
Supervisor: Chung, Kian Fan ; Mak, Judith Choi-wo Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral