PMID- 31678243 OWN - NLM STAT- MEDLINE DCOM- 20200522 LR - 20231213 IS - 1096-0333 (Electronic) IS - 0041-008X (Print) IS - 0041-008X (Linking) VI - 385 DP - 2019 Dec 15 TI - Protective role of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in cigarette smoke-induced mitochondrial dysfunction in mice. PG - 114788 LID - S0041-008X(19)30396-5 [pii] LID - 10.1016/j.taap.2019.114788 [doi] AB - BACKGROUND: Cigarette smoke (CS)-induced lung inflammation and Chronic Obstructive Pulmonary disease (COPD) involves mitochondrial dysfunction. Mesenchymal stem cells (MSC) and MSC-derived exosomes (EXO) are reported to show therapeutic effects in many animal models of inflammation and injury. In the present study, we determined the role of MSC and EXO intervention in CS-induced lung inflammation with a focus on mitochondrial dysfunction. METHODS: EXO were characterized using Western blot for exosomal markers, tunable resistive pulse sensing by qNano and transmission electron microscopy (TEM). Mitochondrial reporter mice (mt-Keima and mito-QC) were exposed to air or CS for 10 days. mt-Keima mice were treated with intraperitoneal injections of MSC or EXO or MSC and EXO (MSC + EXO) for 10 days. Total cell counts, differential cell counts were performed using automated cell counter and flow cytometry respectively. Further, the levels of pro-inflammatory mediators in bronchoalveolar lavage (BAL) fluid were measured using ELISA. Western blot analysis, quantitative PCR, confocal microscopy were used in the current study to determine the effects in the lungs of CS exposed mice. Seahorse flux analyzer was used to measure the oxidative-phosphorylation (OXPHOS) in the BEAS2B cells and BEAS2B - mMSC co-culture experiments. RESULTS: CS exposure increased the inflammatory cellular infiltrations in the lungs of the mt-Keima mice. MSC + EXO treatment showed protection compared to individual treatments (MSC or EXO alone). There were no changes in the mitophagy proteins like PINK1 and Parkin, which was also found using the mito-QC mice. CS exposure led to significant increase in the mitochondrial fission protein DRP1 and other DAMPs pathway mediators like S100A4 and S100A8, HMGB1, RAGE and AGE. MSC + EXO treatment increased the gene expression of (fusion genes) mfn1, mfn2 and opa1. Additionally, the rhot1 gene expression was increased in MSC + EXO treatment group compared to Air- and CS exposed groups. BEAS2B-mMSC co-cultures showed protective response against the CSE-altered mitochondrial respiration parameters, confirming the beneficial effect of MSC towards human bronchial lung epithelial cells. CONCLUSION: CS affects some of early mitochondrial genes involved in the fission/fusion process, enhancing the damage response along with altered cytokine levels. MSC + EXO combination treatment showed their protective effects. MSC + EXO combination treatment may act against these early events caused by CS exposure owing to its anti-inflammatory and other mitochondrial transfer mechanisms. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Maremanda, Krishna Prahlad AU - Maremanda KP AD - Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY, USA. FAU - Sundar, Isaac Kirubakaran AU - Sundar IK AD - Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY, USA. FAU - Rahman, Irfan AU - Rahman I AD - Department of Environmental Medicine, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY, USA. Electronic address: irfan_rahman@urmc.rochester.edu. LA - eng GR - R01 HL135613/HL/NHLBI NIH HHS/United States GR - R01 HL085613/HL/NHLBI NIH HHS/United States GR - R01 ES029177/ES/NIEHS NIH HHS/United States GR - R01 HL133404/HL/NHLBI NIH HHS/United States GR - R21 ES028006/ES/NIEHS NIH HHS/United States GR - R56 ES027012/ES/NIEHS NIH HHS/United States GR - R01 HL137738/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20191031 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (Alarmins) RN - 0 (Cytokines) RN - 0 (Smoke) SB - IM MH - Alarmins/analysis MH - Animals MH - Cytokines/analysis MH - Exosomes/*physiology MH - Lung/metabolism/pathology MH - Mesenchymal Stem Cells/*physiology MH - Mice MH - Mitochondria/*physiology MH - Mitophagy MH - Oxidative Phosphorylation MH - Smoke/*adverse effects MH - Nicotiana/*toxicity PMC - PMC6894395 MID - NIHMS1542582 OTO - NOTNLM OT - COPD OT - Cellular Senescence OT - Exosomes OT - Mesenchymal stem cells OT - Mitochondria COIS- Conflict of interests The authors declare no conflict of interest. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2019/11/05 06:00 MHDA- 2020/05/23 06:00 PMCR- 2020/12/15 CRDT- 2019/11/04 06:00 PHST- 2019/07/24 00:00 [received] PHST- 2019/10/17 00:00 [revised] PHST- 2019/10/21 00:00 [accepted] PHST- 2019/11/05 06:00 [pubmed] PHST- 2020/05/23 06:00 [medline] PHST- 2019/11/04 06:00 [entrez] PHST- 2020/12/15 00:00 [pmc-release] AID - S0041-008X(19)30396-5 [pii] AID - 10.1016/j.taap.2019.114788 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2019 Dec 15;385:114788. doi: 10.1016/j.taap.2019.114788. Epub 2019 Oct 31.