42
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mesenchymal stromal cells (MSC) have been reported to improve bacterial clearance in preclinical models of Acute Respiratory Distress Syndrome (ARDS) and sepsis. The mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the antimicrobial effect of MSC in vivo depends on their modulation of macrophage phagocytic activity which occurs through mitochondrial transfer. We established that selective depletion of alveolar macrophages (AM) with intranasal (IN) administration of liposomal clodronate resulted in complete abrogation of MSC antimicrobial effect in the in vivo model of Escherichia coli pneumonia. Furthermore, we showed that MSC administration was associated with enhanced AM phagocytosis in vivo. We showed that direct coculture of MSC with monocyte‐derived macrophages enhanced their phagocytic capacity. By fluorescent imaging and flow cytometry we demonstrated extensive mitochondrial transfer from MSC to macrophages which occurred at least partially through tunneling nanotubes (TNT)‐like structures. We also detected that lung macrophages readily acquire MSC mitochondria in vivo, and macrophages which are positive for MSC mitochondria display more pronounced phagocytic activity. Finally, partial inhibition of mitochondrial transfer through blockage of TNT formation by MSC resulted in failure to improve macrophage bioenergetics and complete abrogation of the MSC effect on macrophage phagocytosis in vitro and the antimicrobial effect of MSC in vivo. Collectively, this work for the first time demonstrates that mitochondrial transfer from MSC to innate immune cells leads to enhancement in phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS. S tem C ells 2016;34:2210–2223

          Related collections

          Most cited references17

          • Record: found
          • Abstract: found
          • Article: not found

          Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer.

          Mesenchymal stem cells can be used as a novel treatment of ischemic vascular disease; however, their therapeutic effect and mechanism of action require further evaluation. Mitochondrial dysfunction has core functions in ischemia-reperfusion injury of the microvascular network. A recent discovery has shown that intercellular communication using tunneling nanotubes can transfer mitochondria between adjacent cells. This study aimed to investigate the tunneling nanotube mechanisms that might be involved in stem cell-mediated mitochondrial rescue of injured vascular endothelial cells. Using laser scanning confocal microscopy, mitochondrial transfer via a tunneling nanotube-like structure was detected between mesenchymal stem cells and human umbilical vein endothelial cells. Oxygen glucose deprivation and reoxygenation were performed on human umbilical vein endothelial cells, which induced mitochondrial transfer through tunneling nanotube-like structures to become frequent and almost unidirectional from mesenchymal stem cells to injured endothelial cells, thereby resulting in the rescue of aerobic respiration and protection of endothelial cells from apoptosis. We found that the formation of tunneling nanotube-like structures might represent a defense and rescue mechanism through phosphatidylserines exposed on the surface of apoptotic endothelial cells and stem cell recognition. Our data provided evidence that stem cells can rescue damaged vascular endothelial cells through a mechanism that has not yet been identified.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage.

            Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury.

              Mitochondrial damage and dysfunction occur during ischemia and modulate cardiac function and cell survival significantly during reperfusion. We hypothesized that transplantation of autologously derived mitochondria immediately prior to reperfusion would ameliorate these effects. New Zealand White rabbits were used for regional ischemia (RI), which was achieved by temporarily snaring the left anterior descending artery for 30 min. Following 29 min of RI, autologously derived mitochondria (RI-mitochondria; 9.7 ± 1.7 × 10(6)/ml) or vehicle alone (RI-vehicle) were injected directly into the RI zone, and the hearts were allowed to recover for 4 wk. Mitochondrial transplantation decreased (P < 0.05) creatine kinase MB, cardiac troponin-I, and apoptosis significantly in the RI zone. Infarct size following 4 wk of recovery was decreased significantly in RI-mitochondria (7.9 ± 2.9%) compared with RI-vehicle (34.2 ± 3.3%, P < 0.05). Serial echocardiograms showed that RI-mitochondria hearts returned to normal contraction within 10 min after reperfusion was started; however, RI-vehicle hearts showed persistent hypokinesia in the RI zone at 4 wk of recovery. Electrocardiogram and optical mapping studies showed that no arrhythmia was associated with autologously derived mitochondrial transplantation. In vivo and in vitro studies show that the transplanted mitochondria are evident in the interstitial spaces and are internalized by cardiomyocytes 2-8 h after transplantation. The transplanted mitochondria enhanced oxygen consumption, high-energy phosphate synthesis, and the induction of cytokine mediators and proteomic pathways that are important in preserving myocardial energetics, cell viability, and enhanced post-infarct cardiac function. Transplantation of autologously derived mitochondria provides a novel technique to protect the heart from ischemia-reperfusion injury.
                Bookmark

                Author and article information

                Journal
                Stem Cells
                Stem Cells
                10.1002/(ISSN)1549-4918
                STEM
                Stem Cells (Dayton, Ohio)
                John Wiley and Sons Inc. (Hoboken )
                1066-5099
                1549-4918
                29 April 2016
                August 2016
                : 34
                : 8 ( doiID: 10.1002/stem.v34.8 )
                : 2210-2223
                Affiliations
                [ 1 ] Centre for Experimental Medicine, School of Medicine Dentistry & Biomedical SciencesQueen's University Belfast Northern IrelandUK
                [ 2 ] Department of Anaesthesiology & MedicineUniversity of California San Francisco San Francisco CaliforniaUSA
                Author notes
                [*] [* ]Correspondence: Anna Krasnodembskaya, Ph.D., Centre for Experimental Medicine, School of Medicine Dentistry and Biomedical Sciences, Queen's University of Belfast, Room 2.059, The Wellcome Wolfson Building, 97 Lisburn Road, Belfast, BT9 7BL, UK. Telephone: +442890976386; e‐mail: a.krasnodembskaya@ 123456qub.ac.uk
                Article
                STEM2372
                10.1002/stem.2372
                4982045
                27059413
                80857bff-7abc-4bf8-84bd-81e6f0ddc405
                © 2016 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 October 2015
                : 03 March 2016
                : 14 March 2016
                Page count
                Pages: 14
                Funding
                Funded by: Texas A&M Health Science Center College of Medicine Institute for Regenerative Medicine at Scott & White
                Award ID: MRC MR/L017229/1
                Award ID: NHLBI HL51854 (MAM). Some of the materials employed in this work were provided by the
                Funded by: NCRR
                Award ID: through a grant from
                Funded by: NIH
                Award ID: of the
                Award ID: Grant # P40RR017447
                Categories
                Translational and Clinical Research
                Translational and Clinical Research
                Custom metadata
                2.0
                stem2372
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:12.08.2016

                Molecular medicine
                mesenchymal stem cells,macrophages,mitochondrial transfer,ards,phagocytosis
                Molecular medicine
                mesenchymal stem cells, macrophages, mitochondrial transfer, ards, phagocytosis

                Comments

                Comment on this article