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      Regenerative abilities of mesenchymal stem cells through mitochondrial transfer

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          Abstract

          The past decade has witnessed an upsurge in studies demonstrating mitochondrial transfer as one of the emerging mechanisms through which mesenchymal stem cells (MSCs) can regenerate and repair damaged cells or tissues. It has been found to play a critical role in healing several diseases related to brain injury, cardiac myopathies, muscle sepsis, lung disorders and acute respiratory disorders. Several studies have shown that various mechanisms are involved in mitochondrial transfer that includes tunnel tube formation, micro vesicle formation, gap junctions, cell fusion and others modes of transfer. Few studies have investigated the mechanisms that contribute to mitochondrial transfer, primarily comprising of signaling pathways involved in tunnel tube formation that facilitates tunnel tube formation for movement of mitochondria from one cell to another. Various stress signals such as release of damaged mitochondria, mtDNA and mitochondrial products along with elevated reactive oxygen species levels trigger the transfer of mitochondria from MSCs to recipient cells. However, extensive cell signaling pathways that lead to mitochondrial transfer from healthy cells are still under investigation and the changes that contribute to restoration of mitochondrial bioenergetics in recipient cells remain largely elusive. In this review, we have discussed the phenomenon of mitochondrial transfer from MSCs to neighboring stressed cells, and how this aids in cellular repair and regeneration of different organs such as lung, heart, eye, brain and kidney. The potential scope of mitochondrial transfer in providing novel therapeutic strategies for treatment of various pathophysiological conditions has also been discussed.

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          Most cited references58

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          Mitochondrial DNA That Escapes from Autophagy Causes Inflammation and Heart Failure

          Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure 1 . However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA 2,3,4 . Mitochondria damaged by external hemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes 5 . Here, we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis, and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts exhibited infiltration of inflammatory cells and increased mRNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of the inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA 6 , or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9-ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.
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            Mitochondrial transfer between cells can rescue aerobic respiration.

            Current theory indicates that mitochondria were obtained 1.5 billion years ago from an ancient prokaryote. The mitochondria provided the capacity for aerobic respiration, the creation of the eukaryotic cell, and eventually complex multicellular organisms. Recent reports have found that mitochondria play essential roles in aging and determining lifespan. A variety of heritable and acquired diseases are linked to mitochondrial dysfunction. We report here that mitochondria are more dynamic than previously considered: mitochondria or mtDNA can move between cells. The active transfer from adult stem cells and somatic cells can rescue aerobic respiration in mammalian cells with nonfunctional mitochondria.
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              Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.

              Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.
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                Author and article information

                Contributors
                swatzpaliwal@gmail.com
                chaudhuri.rituparna@gmail.com
                +91-11-2659 3085 , a.agrawal@igib.in
                +91-11-2659 3085 , drmohantysujata@gmail.com
                Journal
                J Biomed Sci
                J. Biomed. Sci
                Journal of Biomedical Science
                BioMed Central (London )
                1021-7770
                1423-0127
                30 March 2018
                30 March 2018
                2018
                : 25
                : 31
                Affiliations
                [1 ]ISNI 0000 0004 1767 6103, GRID grid.413618.9, Stem Cell Facility, DBT Centre of Excellence for Stem Cell Research, , All India Institute of Medical Sciences, ; New Delhi, 110029 India
                [2 ]GRID grid.417639.e, Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung disease, , CSIR-Institute of Genomics and Integrative Biology, ; Delhi, 110007 India
                Article
                429
                10.1186/s12929-018-0429-1
                5877369
                29602309
                a2a62897-58d6-461d-8b95-24ccc71fc85e
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 November 2017
                : 14 March 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001407, Department of Biotechnology , Ministry of Science and Technology;
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                Molecular medicine
                mesenchymal stem cells,mitochondrial transfer mechanism,regenerative medicine

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