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      Mesenchymal stem cells microvesicles stabilize endothelial barrier function partly mediated by hepatocyte growth factor (HGF)

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          Abstract

          Background

          Mesenchymal stem cells microvesicles (MSC-MVs) stabilize endothelial barrier function in acute lung injury (ALI); however, the detailed mechanism remains to be further defined. Hepatocyte growth factor (HGF), which is derived from MSC-MVs, might have a key role in the restoration of endothelial barrier function by MSC-MVs.

          Methods

          MSCs with lentiviral vector-mediated HGF gene knockdown (siHGF-MSC) were generated. A co-culture model of pulmonary microvascular endothelial cells and MSC-MVs collected from MSCs or siHGF-MSCs after 24 h of hypoxic culture was utilized. Then, endothelial paracellular and transcellular permeabilities were detected. VE-cadherin, and occludin protein expression in the endothelial cells was measured using Western blot. Endothelial cell proliferation was analysed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Endothelial cell apoptosis was analysed using TUNEL assay. Finally, IL-6 and IL-10 production was determined via an enzyme-linked immunosorbent assay (ELISA).

          Results

          Treatment with MSC-MVs significantly decreased LPS-induced endothelial paracellular and transcellular permeabilities, and the effect was significantly inhibited after HGF gene knockdown in MSC-MVs. Furthermore, treatment with MSC-MVs increased the expression of the endothelial intercellular junction proteins VE-cadherin and occludin. Treatment with MSC-MVs also decreased endothelial apoptosis and induced endothelial cell proliferation. Finally, the treatment reduced IL-6 production and increased IL-10 production in the conditioned media of endothelial cells. However, the effects of the treatment with MSC-MVs were inhibited after HGF gene knockdown.

          Conclusions

          MSC-MVs protect the barrier functions of pulmonary microvascular endothelial cells, which can be partly attributed to the presence of HGF in the MSC-MVs.

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          Regulation of endothelial permeability via paracellular and transcellular transport pathways.

          Yulia Komarova, Asrar B. Malik (2010)
          The endothelium functions as a semipermeable barrier regulating tissue fluid homeostasis and transmigration of leukocytes and providing essential nutrients across the vessel wall. Transport of plasma proteins and solutes across the endothelium involves two different routes: one transcellular, via caveolae-mediated vesicular transport, and the other paracellular, through interendothelial junctions. The permeability of the endothelial barrier is an exquisitely regulated process in the resting state and in response to extracellular stimuli and mediators. The focus of this review is to provide a comprehensive overview of molecular and signaling mechanisms regulating endothelial barrier permeability with emphasis on the cross-talk between paracellular and transcellular transport pathways.
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            A systematic review of preclinical studies on the therapeutic potential of mesenchymal stromal cell-derived microvesicles.

            George B. Richardson, Jason Tay, Dean Fergusson … (2015)
            The therapeutic potential of mesenchymal stromal cells (MSCs) may be largely mediated by paracrine factors contained in microvesicles (MV) released from intracellular endosomes. A systematic review of controlled interventional animal studies was performed to identify models of organ injury where clinical translation of MSC-derived microvesicle therapy appears most promising as regenerative therapy. A total of 190 published articles were identified in our systematic search of electronic databases (MEDLINE, EMBASE, PUBMED). After screening for eligibility, a total of 17 controlled studies testing MSC-derived MVs as therapeutic interventions in animal models of disease underwent comprehensive review, quality assessment, and data extraction. Thirteen studies addressed the regenerative potential following organ injury. Six studies were included on acute kidney injury, 4 on myocardial infarction and reperfusion injury, 1 on hind limb ischemia, 1 on liver injury, and 1 on hypoxic lung injury. Four studies addressed immunological effects of MSC-derived MVs on inhibiting tumor growth. Twelve studies (71%) provided explicit information regarding the number of animals allocated to treatment or control groups. Five studies (29%) randomly assigned animals to treatment or control groups and only 1 study (6%) reported on blinding. Therapeutic intervention involved isolation of exosomes (40-100 nm) in eight studies, while nine studies tested unfractionated microvesicles (<1,000 nm). In studies of tissue regeneration, all 13 reported that treatment with MSC-derived MVs improved at least one major/clinical parameter associated with organ dysfunction. Three of 4 studies evaluating the inhibition of tumor growth reported benefit. In preclinical studies, the use of MSC-derived MVs is strongly associated with improved organ function following injury and may be useful for inhibiting tumor growth. Improved preclinical study quality in terms of treatment allocation reporting, randomization and blinding will accelerate needed progress towards clinical trials that should assess feasibility and safety of this therapeutic approach in humans.
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              Rho GTPases and the regulation of endothelial permeability.

              Beata Wojciak-Stothard, Anne J Ridley (2002)
              Endothelial permeability depends on the integrity of intercellular junctions as well as actomyosin-based cell contractility. Rho GTPases have been implicated in signalling by many vasoactive substances including thrombin, tumour necrosis factor alpha (TNF-alpha), bradykinin, histamine, lysophosphatidic acid (LPA), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF). Two Rho family GTPases, Rho and Rac, have emerged as key regulators acting antagonistically to regulate endothelial barrier function: Rho increases actomyosin contractility, which facilitates breakdown of intercellular junctions, whereas Rac stabilizes endothelial junctions and counteracts the effects of Rho. In this review, we present evidence for the opposing effects of these two regulatory proteins and discuss links between them and other key signalling molecules such as cyclic AMP (cAMP), cyclic GMP (cGMP), phosphatidylinositide 3-kinases (PI3Ks), mitogen-activated protein kinases (MAPKs), and protein kinases C (PKCs). We also discuss strategies for targeting Rho GTPase signalling in therapies for diseases involving altered endothelial permeability.
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                Author and article information

                Contributors
                Hualing Wang: 18051063567@163.com
                Ruiqiang Zheng: 13952721411@163.com
                Qihong Chen: chenqihong00@163.com
                Jun Shao: sjun1982@163.com
                Jiangquan Yu: wanghualing00@126.com
                Shuling Hu: shulinghu2013@163.com
                Journal
                Journal ID (nlm-ta): Stem Cell Res Ther
                Journal ID (iso-abbrev): Stem Cell Res Ther
                Title: Stem Cell Research & Therapy
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1757-6512
                Publication date (Electronic): 29 September 2017
                Publication date PMC-release: 29 September 2017
                Publication date Collection: 2017
                Volume: 8
                Electronic Location Identifier: 211
                Affiliations
                [1 ]GRID grid.268415.c, Department of Cardiology, Subei People’s Hospital, School of Medicine, , Yangzhou University, ; 98 Nantong West Road, Yangzhou, 225001 People’s Republic of China
                [2 ]GRID grid.268415.c, Department of Critical Care Medicine, Subei People’s Hospital, School of Medicine, , Yangzhou University, ; 98 Nantong West Road, Yangzhou, 225001 People’s Republic of China
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Critical Care Medicine, Zhongshan Hospital, , Fudan University, ; Shanghai, 200032 China
                Article
                Publisher ID: 662
                DOI: 10.1186/s13287-017-0662-7
                PMC ID: 5623961
                PubMed ID: 28969681
                SO-VID: 8d135986-8ebe-4bc0-8683-7c8864cbb0fd
                Copyright © © The Author(s). 2017
                License:

                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
                Date received : 21 July 2017
                Date revision received : 31 August 2017
                Date accepted : 6 September 2017
                Funding
                Funded by: Jiangsu Provincial Medical Youth Talent
                Award ID: QNRC2016317
                Award Recipient :
                Funded by: Society development of Jiangsu province-New type of clinical diagnosis and treatment technology
                Award ID: BE2017691
                Award Recipient :
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Molecular medicine
                Keywords: mesenchymal stem cells microvesicles,hepatocyte growth factor,endothelial permeability,acute lung injury
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: mesenchymal stem cells microvesicles, hepatocyte growth factor, endothelial permeability, acute lung injury

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