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      Renal Regenerative Potential of Different Extracellular Vesicle Populations Derived from Bone Marrow Mesenchymal Stromal Cells

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          Abstract

          Extracellular vesicles (EVs) derived from human bone marrow mesenchymal stromal cells (MSCs) promote the regeneration of kidneys in different animal models of acute kidney injury (AKI) in a manner comparable with the cells of origin. However, due to the heterogeneity observed in the EVs isolated from MSCs, it is unclear which population is responsible for the proregenerative effects. We therefore evaluated the effect of various EV populations separated by differential ultracentrifugation (10K population enriched with microvesicles and 100K population enriched with exosomes) on AKI recovery. Only the exosomal-enriched population induced an improvement of renal function and morphology comparable with that of the total EV population. Interestingly, the 100K EVs exerted a proproliferative effect on murine tubular epithelial cells, both in vitro and in vivo. Analysis of the molecular content from the different EV populations revealed a distinct profile. The 100K population, for instance, was enriched in specific mRNAs (CCNB1, CDK8, CDC6) reported to influence cell cycle entry and progression; miRNAs involved in regulating proliferative/antiapoptotic pathways and growth factors (hepatocyte growth factor and insulin-like growth factor-1) that could explain the effect of renal tubular cell proliferation. On the other hand, the EV population enriched in microvesicles (10K) was unable to induce renal regeneration and had a molecular profile with lower expression of proproliferative molecules. In conclusion, the different molecular composition of exosome- and microvesicle-enriched populations may explain the regenerative effect of EVs observed in AKI.

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          FunRich: An open access standalone functional enrichment and interaction network analysis tool.

          Mohashin Pathan, Shivakumar Keerthikumar, Ching-Seng Ang … (2015)
          As high-throughput techniques including proteomics become more accessible to individual laboratories, there is an urgent need for a user-friendly bioinformatics analysis system. Here, we describe FunRich, an open access, standalone functional enrichment and network analysis tool. FunRich is designed to be used by biologists with minimal or no support from computational and database experts. Using FunRich, users can perform functional enrichment analysis on background databases that are integrated from heterogeneous genomic and proteomic resources (>1.5 million annotations). Besides default human specific FunRich database, users can download data from the UniProt database, which currently supports 20 different taxonomies against which enrichment analysis can be performed. Moreover, the users can build their own custom databases and perform the enrichment analysis irrespective of organism. In addition to proteomics datasets, the custom database allows for the tool to be used for genomics, lipidomics and metabolomics datasets. Thus, FunRich allows for complete database customization and thereby permits for the tool to be exploited as a skeleton for enrichment analysis irrespective of the data type or organism used. FunRich (http://www.funrich.org) is user-friendly and provides graphical representation (Venn, pie charts, bar graphs, column, heatmap and doughnuts) of the data with customizable font, scale and color (publication quality).
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            Microvesicles Derived from Mesenchymal Stem Cells Enhance Survival in a Lethal Model of Acute Kidney Injury

            Stefania Bruno, Cristina Grange, Federica Collino … (2012)
            Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.
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              Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

              Johnathon Anderson, Henrik Johansson, Calvin S Graham … (2016)
              Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Tissue Eng Part A
                Journal ID (iso-abbrev): Tissue Eng Part A
                Journal ID (publisher-id): tea
                Title: Tissue Engineering. Part A
                Publisher: Mary Ann Liebert, Inc. (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                ISSN (Print): 1937-3341
                ISSN (Electronic): 1937-335X
                Publication date (Print): 01 November 2017
                Publication date (Electronic): 01 November 2017
                Publication date PMC-release: 01 November 2017
                Volume: 23
                Issue: 21-22
                Pages: 1262-1273
                Affiliations
                [ 1 ]Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino , Torino, Italy.
                [ 2 ]Department of Medical Sciences, Molecular Biotechnology Center, University of Torino , Torino, Italy.
                [ 3 ]Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil.
                [ 4 ]Leibniz Institute on Aging–Fritz Lipmann Institute (FLI) Beutenbergstrasse , Jena, Germany.
                [ 5 ]Human Genetics Foundation, University of Torino , Torino, Italy.
                [ 6 ]Division of Hematology/Oncology, Brown University , Rhode Island Hospital, Providence, Rhode Island.
                Author notes
                [*]

                This article is part of a special focus issue on Emerging Impact of Extracellular Vesicles on Tissue Engineering and Regeneration.

                Address correspondence to: Giovanni Camussi, MD, Department of Medical Sciences, Molecular Biotechnology Center, University of Torino Corso Dogliotti 14, Torino 10126, Italy

                E-mail: giovanni.camussi@ 123456unito.it
                Article
                Publisher ID: 10.1089/ten.tea.2017.0069
                DOI: 10.1089/ten.tea.2017.0069
                PMC ID: 5689130
                PubMed ID: 28471327
                SO-VID: 12da50e4-2189-4aa4-b45f-325f4e5699d4
                Copyright © © Stefania Bruno et al. 2017; Published by Mary Ann Liebert, Inc.
                License:

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

                History
                Date received : 09 February 2017
                Date accepted : 20 April 2017
                Page count
                Figures: 5, Tables: 5, References: 47, Pages: 12
                Categories
                Subject: Special Focus Articles *

                Keywords: adult stem cells,mesenchymal stem cells,kidney,exosomes,microvesicles
                Data availability:
                Keywords: adult stem cells, mesenchymal stem cells, kidney, exosomes, microvesicles

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