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      Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell-free therapy

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          ABSTRACT

          Through traditional medicine, there were diseases and disorders that previously remained untreated or were simply thought to be incurable. Since the discovery of mesenchymal stem cells (MSCs), there has been a flurry of research to develop MSC-based therapy for diseases and disorders. It is now well-known that MSCs do not typically engraft after transplantation and exhibit their therapeutic effect via a paracrine mechanism. In addition to secretory proteins, MSCs also produce extracellular vesicles (EVs), membrane-bound nanovesicles containing proteins, DNA and RNA. The secreted vesicles then interact with target cells and deliver their contents, imparting their ultimate therapeutic effect. Unlike the widely studied cancer cells, the yield of MSC-exosomes is a limiting factor for large-scale production for cell-free therapies. Here we summarise potential approaches to increase the yield of such vesicles while maintaining or enhancing their efficacy by engineering the extracellular environment and intracellular components of MSCs.

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          Most cited references38

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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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            Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes

            Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1α-overexpressing donor MSCs (HIF-MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF-MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF-MSC than in MSC controls. The addition of Jagged1-containing exosomes from MSC and HIF-MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary-like tube formation, and both processes were stimulated by HIF-1α. Finally, subcutaneous injection of Jagged 1-containing exosomes from MSC and HIF-MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF-MSC cultures. All Jagged1-mediated effects could be blocked by prior incubation of exosomes with an anti-Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF-1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia-related disease. Stem Cells 2017;35:1747-1759.
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              Signaling Pathways in Exosomes Biogenesis, Secretion and Fate

              Exosomes are small extracellular vesicles (30–100 nm) derived from the endosomal system, which have raised considerable interest in the last decade. Several studies have shown that they mediate cell-to-cell communication in a variety of biological processes. Thus, in addition to cell-to-cell direct interaction or secretion of active molecules, they are now considered another class of signal mediators. Exosomes can be secreted by several cell types and retrieved in many body fluids, such as blood, urine, saliva and cerebrospinal fluid. In addition to proteins and lipids, they also contain nucleic acids, namely mRNA and miRNA. These features have prompted extensive research to exploit them as a source of biomarkers for several pathologies, such as cancer and neurodegenerative disorders. In this context, exosomes also appear attractive as gene delivery vehicles. Furthermore, exosome immunomodulatory and regenerative properties are also encouraging their application for further therapeutic purposes. Nevertheless, several issues remain to be addressed: exosome biogenesis and secretion mechanisms have not been clearly understood, and physiological functions, as well as pathological roles, are far from being satisfactorily elucidated.
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                Author and article information

                Journal
                J Extracell Vesicles
                J Extracell Vesicles
                ZJEV
                zjev20
                Journal of Extracellular Vesicles
                Taylor & Francis
                2001-3078
                2018
                26 September 2018
                : 7
                : 1
                : 1522236
                Affiliations
                [a ]Surgical Bioengineering Laboratory, Department of Surgery, University of California, Davis School of Medicine , Sacramento, CA, USA
                [b ]CIRM Bridges to Stem Cell Research Program, California State University , Sacramento, CA, USA
                [c ]Institute for Paediatric Regenerative Medicine, Shriners Hospital for Children/UC Davis School of Medicine , Sacramento, CA, USA
                [d ]Department of Burn and Plastic Surgery, The Third Xiangya Hospital of Central South University , Changsha, Hunan, P.R. China
                Author notes
                CONTACT Aijun Wang aawang@ 123456ucdavis.edu Department of Surgery, Surgical Bioengineering Laboratory, University of California Davis School of Medicine, Research II , Suite 3005, 4625 2nd Avenue, Sacramento, CA95817, USA
                Author information
                http://orcid.org/0000-0002-0163-8562
                http://orcid.org/0000-0002-3530-5993
                http://orcid.org/0000-0002-2985-3627
                Article
                1522236
                10.1080/20013078.2018.1522236
                6161586
                30275938
                6eec0a78-f0fa-4780-b5ff-8fccb18e0c0d
                © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 November 2017
                : 08 August 2018
                : 27 August 2018
                Page count
                Figures: 4, References: 75, Pages: 12
                Funding
                Funded by: California Institute for Regenerative Medicine 10.13039/100000900
                Award ID: grant number EDUC2-08390
                Funded by: March of Dimes Foundation 10.13039/100000912
                Award ID: grant number 5-FY16-82
                Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
                Award ID: grant number 5R01NS100761-02
                Funded by: Shriners Hospitals for Children 10.13039/100011781
                Award ID: grant number 87410-NCA-17
                Funded by: Shriners Hospitals for Children 10.13039/100011781
                Award ID: grant number 85119-NCA-18
                Funded by: University of California, Davis 10.13039/100007707
                Award ID: C4B Pilot Grant
                This work was supported by the March of Dimes Foundation [grant number 5-FY16-82]; National Institute of Neurological Disorders and Stroke [grant number 5R01NS100761-02]; California Institute of Regenerative Medicine Bridges to Stem Cell Research Program training grant [grant number EDUC2-08390]; Shriners Hospitals for Children [grant number 87410-NCA-17]; Shriners Hospitals for Children [grant number 85119-NCA-18]; University of California, Davis [C4B Pilot Grant].
                Categories
                Review Article

                mesenchymal stem cells,extracellular vesicles
                mesenchymal stem cells, extracellular vesicles

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