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      The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke

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          Abstract

          Mesenchymal stem cells (MSCs) hold great potential as a regenerative therapy for stroke, leading to increased repair and functional recovery in animal models of cerebral ischaemia. While it was initially hypothesised that cell replacement was an important mechanism of action of MSCs, focus has shifted to their paracrine actions or the so called “bystander” effect. MSCs secrete a wide array of growth factors, chemokines, cytokines and extracellular vesicles, commonly referred to as the MSC secretome. There is evidence suggesting the MSC secretome can promote repair through a number of mechanisms including preventing cell apoptosis, modulating the inflammatory response and promoting endogenous repair mechanisms such as angiogenesis and neurogenesis. In this review, we will discuss the in vitro approaches currently being employed to drive the MSC secretome towards a more anti-inflammatory and regenerative phenotype. We will then examine the role of the secretome in promoting repair and improving recovery in preclinical models of cerebral ischaemia.

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          Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord.

          Hwai-Shi Wang, Shih-Chieh Hung, Shu-Tine Peng … (2004)
          The Wharton's jelly of the umbilical cord contains mucoid connective tissue and fibroblast-like cells. Using flow cytometric analysis, we found that mesenchymal cells isolated from the umbilical cord express matrix receptors (CD44, CD105) and integrin markers (CD29, CD51) but not hematopoietic lineage markers (CD34, CD45). Interestingly, these cells also express significant amounts of mesenchymal stem cell markers (SH2, SH3). We therefore investigated the potential of these cells to differentiate into cardiomyocytes by treating them with 5-azacytidine or by culturing them in cardiomyocyte-conditioned medium and found that both sets of conditions resulted in the expression of cardiomyocyte markers, namely N-cadherin and cardiac troponin I. We also showed that these cells have multilineage potential and that, under suitable culture conditions, are able to differentiate into cells of the adipogenic and osteogenic lineages. These findings may have a significant impact on studies of early human cardiac differentiation, functional genomics, pharmacological testing, cell therapy, and tissue engineering by helping to eliminate worrying ethical and technical issues.
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            Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties.

            Thomas Bartosh, Joni Ylöstalo, Arezoo Mohammadipoor … (2010)
            Previous reports suggested that culture as 3D aggregates or as spheroids can increase the therapeutic potential of the adult stem/progenitor cells referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). Here we used a hanging drop protocol to prepare human MSCs (hMSCs) as spheroids that maximally expressed TNFalpha stimulated gene/protein 6 (TSG-6), the antiinflammatory protein that was expressed at high levels by hMSCs trapped in the lung after i.v. infusion and that largely explained the beneficial effects of hMSCs in mice with myocardial infarcts. The properties of spheroid hMSCs were found to depend critically on the culture conditions. Under optimal conditions for expression of TSG-6, the hMSCs also expressed high levels of stanniocalcin-1, a protein with both antiinflammatory and antiapoptotic properties. In addition, they expressed high levels of three anticancer proteins: IL-24, TNFalpha-related apoptosis inducing ligand, and CD82. The spheroid hMSCs were more effective than hMSCs from adherent monolayer cultures in suppressing inflammatory responses in a coculture system with LPS-activated macrophages and in a mouse model for peritonitis. In addition, the spheroid hMSCs were about one-fourth the volume of hMSCs from adherent cultures. Apparently as a result, larger numbers of the cells trafficked through the lung after i.v. infusion and were recovered in spleen, liver, kidney, and heart. The data suggest that spheroid hMSCs may be more effective than hMSCs from adherent cultures in therapies for diseases characterized by sterile tissue injury and unresolved inflammation and for some cancers that are sensitive to antiinflammatory agents.
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              Autologous mesenchymal stem cell transplantation in stroke patients.

              Oh Young Bang, Jin Soo Lee, Phil Lee … (2005)
              Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. We examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. We prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits into one of two treatment groups: the MSC group (n = 5) received intravenous infusion of 1 x 10(8) autologous MSCs, whereas the control group (n = 25) did not receive MSCs. Changes in neurological deficits and improvements in function were compared between the groups for 1 year after symptom onset. Neuroimaging was performed serially in five patients from each group. Outcomes improved in MSC-treated patients compared with the control patients: the Barthel index (p = 0.011, 0.017, and 0.115 at 3, 6, and 12 months, respectively) and modified Rankin score (p = 0.076, 0.171, and 0.286 at 3, 6, and 12 months, respectively) of the MSC group improved consistently during the follow-up period. Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cereb Blood Flow Metab
                Journal ID (iso-abbrev): J. Cereb. Blood Flow Metab
                Journal ID (publisher-id): JCB
                Journal ID (hwp): spjcb
                Title: Journal of Cerebral Blood Flow & Metabolism
                Publisher: SAGE Publications (Sage UK: London, England )
                ISSN (Print): 0271-678X
                ISSN (Electronic): 1559-7016
                Publication date (Electronic): 17 May 2018
                Publication date (Print): August 2018
                Volume: 38
                Issue: 8
                Pages: 1276-1292
                Affiliations
                [1-0271678X18776802]Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
                Author notes
                [*]Stuart M Allan, Faculty of Biology, Medicine and Health, The University of Manchester, AV Hill Building, Manchester M13 9PT, UK. Email: stuart.allan@ 123456manchester.ac.uk
                Author information
                http://orcid.org/0000-0002-9216-9414
                Article
                Publisher ID: 10.1177_0271678X18776802
                DOI: 10.1177/0271678X18776802
                PMC ID: 6077926
                PubMed ID: 29768965
                SO-VID: ae48ca76-bc5d-4401-8f7e-1c258aaf1a4e
                Copyright © © The Author(s) 2018
                License:

                This article is distributed under the terms of the Creative Commons Attribution 4.0 License ( http://www.creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 26 January 2018
                Date revision received : 11 April 2018
                Date accepted : 14 April 2018
                Categories
                Subject: Review Articles

                ScienceOpen disciplines: Neurosciences
                Keywords: cell therapy,mesenchymal stem cell,repair,stroke,secretome
                Data availability:
                ScienceOpen disciplines: Neurosciences
                Keywords: cell therapy, mesenchymal stem cell, repair, stroke, secretome

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