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      Adiponectin Stimulates Exosome Release to Enhance Mesenchymal Stem-Cell-Driven Therapy of Heart Failure in Mice

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Mesenchymal stem/stromal cells (MSCs) are cultured adult stem cells that originally reside in virtually all tissues, and the gain of MSCs by transplantation has become the leading form of cell therapy in various diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients. Here, we report that the cardioprotective properties of intravenously injected MSCs in a mouse model of pressure-overload heart failure largely depend on circulating adiponectin, an adipocyte-secreted factor. The injected MSCs exert their function through exosomes, extracellular vesicles of endosome origin. Adiponectin stimulated exosome biogenesis and secretion through binding to T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin, on MSCs. A pharmacological or adenovirus-mediated genetic increase in plasma adiponectin enhanced the therapeutic efficacy of MSCs. Our findings provide novel insights into the importance of adiponectin in mesenchymal-progenitor-mediated organ protections.

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          Abstract

          Mesenchymal stem/stromal cell (MSC) therapies are emergently under development for various diseases such as heart failure and also acute respiratory distress syndrome (ARDS) evoked by COVID-19 infections. Nakamura et al. uncovered the importance of adiponectin in the circulation and T-cadherin in human adipose-derived MSCs to enhance exosome synthesis reading to treat a heart failure model.

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          Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.

          C Weyer, T. Funahashi, S. Tanaka … (2001)
          Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.
          Article 0 comments Cited 470 times – based on 0 reviews     Review now
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            Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice

            Takafumi Imai, Yuki Takahashi, Makiya Nishikawa … (2015)
            Previous studies using B16BL6-derived exosomes labelled with gLuc–lactadherin (gLuc-LA), a fusion protein of Gaussia luciferase (a reporter protein) and lactadherin (an exosome-tropic protein), showed that the exosomes quickly disappeared from the systemic circulation after intravenous injection in mice. In the present study, the mechanism of rapid clearance of intravenously injected B16BL6 exosomes was investigated. gLuc-LA-labelled exosomes were obtained from supernatant of B16BL6 cells after transfection with a plasmid DNA encoding gLuc-LA. Labelling was stable when the exosomes were incubated in serum. By using B16BL6 exosomes labelled with PKH26, a lipophilic fluorescent dye, it was demonstrated that PKH26-labelled B16BL6 exosomes were taken up by macrophages in the liver and spleen but not in the lung, while PKH26-labelled exosomes were taken up by the endothelial cells in the lung. Subsequently, gLuc-LA-labelled B16BL6 exosomes were injected into macrophage-depleted mice prepared by injection with clodronate-containing liposomes. The clearance of the intravenously injected B16BL6 exosomes from the blood circulation was much slower in macrophage-depleted mice than that in untreated mice. These results indicate that macrophages play important roles in the clearance of intravenously injected B16BL6 exosomes from the systemic circulation.
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              Mesenchymal stem cell therapy: Two steps forward, one step back.

              James Ankrum, Jeffrey M Karp (2010)
              Mesenchymal stem cell (MSC) therapy is poised to establish a new clinical paradigm; however, recent trials have produced mixed results. Although MSC were originally considered to treat connective tissue defects, preclinical studies revealed potent immunomodulatory properties that prompted the use of MSC to treat numerous inflammatory conditions. Unfortunately, although clinical trials have met safety endpoints, efficacy has not been demonstrated. We believe the challenge to demonstrate efficacy can be attributed in part to an incomplete understanding of the fate of MSC following infusion. Here, we highlight the clinical status of MSC therapy and discuss the importance of cell-tracking techniques, which have advanced our understanding of the fate and function of systemically infused MSC and might improve clinical application. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Shunbun Kita
                Journal
                Journal ID (nlm-ta): Mol Ther
                Journal ID (iso-abbrev): Mol. Ther
                Title: Molecular Therapy
                Publisher: The Author(s).
                ISSN (Print): 1525-0016
                ISSN (Electronic): 1525-0024
                Publication date PMC-release: 10 July 2020
                Publication date (Electronic): 10 July 2020
                Affiliations
                [1 ]Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
                [2 ]Department of Adipose Management, Graduate School of Medicine, Osaka University, Osaka, Japan
                [3 ]ROHTO Pharmaceutical Co., Ltd. Osaka, Japan
                [4 ]Department of Advanced Stem Cell Therapy, Graduate School of Medicine, Osaka University, Osaka, Japan
                [5 ]Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
                [6 ]Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
                [7 ]Medical Center for Translational Research, Osaka University Hospital, Osaka, Japan
                [8 ]Department of Metabolism and Atherosclerosis, Graduate School of Medicine, Osaka University, Osaka, Japan
                Author notes
                [∗ ]Corresponding author: Shunbun Kita, PhD, Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, 2-2 Suita, Osaka 565-0871, Japan. shunkita@ 123456endmet.med.osaka-u.ac.jp
                Article
                Publisher ID: S1525-0016(20)30316-6
                DOI: 10.1016/j.ymthe.2020.06.026
                PMC ID: 7351027
                PubMed ID: 32652045
                SO-VID: a65f1489-75d4-49bd-a6b2-ad73894bd486
                Copyright © © 2020 The Author(s)
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 17 December 2019
                Date accepted : 18 June 2020
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular medicine
                Keywords: adiponectin,exosome,extracellular vesicle,mesenchymal stem/stromal cell,msc,heart failure,tac model,t-cadherin
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: adiponectin, exosome, extracellular vesicle, mesenchymal stem/stromal cell, msc, heart failure, tac model, t-cadherin

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