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      Transplantation of adipose‐derived mesenchymal stem cell sheets directly into the kidney suppresses the progression of renal injury in a diabetic nephropathy rat model

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          Abstract

          Aims/Introduction

          Adipose‐derived mesenchymal stem cell (ASC) transplantation is a promising therapy for diabetic nephropathy (DN). However, intravascular administration of ASCs is associated with low engraftment in target organs. Therefore, we considered applying the cell sheet technology to ASCs. In this study, ASC sheets were directly transplanted into the kidneys of a DN rat model, and therapeutic consequences were analyzed.

          Materials and Methods

          Adipose‐derived mesenchymal stem cells were isolated from adipose tissues of 7‐week‐old enhanced green fluorescent protein rats, and ASC sheets were prepared using a temperature‐responsive culture dish. A DN rat model was established from 5‐week‐old Spontaneously Diabetic Torii fatty rats. Seven‐week‐old DN rats ( n = 21) were assigned to one of the following groups: sham‐operated ( n = 6); ASC suspension (6.0 × 10 6 cells/mL) administered intravenously ( n = 7); six ASC sheets transplanted directly into the kidney ( n = 8). The therapeutic effect of the cell sheets was determined based on urinary biomarker expression and histological analyses.

          Results

          The ASC sheets survived under the kidney capsule of the DN rat model for 14 days after transplantation. Furthermore, albuminuria and urinary tumor necrosis factor‐α levels were significantly lower in the ASC sheets transplanted directly into the kidney group than in the sham‐operated and ASC suspension administered intravenously groups ( P < 0.05). Histologically, the ASC sheets transplanted directly into the kidney group presented mild atrophy of the proximal tubule and maintained the renal tubular structure.

          Conclusions

          Transplantation of ASC sheets directly into the kidney improved transplantation efficiency and suppressed renal injury progression. Therefore, the ASC sheet technology might be a promising novel treatment for DN.

          Abstract

          Adipose‐derived mesenchymal stem cell sheet transplantation enhanced the engraftment efficiency and suppressed the progression of diabetic nephropathy.

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          Most cited references34

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          Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.

          Katarina Le Blanc, Ida Rasmusson, Berit Sundberg … (2004)
          Adult bone-marrow-derived mesenchymal stem cells are immunosuppressive and prolong the rejection of mismatched skin grafts in animals. We transplanted haploidentical mesenchymal stem cells in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver. Clinical response was striking. The patient is now well after 1 year. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
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            Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms.

            T Kinnaird, E STABILE, M. Burnett … (2004)
            Bone marrow cell therapy is reported to contribute to collateral formation through cell incorporation into new or remodeling vessels. However, the possible role of a paracrine contribution to this effect is less well characterized. Murine marrow-derived stromal cells (MSCs) were purified by magnetic bead separation of cultured bone marrow. The release of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1) was demonstrated by analysis of MSC conditioned media (MSC-CM). MSC-CM enhanced proliferation of endothelial cells and smooth muscle cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partly attenuated these effects. Balb/C mice (n=10) underwent distal femoral artery ligation, followed by adductor muscle injection of 1x10(6) MSCs 24 hours later. Compared with controls injected with media (n=10) or mature endothelial cells (n=8), distal limb perfusion improved, and mid-thigh conductance vessels increased in number and total cross-sectional area. MSC injection improved limb function and appearance, reduced the incidence of auto-amputation, and attenuated muscle atrophy and fibrosis. After injection, labeled MSCs were seen dispersed between muscle fibers but were not seen incorporated into mature collaterals. Injection of MSCs increased adductor muscle levels of bFGF and VEGF protein compared with controls. Finally, colocalization of VEGF and transplanted MSCs within adductor tissue was demonstrated. MSCs secrete a wide array of arteriogenic cytokines. MSCs can contribute to collateral remodeling through paracrine mechanisms.
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              The role of inflammatory cytokines in diabetic nephropathy.

              Juan F. Navarro-González, Carmen Mora-Fernández (2008)
              Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
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                Author and article information

                Contributors
                Tatsuya Shimizu: shimizu.tatsuya@twmu.ac.jp
                Journal
                Journal ID (nlm-ta): J Diabetes Investig
                Journal ID (iso-abbrev): J Diabetes Investig
                Journal ID (doi): 10.1111/(ISSN)2040-1124
                Journal ID (publisher-id): JDI
                Title: Journal of Diabetes Investigation
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 2040-1116
                ISSN (Electronic): 2040-1124
                Publication date (Electronic): 06 November 2019
                Publication date (Print): May 2020
                Volume: 11
                Issue: 3 ( doiID: 10.1111/jdi.v11.3 )
                Pages: 545-553
                Affiliations
                [ 1 ] Department of Medicine Diabetes Center School of Medicine Tokyo Women’s Medical University Tokyo Japan
                [ 2 ] Institute of Advanced Biomedical Engineering and Science Tokyo Women’s Medical University Tokyo Japan
                [ 3 ] Department of Medicine Kidney Center Tokyo Women’s Medical University Tokyo Japan
                Author notes
                [*] [* ] Correspondence

                Tatsuya Shimizu

                Tel.: +81‐3‐3353‐8112

                Fax: +81‐3‐3359‐6046

                E‐mail address: shimizu.tatsuya@ 123456twmu.ac.jp

                Author information
                https://orcid.org/0000-0002-6157-6834
                https://orcid.org/0000-0001-8545-3604
                Article
                Publisher ID: JDI13164
                DOI: 10.1111/jdi.13164
                PMC ID: 7232293
                PubMed ID: 31622047
                SO-VID: b3aa8427-f674-44ba-8c65-afd77b1d5b1c
                Copyright © © 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 20 May 2019
                Date revision received : 15 September 2019
                Date accepted : 11 October 2019
                Page count
                Figures: 6, Tables: 1, Pages: 9, Words: 5654
                Funding
                Funded by: CellSeed Inc.
                Categories
                Subject: Original Article
                Subject: Articles
                Subject: Basic Science and Research
                Custom metadata
                source-schema-version-number 2.0
                cover-date May 2020
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:18.05.2020

                Keywords: adipose‐derived mesenchymal stem cell,cell sheet,renal injury
                Data availability:
                Keywords: adipose‐derived mesenchymal stem cell, cell sheet, renal injury

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