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      Human endometrial regenerative cells alleviate carbon tetrachloride-induced acute liver injury in mice

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          Abstract

          Background

          The endometrial regenerative cell (ERC) is a novel type of adult mesenchymal stem cell isolated from menstrual blood. Previous studies demonstrated that ERCs possess unique immunoregulatory properties in vitro and in vivo, as well as the ability to differentiate into functional hepatocyte-like cells. For these reasons, the present study was undertaken to explore the effects of ERCs on carbon tetrachloride (CCl 4)–induced acute liver injury (ALI).

          Methods

          An ALI model in C57BL/6 mice was induced by administration of intraperitoneal injection of CCl 4. Transplanted ERCs were intravenously injected (1 million/mouse) into mice 30 min after ALI induction. Liver function, pathological and immunohistological changes, cell tracking, immune cell populations and cytokine profiles were assessed 24 h after the CCl 4 induction.

          Results

          ERC treatment effectively decreased the CCl 4-induced elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and improved hepatic histopathological abnormalities compared to the untreated ALI group. Immunohistochemical staining showed that over-expression of lymphocyte antigen 6 complex, locus G (Ly6G) was markedly inhibited, whereas expression of proliferating cell nuclear antigen (PCNA) was increased after ERC treatment. Furthermore, the frequency of CD4 + and CD8 + T cell populations in the spleen was significantly down-regulated, while the percentage of splenic CD4 +CD25 +FOXP3 + regulatory T cells (Tregs) was obviously up-regulated after ERC treatment. Moreover, splenic dendritic cells in ERC-treated mice exhibited dramatically decreased MHC-II expression. Cell tracking studies showed that transplanted PKH26-labeled ERCs engrafted to lung, spleen and injured liver. Compared to untreated controls, mice treated with ERCs had lower levels of IL-1β, IL-6, and TNF-α but higher level of IL-10 in both serum and liver.

          Conclusions

          Human ERCs protect the liver from acute injury in mice through hepatocyte proliferation promotion, as well as through anti-inflammatory and immunoregulatory effects.

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          Human mesenchymal stem cells modulate allogeneic immune cell responses.

          Sudeepta Aggarwal, Mark F. Pittenger (2005)
          Mesenchymal stem cells (MSCs) are multipotent cells found in several adult tissues. Transplanted allogeneic MSCs can be detected in recipients at extended time points, indicating a lack of immune recognition and clearance. As well, a role for bone marrow-derived MSCs in reducing the incidence and severity of graft-versus-host disease (GVHD) during allogeneic transplantation has recently been reported; however, the mechanisms remain to be investigated. We examined the immunomodulatory functions of human MSCs (hMSCs) by coculturing them with purified subpopulations of immune cells and report here that hMSCs altered the cytokine secretion profile of dendritic cells (DCs), naive and effector T cells (T helper 1 [T(H)1] and T(H)2), and natural killer (NK) cells to induce a more anti-inflammatory or tolerant phenotype. Specifically, the hMSCs caused mature DCs type 1 (DC1) to decrease tumor necrosis factor alpha (TNF-alpha) secretion and mature DC2 to increase interleukin-10 (IL-10) secretion; hMSCs caused T(H)1 cells to decrease interferon gamma (IFN-gamma) and caused the T(H)2 cells to increase secretion of IL-4; hMSCs caused an increase in the proportion of regulatory T cells (T(Regs)) present; and hMSCs decreased secretion of IFN-gamma from the NK cells. Mechanistically, the hMSCs produced elevated prostaglandin E2 (PGE(2)) in co-cultures, and inhibitors of PGE(2) production mitigated hMSC-mediated immune modulation. These data offer insight into the interactions between allogeneic MSCs and immune cells and provide mechanisms likely involved with the in vivo MSC-mediated induction of tolerance that could be therapeutic for reduction of GVHD, rejection, and modulation of inflammation.
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            Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

            Florian Tögel, Zhuma Hu, Kathleen A. Weiss … (2005)
            Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
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              Immunosuppressive properties of mesenchymal stem cells: advances and applications.

              M P De Miguel, S Fuentes-Julián, A Blazquez-Martinez … (2012)
              Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.
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                Author and article information

                Contributors
                Shanzheng Lu: 837488794@qq.com
                Ganggang Shi: shigg0306@163.com
                Xiaoxi Xu: 37duchuan@sina.com
                Grace Wang: gracewangca@hotmail.com
                Xu Lan: lanxu987@126.com
                Peng Sun: 1105031456@qq.com
                Xiang Li: 3046094621@qq.com
                Baoren Zhang: 644024898@qq.com
                Xiangying Gu: gxy6283@163.com
                Thomas E. Ichim: thomas.ichim@gmail.com
                Hao Wang: 01186-22-60362502 , hwangca272@hotmail.com
                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1479-5876
                Publication date (Electronic): 22 October 2016
                Publication date PMC-release: 22 October 2016
                Publication date Collection: 2016
                Volume: 14
                Electronic Location Identifier: 300
                Affiliations
                [1 ]Department of General Surgery, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052 China
                [2 ]Tianjin General Surgery Institute, Tianjin, China
                [3 ]Faculty of Medicine, University of Toronto, Toronto, ON Canada
                [4 ]Department of General Surgery, Affiliated Hospital of Weifang Medical University, Shandong, China
                [5 ]Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
                [6 ]Immune Advisors LLC, San Diego, CA 92121 USA
                Article
                Publisher ID: 1051
                DOI: 10.1186/s12967-016-1051-1
                PMC ID: 5075169
                PubMed ID: 27770815
                SO-VID: a0d7d0aa-7a6b-43b3-acc8-2958ad18d33f
                Copyright © © The Author(s) 2016
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 31 July 2016
                Date accepted : 5 October 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81273257
                Award ID: 81471584
                Award Recipient :
                Funded by: Tianjin Application Basis and Cutting-Edge Technology Research Grant
                Award ID: 14JCZDJC35700
                Award Recipient :
                Funded by: Li Jieshou Intestinal Barrier Research Special Fund
                Award ID: LJS_201412
                Award Recipient :
                Funded by: Tianjin Medical University Talent Fund
                Categories
                Subject: Research
                Custom metadata
                issue-copyright-statement © The Author(s) 2016

                ScienceOpen disciplines: Medicine
                Keywords: endometrial regenerative cells,acute liver injury,anti-inflammatory,immunoregulation
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: endometrial regenerative cells, acute liver injury, anti-inflammatory, immunoregulation

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