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      Adipose derived mesenchymal stem cells transplantation via portal vein improves microcirculation and ameliorates liver fibrosis induced by CCl4 in rats

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          Abstract

          Introduction

          Adipose derived mesenchymal stem cells (ADMSCs), carrying the similar characteristics to bone marrow mesenchymal stem cells, only much more abundant and easier to obtain, may be a promising treatment for liver fibrosis. We aim to investigate the therapeutic potential of ADMSCs transplantation in liver fibrosis caused by carbon tetrachloride (CCl 4) in rats as well as its underlying mechanism, and to further explore the appropriate infusion pathway.

          Methods

          ADMSCs were isolated, cultured and identified. Placebo and ADMSCs were transplanted via portal vein and tail vein respectively into carbon tetrachloride (CCl 4)-induced liver fibrosis rats. Computed tomography (CT) perfusion scan and microvessel counts were performed to measure the alteration of liver microcirculation after therapy. Liver function tests and histological findings were estimated.

          Results

          CT perfusion scan shown significant decrease of hepatic arterial perfusion index, significant increased portal vein perfusion, total liver perfusion in rats receiving ADMSCs from portal vein, and Factor VIII (FVIII) immunohistochemical staining shown significant decrease of microvessels in rats receiving ADMSCs from portal vein, indicating microcirculation improvement in portal vein group. Vascular endothelial growth Factor (VEGF) was significantly up-regulated in fibrosis models, and decreased after ADMSCs intraportal transplantation. A significant improvement of liver functional test and histological findings in portal vein group were observed. No significance was found in rats receiving ADMSCs from tail vein.

          Conclusions

          ADMSCs have a therapeutic effect against CCl 4-mediated liver fibrosis. ADMSCs may benefit the fibrotic liver through alteration of microcirculation, evidenced by CT perfusion scan and down-regulation of VEGF. Intraportal transplantation is a better pathway than tail vein transplantation.

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          In vitro hepatic differentiation of human mesenchymal stem cells.

          Kuan-Der Lee, Tom Kwang-Chun Kuo, Jacqueline Whang-Peng … (2004)
          This study examined whether mesenchymal stem cells (MSCs), which are stem cells originated from embryonic mesoderm, are able to differentiate into functional hepatocyte-like cells in vitro. MSCs were isolated from human bone marrow and umbilical cord blood, and the surface phenotype and the mesodermal multilineage differentiation potentials of these cells were characterized and tested. To effectively induce hepatic differentiation, we designed a novel 2-step protocol with the use of hepatocyte growth factor and oncostatin M. After 4 weeks of induction, cuboidal morphology, which is characteristic of hepatocytes, was observed, and cells also expressed marker genes specific of liver cells in a time-dependent manner. Differentiated cells further demonstrated in vitro functions characteristic of liver cells, including albumin production, glycogen storage, urea secretion, uptake of low-density lipoprotein, and phenobarbital-inducible cytochrome P450 activity. In conclusion, human MSCs from different sources are able to differentiate into functional hepatocyte-like cells and, hence, may serve as a cell source for tissue engineering and cell therapy of hepatic tissues. Furthermore, the broad differentiation potential of MSCs indicates that a revision of the definition may be required.
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            Mesenchymal stem cells: biology and potential clinical uses.

            R. Deans, A Moseley (2000)
            There has been an increasing interest in recent years in the stromal cell system functioning in the support of hematopoiesis. The stromal cell system has been proposed to consist of marrow mesenchymal stem cells that are capable of self-renewal and differentiation into various connective tissue lineages. Recent efforts demonstrated that the multiple mesenchymal lineages can be clonally derived from a single mesenchymal stem cell, supporting the proposed paradigm. Dexter demonstrated in 1982 that an adherent stromal-like culture was able to support maintenance of hematopoietic stem as well as early B lymphopoeisis. Recent data from in vitro models demonstrating the essential role of stromal support in hematopoiesis shaped the view that cell-cell interactions in the marrow microenvironment are critical for normal hematopoietic function and differentiation. Maintenance of the hematopoietic stem cell population has been used to increase the efficiency of hematopoietic stem cell gene transfer. High-dose chemotherapy and frequently cause stromal damage with resulting hematopoietic defects. Data from preclinical transplantation studies suggested that stromal cell infusions not only prevent the occurrence of graft failure, but they have an immunomodulatory effect. Preclinical and early clinical safety studies are paving the way for further applications of mesenchymal stem cells in the field of transplantation with respect to hematopoietic support, immunoregulation, and graft facilitation.
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              Transplantation of bone marrow cells reduces CCl4-induced liver fibrosis in mice.

              Shuji Terai, Isao Sakaida, Hiroshi Nishina … (2004)
              We investigated the effect of bone marrow cell (BMC) transplantation on established liver fibrosis. BMCs of green fluorescent protein (GFP) mice were transplanted into 4-week carbon tetrachloride (CCl4)-treated C57BL6 mice through the tail vein, and the mice were treated for 4 more weeks with CCl4 (total, 8 weeks). Sirius red and GFP staining clearly indicated migrated BMCs existing along with fibers, with strong expression of matrix metalloproteinase (MMP)-9 shown by anti-MMP-9 antibodies and in situ hybridization. Double fluorescent immunohistochemistry showed the expression of MMP-9 on the GFP-positive cell surface. Film in situ zymographic analysis revealed strong gelatinolytic activity in the periportal area coinciding with the location of MMP-9-positive BMCs. Four weeks after BMC transplantation, mice had significantly reduced liver fibrosis, as assessed by hydroxyproline content of the livers, compared to that of mice treated with CCl4 alone. Subpopulation of Liv8-negative BMCs was responsible for this fibrolytic effect. In conclusion, mice with BMC transplants with continuous CCl4 injection had reduced liver fibrosis and a significantly improved survival rate after BMC transplantation compared with mice treated with CCl4 alone. This finding introduces a new concept for the therapy of liver fibrosis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Transl Med
                Journal ID (iso-abbrev): J Transl Med
                Title: Journal of Translational Medicine
                Publisher: BioMed Central
                ISSN (Electronic): 1479-5876
                Publication date Collection: 2012
                Publication date (Electronic): 26 June 2012
                Volume: 10
                Page: 133
                Affiliations
                [1 ]Department of Interventional Oncology, the First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, China
                [2 ]Department of Rheumatology & Clinical Immunology, the First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, China
                [3 ]Department of Interventional Radiology, the First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, China
                [4 ]Department of Medical Imaging, the First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, China
                Article
                Publisher ID: 1479-5876-10-133
                DOI: 10.1186/1479-5876-10-133
                PMC ID: 3439354
                PubMed ID: 22735033
                SO-VID: 855ad8cb-3ae2-4e5e-b591-c4e67ec085a7
                Copyright © Copyright ©2012 Wang et al.; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 13 March 2012
                Date accepted : 19 June 2012
                Categories
                Subject: Research

                ScienceOpen disciplines: Medicine
                Keywords: liver fibrosis,adipose derived mesenchymal stem cell,vascular endothelial growth factor,portal venous transplantation,computed tomography perfusion scan
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: liver fibrosis, adipose derived mesenchymal stem cell, vascular endothelial growth factor, portal venous transplantation, computed tomography perfusion scan

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