Adipose tissue-derived mesenchymal stem cell transplantation promotes hepatic regeneration after hepatic ischemia-reperfusion and subsequent hepatectomy in rats

Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Journal of Surgical Research (Impact Factor: 1.94). 03/2012; 178(1):63-70. DOI: 10.1016/j.jss.2012.02.014
Source: PubMed


Adipose tissue-derived mesenchymal stem cells (ADSCs) are an attractive source for regenerative medicine because they are easily accessible through minimally invasive methods. We investigated the efficacy of ADSC transplantation on outcome after hepatic ischemia-reperfusion and subsequent hepatectomy in rats.
ADSCs were isolated from subcutaneous adipose tissue of rats. After clamping the hepatoduodenal ligament for 15 min, the rats were subjected to a 70% partial hepatectomy. After releasing the clamp, 2 × 10(6) ADSCs per rat were injected through the penile vein. Phosphate buffered saline was injected as a control. The parameters of hepatic regeneration, such as hepatic regeneration rate, mitotic index, and anti-proliferating cell nuclear antigen levels, were examined. Furthermore, the expression of hepatic regeneration-associated proteins and genes in the regenerating liver was determined.
The hepatic regeneration rate 2 d after hepatectomy was significantly greater in the ADSC transplanted group compared with the sham group. Mitotic index, anti-proliferating cell nuclear antigen levels, and other regeneration-associated proteins in the liver were significantly higher in the ADSC transplanted group than the sham group on 1 d after hepatectomy. A number of hepatic regeneration-associated genes also were significantly upregulated in the ADSC transplanted group.
These results indicate that ADSC transplantation may provide beneficial effects in the process of liver regeneration after hepatic ischemia-reperfusion and subsequent hepatectomy.

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    • "In rodent models of hepatic IRI, autologous adipose tissue-derived MSCs administration significantly preserved hepatocyte integrity, suppressed inflammatory responses and oxidative stress [3] [4] [9] [10]. However, the effect of xenogeneic administration of HADMSCs on liver regeneration has not been fully studied before. "
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    ABSTRACT: Liver regeneration (LR) is of crucial importance to patients with acute liver failure, those undergoing live donor liver transplantations or extended liver resections. Effective treatment strategies aimed at accelerating liver regeneration could offer major benefits in these patients. Due to easy accessibility, human adipose-derived mesenchymal stem cells (HADMSC) are an attractive source for regenerative medicine. Herein, we investigated the effect of HADMSC on LR in a murine model. We hypothesized that HADMSC will promote LR. Mice were subjected to CCl4-induced acute liver failure (ALF). Animals in the experimental arm were treated with HADMSC prior to CCl4-induced ALF. Liver injury was evaluated using serum levels of alanine aminotransferase (ALT), serum interleukin-6 (IL-6), and histopathology. Liver samples were stained for a specific marker of regeneration, proliferating cell nuclear antigen (PCNA). Histology, serum IL-6, and ALT release revealed that HADMSC treatment attenuated liver injury compared with control animals. In addition, animals treated with HADMSC were observed to have improved survival and increased number of PCNA positive cells on histology when compared with controls. HADMSCs represent a potential therapeutic strategy to promote liver regeneration.
    Full-text · Article · Jul 2015 · Journal of Investigative Surgery
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    • "In addition to oval cells, stem cells in other organs such as mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) of bone marrow play a pivotal role in regeneration (2, 3). In reality, the application of stem cells derived from different sources and their differ-entiation to liver cells in laboratory or application of non-induced cells with the normal condition have been the most important cell sources in the regene-rative medicine (4-7). A subpopulation of MSC isolated from bone marrow of human, mouse and rat, express hepatic markers such as CK19, α-fetoprotein, albumin and CK18 (8). "
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    ABSTRACT: Objective(s): Stem cell therapy is believed to be as a promising treatment strategy for tissue repair and regeneration. The plasticity specification of the adult stem cells, such as MSCs, has enabled that these cells to be used in the treatment of a broad spectrum of diseases like liver disorders. In this study, the production of urea and Albumin (Alb), glycogen storage, and expression of some liver genes including α-fetoprotein (AFP), Alb, cytokeratin18 (CK18) and cytokeratin19 (CK19) was compared between mesenchymal stem cells (MSCs) and isolated rat hepatocytes. Materials and Methods: The MSCs were isolated from rat femurs and tibias and cultured in α-MEM, DMEM and RPMI mediums supplemented with serum. Hepatocytes were isolated from Rat livers and cultured in DMEM with serum. The expression of AFP, Alb, CK18, and CK19 genes was evaluated using the reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the synthesis of albumin and urea of the cells was measured. Results: In vitro conditions, MSCs and hepatocytes exhibited the characteristic functions of the liver such as capacity to synthesize Alb, urea, the storage of glycogen. In this study, the expression of some liver genes such as AFP, Alb, CK18 and CK19 at mRNA levels was also shown. Conclusion: The results showed that MSCs exhibited some liver functions, and may be considered as an alternative source for adult stem cell transplantation in liver repair due to the excellent proliferation and differentiation capacities.
    Full-text · Article · Jan 2014 · Iranian Journal of Basic Medical Science
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    • "At day two after ADSC injection, the gene expressions of IL-6, VEGF, and c-jun were significantly upregulated and different proteins associated with hepatic regeneration and the overall mitotic index were increased. GOT, GPT, and total bilirubin levels, however, were not significantly affected by ADSC injection [25]. "
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    ABSTRACT: In the light of the persisting lack of donor organs and the risks of allotransplantations, the possibility of liver regeneration with autologous stem cells from adipose tissue (ADSC) is an intriguing alternative. Using a model of a toxic liver damage in Sprague Dawley rats, generated by repetitive intraperitoneal application of retrorsine and allyl alcohol, the ability of human ADSC to support the restoration of liver function was investigated. A two-thirds hepatectomy was performed, and human ADSC were injected into one remaining liver lobe in group 1 (n = 20). Injection of cell culture medium performed in group 2 (n = 20) served as control. Cyclosporine was applied to achieve immunotolerance. Blood samples were drawn weekly after surgery to determine liver-correlated blood values. Six and twelve weeks after surgery, animals were sacrificed and histological sections were analyzed. ADSC significantly raised postoperative albumin (P < 0.017), total protein (P < 0.031), glutamic oxaloacetic transaminase (P < 0.001), and lactate dehydrogenase (P < 0.04) levels compared to injection of cell culture medium alone. Transplanted cells could be found up to twelve weeks after surgery in histological sections. This study points towards ADSC being a promising alternative to hepatocyte or liver organ transplantation in patients with severe liver failure.
    Full-text · Article · Nov 2013 · Stem cell International
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