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 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.
    Iranian Journal of Basic Medical Science 01/2014; 17(1):27-33. · 1.23 Impact Factor
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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.
    Stem cell International 11/2013; 2013(9):534263. DOI:10.1155/2013/534263 · 2.81 Impact Factor
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    • "Alternatively, in line with the current development of stem cell-based therapeutics for tissue and organ repair, mesenchymal stromal cells (MSC) are suggested to exert significant beneficial effects on the regeneration of injured liver tissue [12], although it is not clear whether the beneficial effect of MSC grafting is direct or indirect. While some studies suggest parenchymal penetration, functional engraftment or hepatocyte differentiation of MSC after transplantation in damaged liver tissue [13,14], others attribute their beneficial influence to the upregulation of hepatic regeneration-associated genes or paracrine effects on stimulation of endogenous regeneration within the injured liver [15–17]. "
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    ABSTRACT: The aim of this study was to evaluate the effect of bone marrow-derived mesenchymal stromal cell (BM-MSC) administration on liver function following partial hepatectomy (PHx) of methionine/choline-deficient (MCD) diet induced steatotic livers in rodents. Here we identified and validated serum cholinesterase (CHE) and triglyceride (TG) levels as non-invasive markers to longitudinally monitor rat liver function. Using in vivo bioluminescence imaging, retention of BM-MSC in the liver was observed following intraportal administration, but not after intravenous administration. Therefore, BM-MSC were intraportally delivered to investigate the effect on liver recovery and/or regeneration after PHx. However, despite recovery to normal body weight, liver weight and NAS score, both serum CHE and TG levels of non-treated and cell-treated rats with PHx after MCD diet remained significantly lower as compared to those of control rats. Importantly, serum CHE levels, but not TG levels, of cell-treated rats remained significantly lower as compared to those of non-treated rats, thereby warranting that certain caution should be considered for future clinical application of IP BM-MSC administration in order to promote liver regeneration and/or function.
    PLoS ONE 07/2013; 8(7):e69092. DOI:10.1371/journal.pone.0069092 · 3.23 Impact Factor
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