Adipose tissue-derived mesenchymal stem cell transplantation promotes hepatic regeneration after hepatic ischemia-reperfusion and subsequent hepatectomy in rats
ABSTRACT 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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ABSTRACT: BACKGROUND: A recent study showed that the injection of mitochondria isolated from a non-ischemic region mitigated myocardial injury. We tested the protective effects of infusing isolated mitochondria on the reperfusion injury in the liver of rats. METHODS: A partial liver ischemia-reperfusion model in male Wistar rats was used. At 45th minute of liver ischemia, the recipient's spleen was infused with vehicle (I/R-Vehicle group) or vehicle containing isolated mitochondria (7.7 × 10 ± 1.5 × 10/ml, I/R-Mito group). After a 240 minutes' reperfusion, the serum and livers were collected to assess tissue injury. RESULTS: Our results show that the elevation of serum ALT (414.3±67.1 U/Lv.s208.8±30.2 U/L), the necrosis of hepatocytes on H&E staining, increase of positive counts in TUNEL staining (59.5 ± 4.4% vs 24.6 ±9.1%), the expression of cytosolic cytochrome c, cleaved caspase 9 and 4-HNE were all reduced in the I/R-Mito group, compared to the I/R-Vehicle group. The membrane potential of the isolated mitochondria measured by JC-1 fluorescence remained high, and the infused mitochondria were distributed in the liver parenchyma 240 minutes after reperfusion. CONCLUSIONS: These results demonstrate that an intra-splenic infusion of viable mitochondria isolated from the donor prior to reperfusion significantly reduced ischemia-reperfusion injury in the liver.Shock (Augusta, Ga.) 01/2013; 39(6). DOI:10.1097/SHK.0b013e318283035f · 2.73 Impact Factor
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ABSTRACT: We quantified rates of hepatic regeneration and functional recovery for 6 months after right hepatic lobectomy in living donors for liver transplantation. Twelve donors were studied at baseline; eight retested at (mean±SD) 11±3 days(T1), 10 at 91±9 days(T2), and 10 at 185±17 days(T3) after donation. Liver and spleen volumes were measured by computed tomography (CT) and single photon emission computed tomography (SPECT). Hepatic metabolism was assessed from caffeine and erythromycin, and hepatic blood flow from cholates,galactose, and perfused hepatic mass (PHM, by SPECT). Regeneration rates (mL liver per kg body weight per day) were 0.60±0.22 from baseline to T1, 0.05±0.02 from T1 to T2,0.01±0.01 from T2 to T3 by CT, 0.54±0.20, 0.04±0.01 and 0.01±0.02 by SPECT. At T3, liver volume was 84±7% of baseline by CT and 92±13% by SPECT. Changes in hepatic metabolism did not achieve statistical significance. At T1, unadjusted clearance ratios relative to baseline were 0.75±0.07 for intravenous cholate (p=0.0001), 0.88±0.15 for galactose (p=0.0681), 0.84±0.08 (p=0.002) for PHM, and 0.83±0.19 (p=0.056) for estimated hepatic blood flow. These ratios approached 1.00 by T3. At T1, ratios adjusted per L liver were 20%-50% greater than baseline and trended toward baseline by T3. Several findings were consistent with alteration of the portal circulation: increased cholate shunt, increased spleen volume, decreased platelet count, and decreased clearance of orally-administered cholate. During the first 2 weeks after donation, hepatic regeneration is rapid and accounts for nearly two-thirds of total regeneration. Increases in hepatic blood flow and uptake of cholate characterize the early phase of regeneration. Right lobe donation alters the portal circulation of living donors, but long-term clinical consequences, if any, are unknown. © 2012 American Association for the Study of Liver Diseases.Liver Transplantation 03/2013; 19(3). DOI:10.1002/lt.23592 · 3.79 Impact Factor
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ABSTRACT: Preexisting cirrhosis usually leads to an inadequate and delayed regeneration of the future liver remnant (FLR) after portal vein embolization (PVE). Bone marrow-derived mesenchymal stem cells (BMSC) are promising candidates for therapeutic applications in liver diseases. In this study, the efficacy of autologous BMSCs transplantation to promote FLR regeneration was investigated in a rat cirrhotic model. Autologous BMSCs were expanded and labeled with PKH26, and then were injected immediately into nonembolized lobes after PVE through portal vein in cirrhotic rat. At 7, 14, and 28 d after this, liver weight and Ki-67 labeling index were measured, and blood analysis was performed. Cirrhotic degree of FLR was assessed by hydroxyproline content assay and histopathology. Gene expressions of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-10 (IL-10), and matrix metalloproteinase-9 (MMP-9) were detected with real-time reverse transcriptase-polymerase chain reaction. Distribution and hepatocyte differentiation of BMSCs in FLR were determined by confocal microscopy. Autologous BMSCs significantly increased the FLR weight ratio to the total liver and the Ki-67 labeling index, and serum albumin levels were significantly higher and total bilirubin levels were significantly lower in the BMSCs group compared with the controls without BMSCs transplantation 14 and 28 d post-PVE. BMSCs significantly decreased the hydroxyproline content and collagen accumulation, up-regulated the expressions of HGF, IL-10, VEGF, and MMP-9 28 d post-PVE, and expressed hepatocyte-specific markers, such as α-fetoprotein, cytokeratin 18, and albumin in a time-dependent manner in FLR. Autologous BMSCs can differentiate into hepatocyte and promote FLR regeneration after PVE in cirrhotic liver, which may be through improving local microenvironment by decreasing cirrhosis, up-regulating the gene expressions of VEGF, HGF, IL-10, and MMP-9.Journal of Surgical Research 05/2013; 184(2). DOI:10.1016/j.jss.2013.04.054 · 2.12 Impact Factor