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Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model.

Zhang J, Zhou S, Zhou Y, Feng F, Wang Q, Zhu X, Ai H, Huang X, Zhang X - PLoS ONE (2014)

Bottom Line: Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group.Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

View Article: PubMed Central - PubMed

Affiliation: Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China.

ABSTRACT
Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs) are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF) is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD). ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD) rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group), as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

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Evaluation of hepatocyte apoptosis 2 days after irradiation.(A) Images of hepatocytes from an electron microscope (×8200). (B) TUNEL staining of liver specimens from all five groups (×400). (C) Quantification of cells that were positive for TUNEL staining: five random fields (200×) were selected from within each liver section, and TUNEL-positive cells were counted. Data are expressed as the mean ± SD. *p<0.05.
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pone-0114670-g003: Evaluation of hepatocyte apoptosis 2 days after irradiation.(A) Images of hepatocytes from an electron microscope (×8200). (B) TUNEL staining of liver specimens from all five groups (×400). (C) Quantification of cells that were positive for TUNEL staining: five random fields (200×) were selected from within each liver section, and TUNEL-positive cells were counted. Data are expressed as the mean ± SD. *p<0.05.

Mentions: Two days after irradiation, five rats from each group were sacrificed to evaluate hepatocyte apoptosis. Electron microscopy was used to observe apoptotic cell morphology, and TUNEL staining was performed to quantify the apoptosis. Electron microscopic scans of liver specimens from rats from the lenti-HGF + ADSC group and from the ADSC group showed significant improvements in nuclear morphology (Fig. 3A). Only slight chromatin condensation was observed in rats from the ADSCs group. The transplantation of ADSCs that overexpressed HGF nearly reversed the apoptotic damage induced by the irradiation. In contrast, in rats from the HGF-knock out group and rats from the RILD group, the liver cells exhibited swollen endoplasmic reticula and Golgi apparatus. TUNEL staining (Fig. 3B) showed that hepatocyte apoptosis was significantly decreased in rats from the ADSC group compared with rats from the RILD group (5.0±0.8 vs. 10.2±1.7, p<0.05) (Fig. 3C). The number of TUNEL-positive cells was even lower in rats from the lenti-HGF + ADSC group than rats from the ADSC group (2.7±0.6 vs. 5.0±0.8, p<0.05). The number of TUNEL-positive cells in rats from the lenti-shHGF + ADSC group was also decreased compared with rats from the RILD group (7.5±0.8 vs. 10.2±1.7, p<0.05), but the anti-apoptotic effect was not equal to that observed in the ADSC group (7.5±0.8 vs. 5.0±0.8, p<0.05) (Fig. 3C).


Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model.

Zhang J, Zhou S, Zhou Y, Feng F, Wang Q, Zhu X, Ai H, Huang X, Zhang X - PLoS ONE (2014)

Evaluation of hepatocyte apoptosis 2 days after irradiation.(A) Images of hepatocytes from an electron microscope (×8200). (B) TUNEL staining of liver specimens from all five groups (×400). (C) Quantification of cells that were positive for TUNEL staining: five random fields (200×) were selected from within each liver section, and TUNEL-positive cells were counted. Data are expressed as the mean ± SD. *p<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264768&req=5

pone-0114670-g003: Evaluation of hepatocyte apoptosis 2 days after irradiation.(A) Images of hepatocytes from an electron microscope (×8200). (B) TUNEL staining of liver specimens from all five groups (×400). (C) Quantification of cells that were positive for TUNEL staining: five random fields (200×) were selected from within each liver section, and TUNEL-positive cells were counted. Data are expressed as the mean ± SD. *p<0.05.
Mentions: Two days after irradiation, five rats from each group were sacrificed to evaluate hepatocyte apoptosis. Electron microscopy was used to observe apoptotic cell morphology, and TUNEL staining was performed to quantify the apoptosis. Electron microscopic scans of liver specimens from rats from the lenti-HGF + ADSC group and from the ADSC group showed significant improvements in nuclear morphology (Fig. 3A). Only slight chromatin condensation was observed in rats from the ADSCs group. The transplantation of ADSCs that overexpressed HGF nearly reversed the apoptotic damage induced by the irradiation. In contrast, in rats from the HGF-knock out group and rats from the RILD group, the liver cells exhibited swollen endoplasmic reticula and Golgi apparatus. TUNEL staining (Fig. 3B) showed that hepatocyte apoptosis was significantly decreased in rats from the ADSC group compared with rats from the RILD group (5.0±0.8 vs. 10.2±1.7, p<0.05) (Fig. 3C). The number of TUNEL-positive cells was even lower in rats from the lenti-HGF + ADSC group than rats from the ADSC group (2.7±0.6 vs. 5.0±0.8, p<0.05). The number of TUNEL-positive cells in rats from the lenti-shHGF + ADSC group was also decreased compared with rats from the RILD group (7.5±0.8 vs. 10.2±1.7, p<0.05), but the anti-apoptotic effect was not equal to that observed in the ADSC group (7.5±0.8 vs. 5.0±0.8, p<0.05) (Fig. 3C).

Bottom Line: Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining.The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group.Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

View Article: PubMed Central - PubMed

Affiliation: Peking University People's Hospital, Peking University Institute of Hematology, Xicheng District, Beijing, China.

ABSTRACT
Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs) are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF) is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD). ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD) rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group), as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

Show MeSH
Related in: MedlinePlus