Effects of mesenchymal stem cells and VEGF on liver regeneration following major resection.
OBJECTIVE
The study aims to determine the effects of mesenchymal stem cell (MSC) therapy and a combination therapy of MSCs transfected with vascular endothelial growth factor (VEGF) for liver regeneration after major resection.


METHODS
Thirty-eight rats were divided into four groups: group 1: control (sham operation); group 2: control (70 % hepatic resection); group 3: 70 % hepatic resection + systemically transplanted MSCs; and group 4: 70 % hepatic resection + systemically transplanted MSCs transfected with the VEGF gene. MSCs were injected via the portal vein route in study groups 3 and 4. Expression levels of VEGF, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF), hepatocyte growth factor (HGF), and augmenter of liver regeneration (ALR) were analyzed in the remnant liver tissue. We investigated the levels of angiogenic factors, VEGF-receptor, angiopoietin-1 (Angpt1) and Angpt2. Biochemical parameters of liver function in blood samples were measured and a histologic assessment of the livers was performed. The postoperative liver weight and volume of each rat were measured 14 days after surgery.


RESULTS
The expression levels of all measured growth factors were significantly increased in groups 3 and 4 compared to the control groups. The levels of Angpt1 and Angpt2 correlated with levels of VEGF and thus were also significantly higher in the study groups. There were significant differences between the estimated liver weights and volumes of group 4 and the resected controls in group 2. With the exception of portal inflammation, levels of all histological parameters were observed to be higher in MSC-treated groups when compared with the resected controls in group 2.


CONCLUSIONS
Transplanted stem cells and MSCs transfected with VEGF significantly accelerated many parameters of the healing process following major hepatic resection. After the injection of MSCs and VEGF-transfected MSCs into the portal vein following liver resection, they were engrafted in the liver. They increased bile duct and liver hepatocyte proliferation, and secreted many growth factors including HGF, TGFβ, VEGF, PDGF, EGF, and FGF via paracrine effects. These effects support liver function, regeneration, and liver volume/weight.
Department of Surgery, Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
Gokhan
G
Adas
Faculty of Medicine, Istanbul Training Hospital, Department of Surgery, Baskent University, Oymaci Sok. No:7, 34662, Altunizade Uskudar, Istanbul, Turkey. drborakoc@hotmail.com.
Bora
B
Koc
Department of Endocrinology, Okmeydani Training and Research Hospital, Istanbul, Turkey.
Mine
M
Adas
Center for Stem Cell and Gene Therapies Research and Practice, Institute of Health Sciences, Stem Cell Department, Kocaeli University, Izmit, Kocaeli, Turkey.
Gokhan
G
Duruksu
Center for Stem Cell and Gene Therapies Research and Practice, Institute of Health Sciences, Stem Cell Department, Kocaeli University, Izmit, Kocaeli, Turkey.
Cansu
C
Subasi
Department of Surgery, Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
Ozgur
O
Kemik
Faculty of Medicine, Department of Biochemistry, Istanbul University, Istanbul, Turkey.
Ahu
A
Kemik
Department of Pathology, Bakirköy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
Damlanur
D
Sakiz
Department of Surgery, Bakirkoy Dr.Sadi Konuk Training and Research Hospital, Istanbul, Turkey.
Mustafa
M
Kalayci
Faculty of Medicine, Department of Statistics, Istanbul University, Istanbul, Turkey.
Sevim
S
Purisa
Center for Stem Cell and Gene Therapies Research and Practice, Institute of Health Sciences, Stem Cell Department, Kocaeli University, Izmit, Kocaeli, Turkey.
Seda
S
Unal
Center for Regenerative Medicine and Stem Cell Research and Manufacturing (LivMedCell), Liv Hospital, Istanbul, Turkey.
Erdal
E
Karaoz
D000818:Animals; D004195:Disease Models, Animal; D006498:Hepatectomy; D008099:Liver / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000627:therapeutic use*
D042461:Vascular Endothelial Growth Factor A
Growth factors; Liver regeneration; Mesenchymal stem cells; Vascular endothelial growth factor