Therapeutic potential of mesenchymal stem cells overexpressing human forkhead box A2 gene in the regeneration of damaged liver tissues

Abstract

Background and Aim: Although a liver transplantation is considered to be the only effective long-term treatment in many cases of liver diseases, it is limited by a lack of donor organs and immune rejection. As an autologous stem cell approach, this study was conducted to assess whether forkhead box A2 (Foxa2) gene overexpression in bone marrow-derived mesenchymal stem cells (MSC) could protect the liver from hepatic diseases by stimulating tissue regeneration after cell transplantation. Methods: Rat MSC (rMSC) were isolated, characterized, and induced to hepatocytes that expressed liver-specific markers. Four different treatments (control [phosphate-buffered saline], rMSC alone, rMSC/pIRESenhanced green fluorescent protein (EGFP) vector, and rMSC/pIRESEGFP/human Foxa2) were injected into the spleen of carbon tetrachloride-injured rats. Biochemical and histological analyses on days 30, 60, and 90 post-transplantation were performed to evaluate the therapeutic capacities of MSC overexpressing hFoxa2. Results: rMSC transfected with hFoxa2 were induced into hepatogenic linage and expressed several liver-specific genes, such as, Foxa2, a-fetoprotein, cytokeratin-18, hepatocyte nuclear factor-1a, and hepatocyte growth factor. A group of animals treated with MSC/hFoxa2 showed significant recovery of liver-specific enzyme expressions to normal levels at the end of the study (90 days). Furthermore, when compared to the fibrotic areas of the samples treated with MSC alone or MSC/vector, the fibrotic area of the samples treated with rMSC/hFoxa2 for 90 days significantly decreased, until they were completely gone. Conclusions: Human Foxa2 efficiently promoted the incorporation of MSC into liver grafts, suggesting that hFoxa2 genes could be used for the structural or functional recovery of damaged liver cells.