Abstract
Healthy livers have a remarkable regenerative capacity for reconstructing functional hepatic parenchyma after 70% partial hepatectomy (PH). Hepatocytes, usually quiescent in normal healthy livers, proliferate to compensate for hepatic loss after PH. However, the mechanism of hepatocyte involvement in liver regeneration remains unclear. Hedgehog (Hh) pathway plays an important role in tissue reconstitution by regulating epithelial-to-mesenchymal transition (EMT) in liver disease. MicroRNA (miRNA) is involved in cell proliferation and differentiation during embryonic development and carcinogenesis. It was recently reported that miR-378 inhibits transdifferentiation of hepatic stellate cells into myofibroblasts by suppressing Gli-Krüppel family member 3 (Gli3), the Hh-target gene. We hypothesized that miR-378 influences EMT in hepatocytes by interfering with Hh signaling during liver regeneration. As hepatocytes were highly proliferative after PH in mice, miR-378 and epithelial marker, Ppar-g or E-cadherin were downregulated, whereas both Hh activators, Smoothened (Smo) and Gli3, and the EMT-inducing genes, Tgfb, Snail and Vimentin, were upregulated in the regenerating livers and in hepatocytes isolated from them. Compared to cells with or without scramble miRNA, primary hepatocytes transfected with miR-378 inhibitor contained higher levels of Gli3 with increased expression of the EMT-promoting genes, Tgfb, Snail, Col1a1, and Vimentin, suggesting that miR-378 influenced EMT in hepatocytes. Smo-depleted hepatocytes isolated from PH livers of Smo-flox mice showed downregulation of EMT-promoting genes and Gli3, with upregulation of miR-378 and E-cadherin compared to Smo-expressing hepatocytes from PH liver. In addition, delivery hepatocyte-specific AAV8 viral vector bearing Cre recombinase into Smo-flox mice impeded EMT in Smo-suppressed hepatocytes of PH liver, indicating that Smo is critical for regulating hepatocyte EMT. Furthermore, the application of miR-378 mimic into mice with PH delayed liver regeneration by interrupting hepatocyte EMT. In conclusion, our results demonstrate that miR-378 is involved in hepatocyte EMT by regulating Hh signaling during liver regeneration.
Highlights
The liver has remarkable regenerative ability, first described in Greek mythology and more recently proven in studies of rodents undergoing two-thirds partial hepatectomy (PH)
The liver weight (LW) and LW-to-body weight (BW) ratio (LW/BW) began to be elevated at 48 h, increasing by almost 2.3-fold at 96 h compared with livers at 0 h post-PH (Supplementary Figure S1A)
Given that Hh signaling orchestrates epithelial-to-mesenchymal transition (EMT) in the liverrepair process[5,13] and that miR-378 targeting GLI3 influenced the transition of hepatic stellate cells (HSCs), with expression regulated by SMO22, we examined the expression of miR-378, Smo, and
Summary
The liver has remarkable regenerative ability, first described in Greek mythology and more recently proven in studies of rodents undergoing two-thirds partial hepatectomy (PH). Surgical removal of two-thirds of the liver leads to a hyperplastic response in the remaining hepatic tissue until the original liver mass is reconstituted[2]. Kim et al Cell Death and Disease (2018)9:721 loss of liver mass[2,4]. Along with these hepatocytes, residual cholangiocytes and hepatic stellate cells (HSCs) are believed to mediate the repopulation of liver cells after PH5,6. Residual cholangiocytes and hepatic stellate cells (HSCs) are believed to mediate the repopulation of liver cells after PH5,6 It is poorly understood how the remnant liver regenerates the various types of liver cells
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