Abstract
Ethnopharmacological Relevance. “Diwu Yanggan” (DWYG) has been reported to regulate liver regeneration, modulate the immune response, ameliorate liver injury, kill virus, ameliorate liver fibrosis, and suppress hepatic cancer. However, its mechanisms are still unknown. Objectives. To investigate the effects of DWYG on oval cell proliferation in 2-AAF/PH rats and determine its mechanism. Methods. Wistar rats were randomly distributed into normal group, sham group, vehicle group, and DWYG group. Hepatic pathological changes were examined by H&E staining. The oval cell markers CD34, AFP, CK-19 and hematopoietic cell markers CD45, Thy1.1, and hepatocyte marker ALB were examined with immunohistochemistry. The percentage of CD34/CD45 double-positive cells in bone marrow was detected by flow cytometry. Cytokine levels were measured with the Bio-plex suspension array system. Results. DWYG significantly increased the survival rates of 2-AAF/PH rats and promoted liver regeneration. Furthermore, DWYG increased the ratio of CD34/CD45 double-positive cells on days 10 and 14. In addition, DWYG gradually restored IL-1, GRO/KC, and VEGF levels to those of the normal group. Conclusions. DWYG increases 2-AAF/PH rat survival rates, suppresses hepatic precarcinoma changes, and restores hepatic tissue structure and function. DWYG may act by modulating the hepatic microenvironment to support liver regeneration.
Highlights
Orthotopic liver transplantation is currently the only definitive therapy for patients with end-stage liver diseases; severe complications such as acute allograft rejection commonly occur
We examined the ratio of CD34 and CD45 double-positive cells in the bone marrow of 2-AAF/partial hepatectomy (PH) rat
In the 2-AAF/PH model, hepatocyte proliferation is efficiently suppressed by 2-AAF, which forces liver regeneration to become dependent on oval cell replication and differentiation [3, 5]
Summary
Orthotopic liver transplantation is currently the only definitive therapy for patients with end-stage liver diseases; severe complications such as acute allograft rejection commonly occur. Stem cell and progenitor cell transplantation, including hepatocytes and hepatic oval cells, that have selfrenewal and differentiation potential have been utilized as alternative approaches for mediating damaged tissue repair to facilitate liver regeneration [3, 4]. Oval cells are considered adult liver progenitors, as they can differentiate into mature hepatocytes or biliary epithelial cells [5]. Upon inhibition of mature hepatocyte proliferation, oval cells expand and differentiate into mature hepatocytes and biliary epithelial cells to regenerate liver mass after hepatic damage [6]. Any excess oval cells that have failed to differentiate into mature hepatocytes stop replicating and undergo apoptosis to prevent liver hyperplasia [5, 7, 8]. It has been previously reported that hepatic oval cells express the hematopoietic stem cell markers Thy-1 and CD34, which support the hypothesis that hepatic oval cells originate from bone marrow [9,10,11]
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