Increased Phosphatase of Regenerating Liver-1 by Placental Stem Cells Promotes Hepatic Regeneration in a Bile-Duct-Ligated Rat Model

Phosphatase of regenerating liver-1 (PRL-1) controls various cellular processes and liver regeneration. However, the roles of PRL-1 in liver regeneration induced by chorionic-plate-derived mesenchymal stem cells (CP-MSCs) transplantation remain unknown. Here, we found that increased PRL-1 expression by CP-MSC transplantation enhanced liver regeneration in a bile duct ligation (BDL) rat model by promoting the migration and proliferation of hepatocytes. Engrafted CP-MSCs promoted liver function via enhanced hepatocyte proliferation through increased PRL-1 expression in vivo and in vitro. Moreover, higher increased expression of PRL-1 regulated CP-MSC migration into BDL-injured rat liver through enhancement of migration-related signals by increasing Rho family proteins. The dual effects of PRL-1 on proliferation of hepatocytes and migration of CP-MSCs were substantially reduced when PRL-1 was silenced with siRNA-PRL-1 treatment. These findings suggest that PRL-1 may serve as a multifunctional enhancer for therapeutic applications of CP-MSC transplantation.

USING OF BIOCORRECTORS IN REGENERATION PACING OF MECHANICALLY INJURED RATS’ FETAL HEPATIC

The article is devoted to studying the influence of biologically active substances on the regeneration of internal organs in mammals at the early stages of development. Complete recovery of the organ after damage does not occur. It is necessary to look for new ways that reveal the processes that contribute to regeneration. The study of processes that occur in the body before birth allows understanding the mechanisms of what happens in the postnatal period in general pathological processes. It was studied the mechanical damage to the liver in rat fetuses under the influence of biocorrectors “Trepel” and “Suvar.” Morphological, morphometric, histochemical, and immunohistochemical methods were used for processing the material. The results of the work indicate that the combined use of these biocorrectors after the development of a necrosis focus in the liver reduces alternative manifestations of hepatocytes, inhibits reactive inflammation around the injury site, slows down the recruitment of fibroblasts to the injury zone, and inhibits collagen genesis. At the same time, biocorrectors have a pronounced stimulating effect on proliferation of hepatocytes, which, against the background of increased enzymatic activity, manifests itself in the form of mitotic division activation and polyploidization of hepatocytes. Despite the signs of regenerative stimulation, as a result, complete recovery of the liver in the site of the dead tissue in experimental rats does not occur; there is only a 34.7% decrease in the focus of fibrosis formed in the place of dead liver tissue, compared to control animals.

Upregulation of PDGF Mediates Robust Liver Regeneration after Nanosecond Pulsed Electric Field Ablation by Promoting the HGF/c-Met Pathway

Nanosecond pulsed electric field (nsPEF) has emerged as a promising tool for hepatocellular carcinoma ablation recently. However, little is known about how nsPEF affects liver regeneration while being applied to eliminate liver lesions. Besides, the impact of nsPEF ablation on liver function should also be taken into consideration in the process. In this paper, we study the impact of nsPEF ablation on liver function by the measurement of serum levels of AST and ALT as well as liver regeneration and relevant molecular mechanisms in vivo. We found that mouse liver function exhibited a temporary injury without weight loss after ablation. In addition, local hepatic nsPEF ablation promoted significant proliferation of hepatocytes of the whole liver with an increase in HGF level. Moreover, the proliferation of hepatocytes was dramatically inhibited by the inhibitor of c-Met. Of interest, the periablational area is characterized by high level of PDGF and a large amount of activated hepatic stellate cells. Furthermore, neutralizing PDGF was able to significantly inhibit liver regeneration, the increased HGF level, and the accumulation of activated HSCs. Our findings demonstrated that nsPEF not only was a safe ablation approach but also could stimulate the regeneration of the whole liver through the activation of the HGF/c-Met pathway by upregulation of PDGF within the periablational zone.

Features of regenerative processes in case of extreme factors influencing the body

Changes in the specific liver mass, number of single and binucleate cells of different ploidy, mitotic index and alteration index, DNA content and inclusion of 3H-thymidine in DNA of Wistar rats and CBA mice in the following conditions: at 0°C for 3, 7, 14 days for 23 hours per day, and in the highlands conditions (3, 200 m above sea level) for 3 and 30 days. Activation of regenerative processes has been established — proliferation of hepatocytes (mainly diploid) in combination with polyploid cell share reduction, as well as cellular hypertrophy development. Cell dynamics shifts persisted throughout the observation duration and were opposite in direction when growing up and aging.

Noncoding RNA in Liver Regeneration—From Molecular Mechanisms to Clinical Implications

The unique ability of the adult liver to regenerate after injury is the basis for efficient surgical resection and liver transplantation and provides solutions for the treatment of liver cancer and acute liver failure. Current success in surgical treatments could be enhanced by directed regulation of liver regeneration. A number of small molecules and growth factors have been tested in mice models to improve liver regeneration. Noncoding ribonucleic acids (ncRNA) are less studied regulators of various cellular processes. Here, the authors carefully review ncRNA involved in liver regeneration and discuss molecular mechanisms and regulatory networks. These ncRNAs modulate the expression of pro- and antiproliferative genes allowing to orchestrate precisely the proliferation of hepatocytes. The authors expect that ncRNA will become new targets in liver regeneration due to recent progress in therapeutic nucleic acids. Among a large number of preclinical studies on ncRNA, only a few entered clinical trials, and further studies are needed to uncover their potential as therapeutic targets.

NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte

Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). Nlrp12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, Nlrp12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in Nlrp12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in Nlrp12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of Nlrp12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.

miR-155 accelerates proliferation of mouse hepatocytes during liver regeneration by directly targeting SOCS1

Liver regeneration after two-thirds partial hepatectomy (PH) is a clinically significant repair process for restoring proper liver architecture. Although microRNA-155 (miR-155) has been found to serve as a crucial microRNA regulator that controls liver cell function and proliferation, little is known about its specific role in the regenerating liver. Using a mouse model with miR-155 overexpression or miR-155 knockout, we investigated the molecular mechanisms of miR-155 in liver regeneration. We found a marked induction of miR-155 in C57BL/6 mice after PH. Furthermore, RL-m155 mice showed enhanced liver regeneration as a result of accelerated progression of hepatocytes into the cell cycle, mainly through an increase in cyclin levels. However, proliferation of hepatocytes was delayed in miR-155-deficient livers. Expression of suppressor of cytokine signaling 1 (SOCS1) was dramatically downregulated in the process of liver regeneration, and enhancement of SOCS1 contributed to impaired proliferation of hepatocytes. Additionally, in vitro and in vivo experiments showed that adenovirus- or adeno-associated virus-mediated overexpression of SOCS1 attenuated improved liver regeneration induced by miR-155 overexpression. Our study shows that miR-155 is a pro-proliferative regulator in liver regeneration by facilitating the cell cycle and directly targeting SOCS1. NEW & NOTEWORTHY Our findings suggest a microRNA-155 (miR-155)-mediated positive regulation pattern in liver regeneration. A series of in vivo and in vitro studies showed that miR-155 upregulation enhanced partial hepatectomy-induced proliferation of hepatocytes by promoting the cell cycle without inducing DNA damage or apoptosis. Suppressor of cytokine signaling 1, a target gene of miR-155, antagonized the proliferation-promoting effect of miR-155. Therefore, pharmacological intervention targeting miR-155 may be therapeutically beneficial in various liver diseases.