Combination Therapy of Placenta-Derived Mesenchymal Stem Cells with WKYMVm Promotes Hepatic Function in a Rat Model with Hepatic Disease via Vascular Remodeling

Changes in the structure and function of blood vessels are important factors that play a primary role in regeneration of injured organs. WKYMVm has been reported as a therapeutic factor that promotes the migration and proliferation of angiogenic cells. Additionally, we previously demonstrated that placenta-derived mesenchymal stem cells (PD-MSCs) induce hepatic regeneration in hepatic failure via antifibrotic effects. Therefore, our objectives were to analyze the combination effect of PD-MSCs and WKYMVm in a rat model with bile duct ligation (BDL) and evaluate their therapeutic mechanism. To analyze the anti-fibrotic and angiogenic effects on liver regeneration, it was analyzed using ELISA, qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry. Collagen accumulation was significantly decreased in PD-MSCs with the WKYMVm combination (Tx+WK) group compared with the nontransplantation (NTx) and PD-MSC-transplanted (Tx) group (p < 0.05). Furthermore, the combination of PD-MSCs with WKYMVm significantly promoted hepatic function by increasing hepatocyte proliferation and albumin as well as angiogenesis by activated FPR2 signaling (p < 0.05). The combination therapy of PD-MSCs with WKYMVm could be an efficient treatment in hepatic diseases via vascular remodeling. Therefore, the combination therapy of PD-MSCs with WKYMVm could be a new therapeutic strategy in degenerative medicine.

EFFECTS OF LOW-LEVEL LASER THERAPY ON LIVER REGENERATION AND THE LASER PARAMETERS EMPLOYED

Low-level laser therapy has various biological effects; one of them is tissue regeneration. Its application in the liver of rats after partial hepatectomy to promote liver regeneration has recently been studied. The aim of this article was to review the recent studies on the effects of low-level laser therapy on rat liver regeneration after partial hepatectomy and the laser parameters used. A review of recent relevant literature was performed in Pubmed, Scielo, Medline and Bireme databases. Articles about the application of low-level laser therapy on hepatic regeneration were included. Articles with hepatic regeneration in the presence of pathologies were not included. Nine studies were found matching the study criteria. In most studies, low-level laser therapy promoted liver regeneration after partial hepatectomy, without further damage to the remaining liver. Not all laser parameters necessary for the reproducibility of the study were described by all authors. The therapeutic use of low-level laser therapy in liver regeneration can be promising, however, as liver is a vital organ and the laser application is intraoperative, future studies are needed. The parameters used must be properly described and standardized to allow the reproducibility of the study, so that a therapeutic window can be defined and its clinical use can be considered. It is also essential to clarify the mechanisms by which the laser promotes liver regeneration, to guarantee its safety and therapeutic efficacy.

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.

Wnt Pathway Activation by Placental Mesenchymal Stem Cells Promotes Hepatic Regeneration in a Cirrhotic Rat Model

Background: Sinusoidal endothelial cells (SECs) in liver play important roles in hepatocyte regeneration. We recently reported placenta-derived mesenchymal stem cells (PD-MSCs) can promote hepatic regeneration in a damaged liver model via dynamic events. However, the effects of PD-MSCs on vascular structure in liver tissues remain unknown. We therefore investigated alteration of vascular structure and function in carbon tetrachloride (CCl4)-injured rat model following transplantation (Tx) with PD-MSCs. Methods: PD-MSCs were engrafted into CCl4-injured rat model via intravenous Tx. Expression markers related to angiogenic factors and Wnt signaling pathway were analyzed by quantitative real time-PCR, Western blot, and immunofluorescence in vitro and in vivo. Furthermore, endothelial permeability assay was performed to confirm the effect of PD-MSCs on the functional regeneration of injured endothelial cells in vitro co-culture system.Results: PD-MSCs were found to significantly reduce the expanded hepatic vein diameter and increased tube formation of the aorta in both in vitro and ex vivo co-culture systems. PD-MSCs also increased the expression of angiogenic factors and activated the Wnt signaling pathway. Furthermore, PD-MSCs reduced endothelial permeability via activation of β-catenin in the in vitro co-culture system. Conclusions: Taken together, PD-MSCs transplantation (PD-MSC Tx) improves the structure and function of SECs by activating Wnt signaling, which triggers hepatic regeneration, in a CCl4-injured rat model. Therefore, these findings suggest that vascular restoration induced by PD-MSCs supports liver regeneration in a hepatic failure model and can be applied as a cell-based therapy.

The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling

It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.

Capability of Hepatic Regeneration of Albino Mice against Hepatic Injuries Induced by Phentolep Drug

The major theme of our research was to evaluate the condition of the regenerative capacity of liver with proper consumption of phenytoin medicines with proper precautionary factors. DNA damage was measured through the comet assay via hepatocytes and histological examination was conducted in order to ensure the liver injuries. Current study comprises of four different group of Balb/c albino mice, from them 1st group was facilitated with normal saline as per recommended dose of 1ml/kg. In 2nd group of mice, phenotolep drug was injected with the dose of 12mg/kg for two continuous weeks. Whereas; in 3rd group same, the drug is administered into the mice with same dosing regimen for 02 weeks and then allowed to recover for 02 weeks. In the last group of mice, phenotolep was given to the remaining mice with a similar regimen and managed for 04 weeks for normal physiological functions and it was concluded that induction of phentolep among various groups of mice can induce alteration the nucleus of hepatocytes and ultimately variation occurred within DNA. 3rd and 4th groups showed quite differ results than the positive group as regression was observed in these groups and restore the normal physiology of the liver and the current study indicates that hepatic injuries can be sorted out with passage of time.