Experimental Correction and Treatment of Chronic Liver Failure Using Implantable Cell-Engineering Constructs of the Auxiliary Liver Based on a Bioactive Heterogeneous Biopolymer Hydrogel.

Our study sought approaches for chronic liver failure (CLF) treatment and correction via cell-engineered constructs (CECs). They are built from biopolymer-based, microstructured, and collagen-containing hydrogel (BMCG). We also strove to evaluate the functional activity of BMCG in liver regeneration. MATERIALS AND METHODS: Allogeneic liver cells (namely, hepatocytes; LC) together with mesenchymal multipotent stem cells of bone marrow origin (MMSC BM; BMSCs) were adhered to our BMCG to compose implanted liver CECs. Thereafter, we investigated a model of CLF in rats receiving the implanted CECs. The CLF had been provoked by long-term exposure to carbon tetrachloride. The study comprised male Wistar rats (n = 120) randomized into 3 groups: Group 1 was a control group with the saline treatment of the hepatic parenchyma (n = 40); Group 2 received BMCG only (n = 40); and Group 3 was loaded with CECs implanted into the parenchyma of their livers (n = 40). August rats (n = 30) made up a donor population for LCs and MMSC BM to develop grafts for animals from Group 3. The study length was 90 days. RESULTS: CECs were shown to affect both biochemical test values and morphological parameters in rats with CLF. CONCLUSION: We found BMCG-derived CECs to be operational and active, with regenerative potential. Group 3 showed significant evidence of forced liver regeneration that tended to persist until the end of the study (day 90). The phenomenon is reflected by biochemical signs of hepatic functional recovery by day 30 after grafting (compared to Groups 1 and 2), whereas structural features of liver repair (necrosis prevention, missing formation of vacuoles, degenerating LC number decrease, and delay of hepatic fibrotic transformation). Such implantation of BMCG-derived CECs with allogeneic LCs and MMSC BM might represent a proper option to correct and treat CLF, as well as to maintain affected liver function in patients with liver grafting needed.

Aminodihydrophthalazinedione Sodium Transdermal Therapeutic System Specific Activity on an ExperimentalModel of Extensive Liver Resection.

Previously, the authors showed that the application of the aminodihydrophthalazinedione sodium (ADPS) immunomodulator transdermal therapeutic system (TTS) to laboratory animals provides bioavailability analogous to the intramuscular administration of this drug at the same dose. At the same time, its maximum blood concentration is significantly reduced, and the retention time of the drug in the body is increased more than 10-fold, which can contribute to prolonging the drug effect. The aim of the work was to identify a possible positive effect of the transdermal administration of the ADPS immunomodulator on reparative liver regeneration on an experimental model of extensive liver resection (ELR). It has been shown that at a period of 48 h after ELR, the percutaneous administration of the immunomodulator has a pronounced stimulating effect on the mitotic activity of rat liver cells; by 72 h after ELR, an accelerated rate of recovery of hepatic homeostasis in the body was observed in laboratory animals in groups with the application of the ADPS TTS versus the control group.

Recombinant Spidroin Microgel as the Base of Cell-Engineered Constructs Mediates Liver Regeneration in Rats.

Aim: In this study, we seek to check if recombinant spidroin rS1/9 is applicable for cell-engineering construct development. Novel technologies of cell and tissue engineering are relevant for chronic liver failure management. Liver regeneration may represent one of the possible treatment options if a cell-engineered construct (CEC) is used. Nowadays, one can see the continuous study of various matrices to create an appropriate CEC. Materials and Methods: We have adhered allogenic liver cells and multipotent mesenchymal bone marrow stem cells (MMSC BM) to a microgel with recombinant spidroin rS1/9. Then we have studied the developed implantable CEC in a rat model (n = 80) of chronic liver failure achieved by prolonged poisoning with carbon tetrachloride. Results: Our results demonstrate that the CECs change the values of biochemical tests and morphological parameters in chronic liver failure in rats. Conclusion: We consider there to be a positive effect from the microgel-based CECs with recombinant spidroin rS1/9 in the treatment of chronic liver failure.

The Antioxidant Cofactor Alpha-Lipoic Acid May Control Endogenous Formaldehyde Metabolism in Mammals.

The healthy human body contains small amounts of metabolic formaldehyde (FA) that mainly results from methanol oxidation by pectin methylesterase, which is active in a vegetable diet and in the gastrointestinal microbiome. With age, the ability to maintain a low level of FA decreases, which increases the risk of Alzheimer's disease and dementia. It has been shown that 1,2-dithiolane-3-pentanoic acid or alpha lipoic acid (ALA), a naturally occurring dithiol and antioxidant cofactor of mitochondrial α-ketoacid dehydrogenases, increases glutathione (GSH) content and FA metabolism by mitochondrial aldehyde dehydrogenase 2 (ALDH2) thus manifests a therapeutic potential beyond its antioxidant property. We suggested that ALA can contribute to a decrease in the FA content of mammals by acting on ALDH2 expression. To test this assumption, we administered ALA in mice in order to examine the effect on FA metabolism and collected blood samples for the measurement of FA. Our data revealed that ALA efficiently eliminated FA in mice. Without affecting the specific activity of FA-metabolizing enzymes (ADH1, ALDH2, and ADH5), ALA increased the GSH content in the brain and up-regulated the expression of the FA-metabolizing ALDH2 gene in the brain, particularly in the hippocampus, but did not impact its expression in the liver in vivo or in rat liver isolated from the rest of the body. After ALA administration in mice and in accordance with the increased content of brain ALDH2 mRNA, we detected increased ALDH2 activity in brain homogenates. We hypothesized that the beneficial effects of ALA on patients with Alzheimer's disease may be associated with accelerated ALDH2-mediated FA detoxification and clearance.

Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Fourth Meeting: lessons learned from first clinical trials.

The Fourth Expert Meeting of the Mesenchymal Stem Cells in Solid Organ Transplantation (MiSOT) Consortium took place in Barcelona on October 19 and 20, 2012. This meeting focused on the translation of preclinical data into early clinical settings. This position paper highlights the main topics explored on the safety and efficacy of mesenchymal stem cells as a therapeutic agent in solid organ transplantation and emphasizes the issues (proper timing, concomitant immunossupression, source and immunogenicity of mesenchymal stem cells, and oncogenicity) that have been addressed and will be followed up by the MiSOT Consortium in future studies.

Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT).

There is evolving interest in the use of mesenchymal stem cells (MSC) in solid organ transplantation. Pre-clinical transplantation models show efficacy of MSC in prolonging graft survival and a number of clinical studies are planned or underway. At a recent meeting of the MISOT consortium (MSC In Solid Organ Transplantation) the advances of these studies were evaluated and mechanisms underlying the potential effects of MSC discussed. Continued discussion is required for definition of safety and eventually efficacy endpoints for MSC therapy in solid organ transplantation.