Treatment Of Fulminant Hepatic Failure Research Articles

Therapeutic plasma exchange for neonatal hepatic failure

We report a case of therapeutic plasma exchange in a neonate with fulminant liver failure. A six-day old, 2800-gram baby was referred to our medical center for evaluation and treatment of fulminant hepatic failure. The working diagnosis at admission was gestational alloimmune liver disease, and therapeutic plasma exchange was proposed. A double volume plasma exchange was successfully performed, using the Spectra Optia apheresis system, primed with packed red blood cells. Access was obtained via a radial artery catheter and a peripheral intravenous line. On hospital D-14 a diagnosis of E3 deficiency was confirmed, and disease-specific therapy was started. Automated TPE using peripheral arterial and venous catheters may be safely performed in neonates, and should be considered in the treatment of a variety of disorders including neonatal fulminant hepatic failure.

Anti-tuberculosis drug-induced acute liver failure requiring transplantation in the second trimester of pregnancy: a case report

BackgroundTreatment of tuberculosis (TB) during pregnancy can reduce maternal and foetal complications. However, it may also induce fatal liver injury.Case presentationWe present a case of a 26-year-old pregnant woman who underwent orthotopic liver transplantation for anti-TB drug-induced fulminant hepatic failure (FHF). Her tuberculous pleurisy was treated with rifampin, isoniazid and pyrazinamide. An artificial liver support system (ALSS) was unable to reverse the liver injury while serving as a bridge to liver transplantation. She had a successful liver transplantation operation at 17 3/7 weeks of gestation. The foetal ultrasound scan showed mild foetal bilateral ventriculomegaly at 21 5/7 weeks of gestation, and labour was induced via double-balloon catheter as soon as the allograft function was stable. Despite immunosuppression, the TB was well controlled with linezolid, levofloxacin and pyridoxine at the 8 months follow-up.ConclusionsAnti-TB drug-induced liver failure during pregnancy is rare. We present a case of successful treatment of FHF in which an artificial liver support system combined with liver transplantation. The FHF was caused by anti-TB drugs with difficulties due to pregnancy status and post-transplant anti-TB treatment. Mild foetal ventriculomegaly was found in our case. Further research is still needed to identify the risks of TB treatment and liver transplantation in pregnant women. A multidisciplinary team coordinated properly to optimize patient outcomes.

OLDER LIVERS SHOULD NOT BE UTILIZED IN PEDIATRIC LIVER TRANSPLANTATION

Introduction: Organ scarcity in liver transplantation has required expansion of the acceptable criteria used for donor selection. The utilization of older donors (>60 years) has become common practice in adult liver transplantation. We examined outcomes in pediatric liver transplantation where recipients received a liver from a donor >60 years in age. Methods: The UNOS database was used to identify all pediatric liver transplant recipients (<18 years) transplanted between 1987—2018. Only recipients of solitary, deceased donor organs were included. Pediatric recipients were grouped according to donor age; <60 years (YOUNG) and >60 years (OLD). Donor and recipient demographic data were examined, as were survival and outcomes. A p-value of <0.05 was considered to be significant. Results: Of 15,448 pediatric transplants, 71 received an OLD liver while 15,377 received a YOUNG liver. Donors were significantly older in the OLD group (67.3 vs. 11.7 years), with higher BMI (24.1 vs. 19.5 kg/m2), more frequently Caucasian (85.9% vs. 62.6%) and female (62.0% vs. 41.2%) compared with YOUNG donors. Cause of death was frequently a cerebrovascular accident (85.9% vs. 12.5%) in OLD donors. There were no differences in cold ischemia time, biopsy fat content, or transaminases. OLD donors were not donation after cardiac death (DCD) donors. Recipients of OLD livers were significantly older (11.3 vs. 5.1 years), had a shorter wait time (23.5 vs. 148.5 days), increased BMI (21.1 vs. 18.3 kg/m2), and higher initial and final PELD/MELD scores (34 vs. 12 initial; 31 vs. 14 final). OLD donors were more likely to have used in treatment of fulminant hepatic failure (FHF, 74.7% vs. 35.1%). In addition, recipients of older livers were more likely to be on life support (62.0% vs. 16.6%) or the ventilator (57.8% vs. 13.8%), have had dialysis in the week prior to transplant (9.9% vs. 5.0%) and to have had a previous liver transplant (23.4% vs. 13.8%). Importantly, allograft survival in recipients of OLD livers were found to be significantly diminished when compared to YOUNG livers (Figure 1).Conclusions: Pediatric recipients of older liver allografts are significantly sicker than those who receive younger allografts. Allograft survival, however, was greatly reduced when compared to younger allografts. Use of older liver donors should be avoided, especially in younger or fulminant recipients.

Therapeutic Effect of Yttrium Oxide Nanoparticles for the Treatment of Fulminant Hepatic Failure

Aim: To explore the potential therapeutic effect of yttrium oxide nanoparticles (Y2O3 NPs) on fulminant hepatic failure. Materials & methods: RAW264.7 cells and a lipopolysaccharide/D-galactosamine-induced hepatic failure murine model were used to assess the effects of Y2O3NPs. Results: Y2O3 NPs exhibited anti-inflammatory activity by scavenging cellular reactive oxygen species and dampening reactive oxygen species-mediated NF-κB activation in vitro. A single intraperitoneal administration of Y2O3 NPs (30mg/kg) enhanced hepatic antioxidant status and reduced oxidative stress and inflammatory response in lipopolysaccharide/galactosamine-induced mice. Y2O3 NPs also attenuated hepatic NF-κB activation, cell apoptosis and liver injury. Conclusion: Y2O3 NP administration could be used as a novel therapeutic strategy for treating fulminant hepatic failure and oxidative stress-related diseases.

Prognostic Factors Predicting Poor Outcome in Living-Donor Liver Transplantation for Fulminant Hepatic Failure

BackgroundLiving-donor liver transplantation (LDLT) has been accepted as feasible treatment for fulminant hepatic failure (FHF), although it has generated several debatable issues. In this study, we investigated the prognostic factors predicting fatal outcome after LDLT for FHF. MethodsFrom April 1999 to April 2011, 60 patients underwent LT for acute liver failure, including 42 patients for FHF at Samsung Medical Center, Seoul, Korea. Among 42 patients, 30 patients underwent LDLT for FHF, and the database of these patients was analyzed retrospectively to investigate the prognostic factors after LDLT for FHF. ResultsAmong 30 patients, 7 patients (23%) died during the in-hospital period within 6 months, and 23 patients (77%) survived until recently. In univariate analyses, donor age (>35 years), graft volume (GV)/standard liver volume (SLV) (<50%), cold ischemic time (>120 minutes), hepatic encephalopathy (grade IV), hepato-renal syndrome (HRS), and history of ventilator care were associated with fatal outcome after LDLT for FHF. In multivariate analyses, HRS, GV/SLV (<50%), and donor age (>35 years) were significantly associated with fatal outcome. Although the statistical significance was not shown in this analysis (P = .059), hepatic encephalopathy grade IV also appears to be a risk factor predicting fatal outcome. ConclusionsThe survival of patients with FHF undergoing LDLT was comparable to that in published data. In this study, HRS, GV/SLV <50%, and donor age >35 years are the independent poor prognostic factors.

Immunomodulatory Effects of Adipose Tissue-Derived Stem Cells on Concanavalin A-Induced Acute Liver Injury in Mice.

Cell therapy with adipose tissue-derived stem cells (ASCs) is expected to be a candidate for the treatment of fulminant hepatic failure (FHF), which is caused by excessive immune responses. In order to evaluate the therapeutic effects of ASCs on FHF, the in vitro and in vivo immunomodulatory effects of ASCs were examined in detail in the mouse model. The in vitro effects of ASCs were examined by assessing their influence on the proliferation of lymphomononuclear cells (LMCs) stimulated with three kinds of mitogens: phorbol 12-myristate 13-acetate (PMA) plus ionomycin, concanavalin A (ConA), and lipopolysaccharide (LPS). The proliferation of LMCs was efficiently suppressed in a dose-dependent manner by ASCs in the cases of PMA plus ionomycin stimulation and ConA stimulation, but not in the case of LPS stimulation. The in vivo effects of transplanted ASCs were examined in the murine FHF model induced by ConA administration. The ALT levels and histological inflammatory changes in the ConA-administered mice were apparently relieved by the transplantation of ASCs. The analysis of mRNA expression patterns in the livers indicated that the expressions of the cytokines such as Il-6, Il-10, Ifn-γ, and Tnf-α, and the cell surface markers such as Cd3γ, Cd4, Cd8α, Cd11b, and Cd11c were downregulated in the ASC-transplanted mice. The immunomodulatory and therapeutic effects of ASCs were confirmed in the mouse model both in vitro and in vivo. These suggest that the cell therapy with ASCs is beneficial for the treatment of FHF.

CRISPR/Cas9 Technology Targeting Fas Gene Protects Mice From Concanavalin-A Induced Fulminant Hepatic Failure.

Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively. The in vivo delivery of CRISPR/Cas9 could maintain liver homeostasis and protect hepatocytes from Fas-mediated cell apoptosis in the fulminant hepatic failure model. Our study indicates the clinical potential of developing the CRISPR/Cas9 system as a novel therapeutic strategy to rescue Concanavalin-A-induced fulminant hepatic failure in the mouse model. J. Cell. Biochem. 118: 530-536, 2017. © 2016 Wiley Periodicals, Inc.

Quantitative evaluation of human bone mesenchymal stem cells rescuing fulminant hepatic failure in pigs.

Stem cell transplantation provides a promising alternative for the treatment of fulminant hepatic failure (FHF). However, it lacks fundamental understanding of stem cells' activities. Our objective was to clarify stem cell-recipient interactions for overcoming barriers to clinical application. We used an in-house large-animal (pig) model of FHF rescue by human bone marrow mesenchymal stem cells (hBMSCs) and profiled the cells' activities. The control and transplantation groups of pigs (n=15 per group) both received a D-galactosamine (D-Gal) injection (1.5 g/kg). The transplantation group received hBMSCs via intraportal vein infusion (3×106 cells/kg) immediately after D-Gal administration. The stem cell-recipient interactions were quantitatively evaluated by biochemical function, cytokine array, metabolite profiling, transcriptome sequencing and immunohistochemistry. All pigs in the control group died within an average of 3.22 days, whereas 13/15 pigs in the transplantation group lived >14 days. The cytokine array and metabolite profiling analyses revealed that hBMSC transplantation suppressed D-Gal-induced life-threatening cytokine storms and stabilised FHF within 7 days, while human-derived hepatocytes constituted only ∼4.5% of the pig hepatocytes. The functional synergy analysis of the observed profile changes indicated that the implanted hBMSCs altered the pigs' cytokine responses to damage through paracrine effects. Delta-like ligand 4 was validated to assist liver restoration in both pig and rat FHF models. Our results delineated an integrated model of the multifaceted interactions between stem cells and recipients, which may open a new avenue to the discovery of single molecule-based therapeutics that simulate stem cell actions.

The Role of Cell-Based Bioartificial Liver Therapy in the Treatment of Fulminant Hepatic Failure

The Role of Cell-Based Bioartificial Liver Therapy in the Treatment of Fulminant Hepatic Failure

Partial Portal Vein Arterialization Maintains Regeneration after Critical Major Hepatectomy : Experimental Study

Portal vein arterialization (PVA) is often referred to as a salvage procedure for insufficient arterial or portal inflow. Its main role focuses on two domains, liver transplantation and extensive surgery for malignancies of liver, biliary tract and pancreas. It ha been applied in treatment of fulminant hepatic failure due to intoxications and as a bridging procedure for transplantation or re-transplant. Radical resections with arterial reconstruction are a major challenge for surgeons especially in prolonging survival in advanced malignancies of the liver or biliary tract. This study revisited the benefits of this procedure to test the hypothesis of supporting a failing liver during critical period of regeneration following major hepatectomy with insufficient arterial inflow. The endpoints were to identify the histopathological and biochemical evidence of regeneration. The experimental design: 24 adult dogs of both sexes were included. They were divided into 3 groups: G1 (n = 7): animals subjected to 65% hepatectomy (control), G2 (n = 8): animals subjected to 65% hepatectomy & hepatic artery ligation, G3 (n = 8): animals subjected to 65% hepatectomy & partial portal vein arterialization (PPVA). Blood samples were taken for assessment of liver functions and blood gas analysis. Liver biopsy was assessed for morphological and histopathological changes of regeneration. Gross specimens were used to calculate the liver regeneration rate. Results showed the presence of mitotic activity and regeneration in groups with PPVA comparable to controls. No evidence of regeneration observed in G2. Shunt patency was confirmed by increase in PO2 levels of arterialized portal vein. A significant increase in the regeneration rate in groups with arterialized portal vein 1 week post procedure was noted.

Herpes Simplex Virus (HSV) in the Differential for Fulminant Hepatic Failure

Following an elective transphenoidal resection of a pituitary tumor, a 66-year-old Hispanic male acutely developed fulminant hepatic failure and severe coagulopathy. He received parenteral corticosteroids the day prior to surgery, and was first noted to have significant coagulopathy intraoperatively. Despite aggressive workup and treatment for fulminant hepatic failure, the patient developed multiorgan failure by post-operative day 2, and expired on post-operative day 3. On post-mortem examination, hemorrhagic necrosis of the liver was noted and microscopic examination revealed Cowdry type A inclusions, consistent with Herpes Simplex Virus (HSV) infection. This diagnosis was subsequently confirmed by immunehistochemistry. Fulminant hepatic failure due to HSV is a rare but highly fatal disease if untreated. Most case reports include only immunocompromised or pregnant patients. However, the lack of clinical suspicion in this previously healthy patient may have delayed prompt treatment with antiviral agents. It is important to raise the awareness of this rare and life-threatening, but potentially treatable, etiology when clinicians are faced with acute idiopathic fulminant hepatic failure.

The subtype CD200-positive, chorionic mesenchymal stem cells from the placenta promote regeneration of human hepatocytes

Human placental mesenchymal stem cells (hPMSCs), for the treatment of fulminant hepatic failure, have been widely studied. Only a few studies have investigated the effect of the subtype CD200(+)hPMSCs on regeneration of human hepatocytes. CD200(+)hPMSCs can down-regulate activity of several immunocytes and suppress TNF-α secretion from macrophages via the CD200-CD200R axis. We have investigated the influence of CD200-positive human placenta chorionic mesenchymal stem cells (CD200(+)hPCMSCs) on metabolism, proliferation and apoptosis of human hepatocytes in vitro. CD200(+)hPCMSCs promote urea synthesis, albumin secretion and hepatocytes proliferation at co-culture ratios of 1:1 and 3:1. Additionally, CD200(+)hPCMSCs inhibit hepatocyte apoptosis via up-regulation of an anti-apoptotic protein, Bcl-xL. Thus, CD200(+)hPCMSCs can provide supportive benefit for the regeneration of human hepatocytes and also have immunosuppressive properties. Therefore, CD200(+)hPCMSCs may be an ideal candidate for stem cell-based therapy in hepatic failure.

Development of PEGylated serum albumin with multiple reduced thiols as a long-circulating scavenger of reactive oxygen species for the treatment of fulminant hepatic failure in mice

Reactive oxygen species (ROS) are involved in the pathophysiology of fulminant hepatic failure. Therefore, we developed polyethylene glycol-conjugated bovine serum albumin with multiple reduced thiols (PEG-BSA-SH) for the treatment of fulminant hepatic failure. As a long-circulating ROS scavenger, PEG-BSA-SH effectively scavenged highly reactive oxygen species and hydrogen peroxide in buffer solution. PEG-BSA-SH showed a long circulation time in the plasma after intravenous injection into mice. Fulminant hepatic failure was induced by intraperitoneal injection of lipopolysaccharide and d-galactosamine (LPS/d-GalN) into mice. The LPS/d-GalN-induced elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was significantly inhibited by a bolus intravenous injection of PEG-BSA-SH. Furthermore, the changes in hepatic lipid peroxide and hepatic blood flow were effectively suppressed by PEG-BSA-SH. In contrast, l-cysteine, glutathione, and dithiothreitol, three traditional reduced thiols, had no statistically significant effects on the serum levels of ALT or AST. These findings indicate that PEG-BSA-SH is a promising ROS scavenger and useful in the treatment of fulminant hepatic failure.

How important is differentiation in the therapeutic effect of mesenchymal stromal cells in liver disease?

Background aimsThe protocols for differentiation of hepatocyte-like cells (HLCs) from mesenchymal stromal cells (MSCs) have been well established. Previous data have shown that MSCs and their derived HLCs were able to engraft injured liver and alleviate injuries induced by carbon tetrachloride. The goal of the current study was to determine the differences of MSCs and their derived HLCs in terms of therapeutic functions in liver diseases. MethodsAfter hepatic differentiation of umbilical cord–derived MSCs in vitro, we detected both MSC and HLC expressions of adhesion molecules and chemokine receptor CXCR4 by flow cytometry; immunosuppressive potential and hepatocyte growth factor expression were determined by means of enzyme-linked immunosorbent assay. We compared the therapeutic effect for fulminant hepatic failure in a mouse model. ResultsMSC-derived-HLCs expressed lower levels of hepatocyte growth factor, accompanied by impaired immunosuppression in comparison with MSCs. Furthermore, undifferentiated MSCs showed rescuing potentials superior to those in HLCs for the treatment of fulminant hepatic failure. ConclusionsAfter differentiation, HLCs lost several major properties in comparison with undifferentiated MSCs, which are beneficial for their application in liver diseases. Undifferentiated MSCs may be more appropriate than are HLCs for the treatment of liver diseases.

Therapeutic effects of blood purification in treatment of fulminant hepatic failure

ObjectivesTo evaluate the clinical effects of blood purification for treating fulminant hepatic failure (FHF). MethodsThirty-three severe FHF patients with hepatic encephalopathy (HE) above grade III were subjected to a combined blood purification treatment in addition to the comprehensive liver protection therapy. Patients underwent continuous hemofiltration on a daily basis during the daytime followed by sequential treatment with plasma exchange or hemodialysis every 2–3 days. The therapeutic effects of this treatment were evaluated. ResultsAfter treatment with blood purification, restoration of consciousness (those who abandoned the treatment without restoration of consciousness were excluded) was achieved in 6 of 8 cases (75%) in acute liver failure (ALF) group, 3 of 3 cases (100%) in subacute liver failure (SALF) group, and 9 of 14 cases (64.29%) in acute/subacute on chronic liver failure (A/SCLF) group. Of all cases, 11 patients restored consciousness after 7 days in a coma. The rate of long-term survival (those who abandoned the treatment were excluded) was 3/7 (42.86%) for ALF group, 2/2 (100%) for SALF group, and 1/11 (9.09%) for A/SCLF group. The levels of hemoglobin and platelet in peripheral blood were significantly reduced after blood purification. ConclusionsTreatment of FHF patients with daily continuous hemofiltration during the daytime is effective in treating HE and in improving health status in the early stages of the disease. Long-term prognosis also benefits from this treatment. The rate of consciousness recovery and long-term survival is highest in SALF group followed by ALF group. This treatment is less effective in A/SCLF patients. It should be noted that blood purification procedure may cause damage to blood cells.

Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs

The effectiveness of human bone marrow mesenchymal stem cell (hBMSC) transplantation to treat acute and chronic liver injury has been demonstrated in animal models and in a few nonrandomized clinical trials. However, no studies have investigated hBMSC transplantation in the treatment of fulminant hepatic failure (FHF), especially in large animal (pig) models. The aim of this study was to demonstrate the safety, effectiveness, and underlying mechanism of hBMSC transplantation for treating FHF in pigs through the intraportal route. Human BMSCs (3 × 107) were transplanted into pigs with FHF via the intraportal route or peripheral vein immediately after D-galactosamine injection, and a sham group underwent intraportal transplantation (IPT) without cells (IPT, peripheral vein transplantation [PVT], and control groups, respectively, n = 15 per group). All of the animals in the PVT and control groups died of FHF within 96 hours. In contrast, 13 of 15 animals in the IPT group achieved long-term survival (>6 months). Immunohistochemistry demonstrated that transplanted hBMSC-derived hepatocytes in surviving animals were widely distributed in the hepatic lobules and the liver parenchyma from weeks 2 to 10. Thirty percent of the hepatocytes were hBMSC-derived. However, the number of transplanted cells decreased significantly at week 15. Only a few single cells were scattered in the regenerated liver lobules at week 20, and the liver tissues exhibited a nearly normal structure. Conclusion: Immediate IPT of hBMSCs is a safe and effective treatment for FHF. The transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation into hepatocytes during the initial stage of FHF. This method can possibly be used in future clinical therapy. (HEPATOLOGY 2012;56:1044–1052)

Immediate intraportal transplantation of human bone marrow mesenchymal stem cells prevents death from fulminant hepatic failure in pigs

The effectiveness of human bone marrow mesenchymal stem cell (hBMSC) transplantation to treat acute and chronic liver injury has been demonstrated in animal models and in a few nonrandomized clinical trials. However, no studies have investigated hBMSC transplantation in the treatment of fulminant hepatic failure (FHF), especially in large animal (pig) models. The aim of this study was to demonstrate the safety, effectiveness, and underlying mechanism of hBMSC transplantation for treating FHF in pigs through the intraportal route. Human BMSCs (3 × 10(7) ) were transplanted into pigs with FHF via the intraportal route or peripheral vein immediately after D-galactosamine injection, and a sham group underwent intraportal transplantation (IPT) without cells (IPT, peripheral vein transplantation [PVT], and control groups, respectively, n = 15 per group). All of the animals in the PVT and control groups died of FHF within 96 hours. In contrast, 13 of 15 animals in the IPT group achieved long-term survival (>6 months). Immunohistochemistry demonstrated that transplanted hBMSC-derived hepatocytes in surviving animals were widely distributed in the hepatic lobules and the liver parenchyma from weeks 2 to 10. Thirty percent of the hepatocytes were hBMSC-derived. However, the number of transplanted cells decreased significantly at week 15. Only a few single cells were scattered in the regenerated liver lobules at week 20, and the liver tissues exhibited a nearly normal structure. Immediate IPT of hBMSCs is a safe and effective treatment for FHF. The transplanted hBMSCs may quickly participate in liver regeneration via proliferation and transdifferentiation into hepatocytes during the initial stage of FHF. This method can possibly be used in future clinical therapy.

Amniotic fluid-derived mesenchymal stem cells as a novel therapeutic approach in the treatment of fulminant hepatic failure in rats

As a potential alternative treatment for terminal liver diseases, amniotic fluid derived mesenchymal stem cells (AFMSCs) have many advantages over other stem cells: avoiding much ethical controversy and decrease in both quantity and differentiation potential with age. However, the therapeutic role of AFMSC for fulminant hepatic failure (FHF) has not yet been clearly elucidated. Therefore, we investigated the reparation effects of transplanted AFMSCs in rats with FHF. AFMSCs were transplanted into injured liver via the portal vein in the rat FHF model. Therapeutic effect was evaluated after cell transfusion by histologic pathology, hepatic enzyme levels and animal survival. Cryostat sections were prepared and directly assessed for green fluorescent protein (GFP) expression and localization, and in vivo differentiation of AFMSC was confirmed by double-immunostaining analyses. Our results show that AFMSCs prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and animals survival after injection with AFMSCs using GFP, we demonstrated that the engrafted cells and their progeny incorporated into injured livers and produced albumin. We found that AFMSCs transplantation modestly promoted the repair of FHF in rats. AFMSCs implanted in the injured liver may be a novel therapeutic approach in the treatment of FHF. Key words : Amniotic fluid-derived mesenchymal stem cells, fulminant hepatic failure, cell transplantation, treatment, hepatogenic differentiation.

Return of the Metabolic Trajectory to the Original Area after Human Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Fulminant Hepatic Failure

Our recent study first demonstrated that human bone marrow mesenchymal stem cell (hBMSC) transplantation could prevent death from fulminant hepatic failure (FHF) in pigs. To further clarify the metabolic mechanism of hBMSC transplantation in FHF, the plasma collected from FHF pigs that received transplantation of hBMSCs was examined using metabolic analysis to identify the key molecular markers that regulate recovery. The results showed that obvious metabolic disturbance occurred during FHF, whereas the hBMSC transplantation group showed less severe liver injury. The metabolic trajectory returns to its original state at week 3 following the hBMSC transplantation. In total, the concentration of 26 metabolites, including conjugated bile acids, phosphatidylcholines, lysophosphatidylcholines, fatty acids, amino acid and sphingomyelin, are significantly different between the FHF group and the hBMSC transplantation group. Moreover, the time course of changes in the metabolites corresponded with that of the biochemical and histological analyses. Real-time PCR further confirmed that the gene expression of phospholipase A1, lecithin-cholesterol acyltransferase and lysophosphatidylcholine acyltransferase 1 decreased significantly, whereas that of phospholipase A2 remained stable, which explains the decrease of the phosphatidylcholines and lysophosphatidylcholines. These novel results have revealed a metabolic mechanism for the hBMSC transplantation in FHF, which could lead to the future development of treatment strategies for stem cell therapies.

Transplantation of Co-Microencapsulated Hepatocytes and HUVECs for Treatment of Fulminant Hepatic Failure

Microencapsulated hepatocytes might solve immunological rejection, broadening a new perspective for the treatment of fulminant hepatic failure (FHF). However, the transplantation of microcapsulated hepatocytes is limited by low cell viability. Nevertheless, the co-microencapsulation of hepatocytes and human umbilical vein endothelial cells (HUVECs) may make the treatment of FHF more promising. We prepared the microcapsules using the high-voltage electrostatic droplet spray method, transplanted the empty microcapsules, isolated hepatocytes, microcapsulated hepatocytes, and co-microencapsulated hepatocytes and HUVEC intraperitoneally into rat models of FHF induced by D-aminogalactose (D-gal). After 1, 3, and 7 days, and 2, 3, and 4 weeks posttransplantation, we calculated the mortality and assessed alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) levels in the serum of the model; evaluated the integrality and recovery of microcapsules; and stained with hematoxylin and eosin (H&E) the recovered microcapsules as well as the liver of the FHF rats. Hepatocyte-specific functions, including the levels of ALT, AST, and ALB in the serum of the co-microencapsulation group, were significantly better than those in the other groups (p<0.05) from 2 to 4 weeks after transplantation. Moreover, cotransplantation of the microencapsulated hepatocytes and HUVECs decreased the mortality rate of the FHF rats. The recovered microcapsules were intact, and recovery was up to 90%. H&E staining showed that the microencapsulated cells were still alive, and the liver tissues had started to recover after 4 weeks posttransplantation. The microcapsules have good biocompatibility and immunoprotection to protect the hepatocytes from immunological rejection. Cotransplantation of the microencapsulated hepatocytes and HUVECs could decrease mortality rates and improve liver function in FHF.