Liver repopulation with bone marrow derived cells improves the metabolic disorder in the Gunn rat.

BACKGROUND: Reversible ischaemia/reperfusion (I/R) liver injury has been used to induce engraftment and hepatic parenchymal differentiation of exogenous beta2-microglubulin(-)/Thy1(+) bone marrow derived cells. AIM: To test the ability of this method of hepatic parenchymal repopulation, theoretically applicable to clinical practice, to correct the metabolic disorder in a rat model of congenital hyperbilirubinaemia. METHODS AND RESULTS: Analysis by confocal laser microscopy of fluorescence labelled cells and by immunohistochemistry for beta2-microglubulin, 72 hours after intraportal delivery, showed engraftment of infused cells in liver parenchyma of rats with I/R, but not in control animals with non-injured liver. Transplantation of bone marrow derived cells obtained from GFP-transgenic rats into Lewis rats resulted in the presence of up to 20% of GFP positive hepatocytes in I/R liver lobes after one month. The repopulation rate was proportional to the number of transplanted cells. Infusion of GFP negative bone marrow derived cells into GFP positive transgenic rats resulted in the appearance of GFP negative hepatocytes, suggesting that the main mechanism underlying parenchymal repopulation was differentiation rather than cell fusion. Transplantation of wild type bone marrow derived cells into hyperbilirubinaemic Gunn rats with deficient bilirubin conjugation after I/R damage resulted in 30% decrease in serum bilirubin, the appearance of bilirubin conjugates in bile, and the expression of normal UDP-glucuronyltransferase enzyme evaluated by polymerase chain reaction. CONCLUSIONS: I/R injury induced hepatic parenchymal engraftment and differentiation into hepatocyte-like cells of bone marrow derived cells. Transplantation of bone marrow derived cells from non-affected animals resulted in the partial correction of hyperbilirubinaemia in the Gunn rat.

Hepatic assist devices.

Acute liver failure (ALF) is associated with significant morbidity and mortality. Better understanding of the pathophysiology of the disease and improvements in patient management have resulted in increased survival. Liver transplantation remains the only proven therapeutic modality. Primarily because of organ donor shortage, a number of strategies have been developed in an attempt to support patients with severe ALF until either an organ becomes available for transplantation or until they recover. Liver support strategies include use of either non-biological or biological systems. Non-biological systems include plasma exchange, hemodialysis, hemofiltration, charcoal and resin hemoperfusion. These systems are able to remove toxins, but their utility is limited by their inability to provide missing liver synthetic function. Biological liver support systems include ex vivo liver perfusion and use of hepatocyte-based extracorporeal devices. Like non-biological systems, biological ones provide a means of detoxification and in addition biotransformation and biosynthetic functions. The major limitation of these systems is the lack of availability of an effective highly differentiated human hepatocyte line for clinical use. Currently clinically tested liver support systems use either porcine hepatocytes or human hepatoma cell lines. As liver support therapy evolves, there will be a role for both biological and non-biological liver support systems to treat specific forms of liver failure.

Isolation, characterization, and transplantation of bone marrow-derived hepatocyte stem cells.

Recently it was shown that a population of cells in the bone marrow-expressing hematopoietic stem cell antigens could differentiate into hepatocytes. However, explicitly committed hepatocyte progenitors, which exhibit highly differentiated liver functions, immediately upon isolation, have not yet been isolated from bone marrow. After studying common antigens on blast-like cells in fetal and adult regenerating cholestatic rat livers and human regenerating and malignant livers, we hypothesized that beta-2-microglobulin-negative (beta(2)m(-)) cells might represent dedifferentiated hepatocytes and/or their progenitors. Utilizing a two-step magnetic bead cell-sorting procedure, we show that in bone marrow from rat and human, beta(2)m(-)/Thy-1(+) cells consistently express liver-specific genes and functions. After intraportal infusion into rat livers, bone marrow-derived hepatocyte stem cells (BDHSC) integrated with hepatic cell plates and differentiated into mature hepatocytes. In a culture system simulating liver regeneration and containing cholestatic serum, these cells differentiated into mature hepatocytes and metabolized ammonia into urea. This differentiation was dependent on a yet nondescript humoral signal existing in the cholestatic serum. Transmission electron microscopy and three-dimensional digital reconstruction confirmed hepatocyte ultrastructure of cultured BDHSC.

Enhanced proliferation and differentiation of rat hepatocytes cultured with bone marrow stromal cells.

Liver transplantation is the only clinically effective method of treating acute liver failure. However, wider application of this therapeutic modality is restricted primarily by shortage of donor organs. In the search for alternative methods of liver replacement therapy, investigators have focused on transplantation of normal allogeneic hepatocytes and on the development of liver support systems utilizing isolated hepatocytes. Since all human livers suitable for cell harvest are being used for transplantation, hepatocyte therapy using human tissue would require growing of cells in vitro. Unfortunately, although hepatocytes have tremendous capacity to proliferate in vivo, their ability to grow in culture is severely limited. Stromal cells from bone marrow and other blood-forming organs have been found to support hematopoiesis. In this paper, we show that bone marrow-derived stromal cells (BMSCs) enhance proliferation and support differentiation of rat hepatocytes in culture. Further, we demonstrate that in hepatocyte/BMSC co-cultures, clonal expansion of small hepatocytes (SH) is increased. Using semipermeable membrane cultures, we established that direct cell-cell contact is necessary for stimulation of cell proliferation. We also show that BMSCs which are in direct contact with hepatocytes and SH colonies express Jagged1. This suggests a potential role for Notch signaling in the observed effects. Finally, we present evidence that the expression and activity of liver specific transcription factors, CCAAT/enhancer binding proteins and liver specific key enzymes such as tryptophan 2,3-dioxygenase, are improved in hepatocyte/BMSC co-cultures. In conclusion, results of this study indicate that BMSCs could facilitate proliferation and differentiation of primary rat hepatocytes and their progenitors (SH) in vitro.

Regulation of c-met expression in rats with acute hepatic failure.

BACKGROUND: Earlier we described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of hepatocyte proliferation was associated with delayed expression of HGF and HGF receptor c-met. Since the c-met promoter region has Sp1 binding sites, we decided to examine whether in FHF rats down-regulation of c-met is associated with decreased Sp1 function and whether changes in blood HGF, IL-6, and TGFbeta1 levels might be responsible for these effects. MATERIALS AND METHODS: Induction of FHF, partial (2/3) hepatectomy (PH), and sham hepatectomy (SH) was performed in adult Sprague-Dawley rats. The levels of c-met mRNA and Sp1 DNA binding activity were studied in rat liver remnants at different time points after surgery. Blood levels of HGF, IL-6, and TGFbeta1 were also measured in these rats. Additionally, the effects of treatment with TGF-beta1, IL-6, or a combination of both on c-met expression and Sp1 DNA binding were studied in HGF-induced rat hepatocyte cultures. RESULTS: Compared to SH rats, in PH rat livers c-met was up-regulated after 6 h and Sp1 DNA binding was at or only slightly lower than levels at all time points studied. In FHF rat livers, c-met expression was markedly reduced after 2 and 6 h, moderate after 12 h, and undetectable after 24 h. At the same time, Sp1 DNA binding was detected at 2 h postinduction only. In FHF rats, blood levels of all three cytokines showed early and sustained elevation. In vitro, IL-6 had no effect on c-met expression, whereas TGFbeta1 up-regulated c-met. When used alone, none of the cytokines affected Sp1 DNA binding activity. In contrast, a combination of IL-6 and TGFbeta1 down-regulated c-met expression as well as Sp1 DNA binding activity. These effects were dependent on the IL-6 concentration used. This study suggests that following massive loss of hepatocyte mass in rats, early increase in blood IL-6 and TGFbeta1 levels may weaken the expression of HGF receptor c-met in surviving hepatocytes through suppression of Sp1 DNA binding.

Bioartificial liver support.

Orthotopic liver transplantation is the only definitive therapy for patients with fulminant hepatic failure (FHF). However, due to shortage of organs, a large number of patients die before a liver can be procured for transplantation. In FHF the need for a liver is particularly urgent because of rapid deterioration in the patients' condition with the onset of cerebral edema and intracranial hypertension leading to irreversible brain damage. It is thus necessary to develop an extracorporeal liver support system to help maintain patients alive and neurologically intact until an organ becomes available for transplantation. Multiple attempts have been made, ranging from the use of plasma exchange to utilization of charcoal columns and extracorporeal devices loaded with liver tissue to develop liver support systems for treating patients with acute severe liver failure. None of these systems has achieved wide clinical use, and FHF due to multiple causes continues to be associated with significant morbidity and mortality. In this paper, the authors review the history of extracorporeal liver support for acute liver failure and discuss their experience with a hollow fiber bioartificial liver support system utilizing porcine hepatocytes in the treatment of patients with acute liver failure.

Inhibition of signal transducer and activator transcription factor 3 in rats with acute hepatic failure.

In fulminant hepatic failure, survival is not possible without recovery of sufficient hepatocyte mass. Remarkably, only a few studies exist that provide insight into the mechanisms that control proliferation of residual hepatocytes after extensive hepatocyte loss. In this regard, the role of growth-regulatory factors, including pro-inflammatory cytokines such as interleukin-6 (IL-6), is not well understood. In the present study we show that in rats with critically low (10%) hepatocyte mass, whether with or without ongoing liver cell necrosis, inhibition of liver regeneration is associated with early and sustained increase in blood IL-6 levels. Under these conditions, the signal transducer and activator of transcription (Stat3) DNA binding activity was lowered at the time of G1/S cell-cycle transition. We further demonstrate that the protein inhibitor of activated Stat3 (PIAS3) and the suppressor of cytokine signaling (SOCS-1) were up-regulated early after induction of liver failure (6-12 h). In vitro, IL-6 induced PIAS3 expression in HGF stimulated rat hepatocytes. These findings suggest that after massive hepatocyte loss, an early and rapid rise in blood IL-6 levels may weaken the hepatic regenerative response through up-regulation of Stat3 inhibitors PIAS3 and SOCS-1.

Bioartificial liver treatment in rats with fulminant hepatic failure: effect on DNA-binding activity of liver-enriched and growth-associated transcription factors.

BACKGROUND: We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of regeneration of the residual liver was associated with delayed expression of HGF and HGF receptor c-met and elevated blood HGF and TGF-beta1 levels. We then found that intrasplenic hepatocyte transplantation prolonged survival in FHF rats and triggered hepatocyte proliferation in the native liver. The latter effect was associated with accelerated expression of HGF and c-met mRNA in the liver and lowering of blood HGF and TGF-beta1 levels. In the present study we show that in FHF rats, treatment with a bioartificial liver (BAL) had similar effects. MATERIALS AND METHODS: FHF was induced in inbred Lewis rats and after 4 h, Group 1 rats were subjected to a 4-h whole blood perfusion through the BAL loaded with 3 x 10(8) microcarrier-attached syngeneic hepatocytes, whereas Group 2 control rats were treated with the BAL containing microcarriers only. RESULTS: Compared to sham-BAL-treated rats, the test rats lived longer (28 +/- 5 vs 17 +/- 2 h; P = 0.0005), had better coagulation parameters, maintained higher body core temperature, and showed decreased plasma TGF-beta1 levels. In addition, their liver remnants were HGF positive and showed increased DNA binding of transcription factors engaged in the modulation of hepatocyte proliferation (e.g., STAT3) and liver-specific gene expression (e.g., HNF1, HNF4, C/EBP). CONCLUSIONS: This study demonstrates that hepatocyte-based extracorporeal support not only can provide metabolic support by increasing the available functional liver mass but also is capable of modifying humoral and molecular mechanisms which are responsible for proliferation and organ-specific functions of residual hepatocytes.

Novel human malignancy-associated gene (MAG) expressed in various tumors and in some tumor preexisting conditions.

We have identified a novel human malignancy-associated gene (MAG) expressed in various malignant tumors including glioblastomas and hepatocellular carcinomas (HCCs) and in tumor preexisting conditions such as hepatitis C virus- and hepatitis B virus-induced liver cirrhosis. The expression of MAG was characterized using reverse transcription-PCR (RT-PCR), rapid amplification of cDNA ends PCR, RNA dot blotting, RNase protection assay, and Northern blot analysis. Rapid amplification of cDNA ends PCR yielded a 536-bp MAG fragment in HCC, macroregenerative liver nodules with dysplasia, and liver cirrhosis but not in normal liver or placenta. By RT-PCR, MAG expression was not found in 12 different normal tissues but found in 46 of 51 (90%) premalignant and malignant tissues of various sites. Embryonic liver and brain were positive for MAG expression together with tumors from the same organs, but the corresponding normal adult tissues were negative. By RNase protection assay, MAG mRNA was expressed in the HepG2 liver tumor cell line and in an ovarian carcinoma but not in normal liver. The estimated transcript size from Northern blot analysis was 8.8 kb. This novel gene may play a role in the progression of premalignant conditions and in the development of HCC and other cancers.

Transplantation of hepatocytes for prevention of intracranial hypertension in pigs with ischemic liver failure.

Intracranial hypertension leading to brain stem herniation is a major cause of death in fulminant hepatic failure (FHF). Mannitol, barbiturates, and hyperventilation have been used to treat brain swelling, but most patients are either refractory to medical management or cannot be treated because of concurrent medical problems or side effects. In this study, we examined whether allogeneic hepatocellular transplantation may prevent development of intracranial hypertension in pigs with experimentally induced liver failure. Of the two preparations tested--total hepatectomy (n = 47), and liver devascularization (n = 16)--only pigs with liver ischemia developed brain edema provided, however, that animals were maintained normothermic throughout the postoperative period. This model was then used in transplantation studies, in which six pigs received intrasplenic injection of allogeneic hepatocytes (2.5 x 10(9) cells/pig) and 3 days later acute liver failure was induced. In both models (anhepatic state, liver devascularization), pigs allowed to become hypothermic had significantly longer survival compared to those maintained normothermic. Normothermic pigs with liver ischemia had, at all time points studied, ICP greater than 20 mmHg. Pigs that received hepatocellular transplants had ICP below 15 mmHg until death; at the same time, cerebral perfusion pressure (CPP) in transplanted pigs was consistently higher than in controls (45 +/- 11 mmHg vs. 16 +/- 18 mmHg; p < 0.05). Spleens of transplanted pigs contained clusters of viable hepatocytes (hematoxylin-eosin, CAM 5.2). It was concluded that removal of the liver does not result in intracranial hypertension; hypothermia prolongs survival time in both anhepatic pigs and pigs with liver devascularization, and intrasplenic transplantation of allogeneic hepatocytes prevents development of intracranial hypertension in pigs with acute ischemic liver failure.

Growth of intraportally transplanted islets under liver regeneration stimulus and restoration of normoglycemia in streptozocin-diabetic rats.

BACKGROUND: Limitation of beta-cell growth after intraportal islet transplantation plays an important role in graft failure. To induce transplanted beta-cell proliferation, we studied the effect of compensatory liver growth in diabetic rats that had a subtherapeutic islet mass previously injected into the liver. METHODS: Syngeneic rats were used as islet donors or recipients; diabetes was induced by streptozocin. Three groups of streptozocin-treated rats were studied. In group 1, 250 islets were selectively transplanted into the posterior liver lobes and 10 days later anterior portal branch ligation (PBL) was performed (n = 18); in group 2, 250 islets were transplanted into the posterior lobes and 10 days later sham PBL was performed (n = 13); in group 3, rats underwent a sham transplantation and PBL (n = 6). Nonfasting blood glucose levels and body weight were monitored. Six rats in groups 1 and 2 were killed 48 hours after PBL, liver sections were stained for proliferating cell nuclear antigen, and islet cell labeling index was calculated. The remaining rats were killed 30 days later. Liver compensatory growth or atrophy was calculated and morphometric determination of beta-cell area was assessed on insulin-immunostained sections of the liver. RESULTS: In group 1 rats killed 48 hours after PBL, islet cell labeling index was significantly higher than in group 2 (p < 0.0001). After PBL, we observed normalization of nonfasting blood glucose levels in 10 of 12 rats. At 30 days, posterior liver lobes showed compensatory growth (218.5% +/- 18.6%) accompanied by atrophy of the anterior lobes; morphometric study of liver-engrafted islets showed a significant increase of individual beta-cell area, compared with group 2 (p < 0.0001). In groups 2 and 3, normoglycemia was not achieved. CONCLUSIONS: In streptozocin-diabetic rats, normoglycemia was restored after transplantation of a sub-therapeutic islet mass, followed by PBL-induced liver regeneration. Histologic and morphometric results indicating islet cell proliferation suggest that compensatory liver growth might have induced a hypertrophic/hyperplastic response in the intraportally transplanted beta-cells.

Artificial liver: review and Cedars-Sinai experience.

During the past decade, whole organ transplantation has become the only clinically effective method of treating fulminant hepatic failure and chronic liver failure due to specific genetic, hepatocellular, and anatomic defects of liver function. However, wider application of liver transplantation is restricted by shortage of organ donors, high cost, relatively high morbidity, and need for life-long immunosuppression. As a result, investigators have attempted to develop alternative methods to treat liver insufficiency. These ranged from use of plasma exchange to utilization of detoxification columns and extracorporeal devices loaded with various liver tissue preparations. Recently, advances in hepatocyte isolation and culture techniques, improved understanding of hepatocyte-matrix interactions, availability of new biomaterials, improved hollow-fiber technology, and better understanding of flow and mass transport across semipermeable membranes have resulted in the development of a new generation of liver assist devices. Some of these devices, including the one developed by the authors, are currently being tested in the clinical setting. In this paper, the past experience with liver support systems is reviewed, the present status of the field is critically examined, and the results of a phase I clinical trial with the bioartificial liver, utilizing primary porcine hepatocytes, are summarized.

Loss and recovery of liver regeneration in rats with fulminant hepatic failure.

We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobes necrosis. After this procedure, lack of regenerative response in the residual viable liver tissue (omental lobes) was associated with elevated plasma hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1) levels and delayed expression of HGF and c-met mRNA in the remnant liver. Here, we investigated whether syngeneic isolated hepatocytes transplanted in the spleen will prolong survival and facilitate liver regeneration in FHF rats. Inbred male Lewis rats were used. Group I rats (n = 46) received intrasplenic injection of 2 x 10(7) hepatocytes and 2 days later FHF was induced. Group II FHF rats (n = 46) received intrasplenic injection of saline. Rats undergoing partial hepatectomy of 68% (PH; n = 30) and a sham operation (SO; n = 30) served as controls. In 20 FHF rats (10 rats/group), survival time was determined. The remaining 72 FHF rats (36 rats/group) were used for physiologic studies (liver function and regeneration and plasma growth factor levels). In Group I rats survival was longer than that of Group II controls (73 +/- 22 hr vs. 33 +/- 9 hr; P < 0. 01). During the first 36 hr, Group I rats had lower blood ammonia, lactate, total bilirubin, PT, and PTT values, lower activity of liver enzymes, and higher monoethylglycinexylidide (MEGX) production than Group II rats. In Group I rats, livers increased in weight at a rate similar to that seen in PH controls and showed distinct mitotic and DNA synthetic activity (incorporation of bromodeoxyuridine and proliferation cell nuclear antigen expression). Plasma HGF and TGF-beta1 levels in these rats decreased and followed the pattern seen in PH rats; additionally, c-met expression in the remnant liver was accelerated. Hepatocyte transplantation prolonged survival in FHF rats and facilitated liver regeneration. Even though the remnant liver increased in weight four times reaching 30% of the original liver mass, the transplant-bearing rats expired due to inability of the regenerating liver to support the rat.

Lack of hepatocyte growth factor receptor (c-met) gene expression in fulminant hepatic failure livers before transplantation.

To gain insight into liver regeneration mechanisms in fulminant hepatic failure, we compared gene expression of hepatocyte growth factor, its receptor c-met, c-myc, and albumin in human normal (4 cases) and fulminant (14 cases) livers by reverse transcription-polymerase chain reaction. In normal livers, hepatocyte growth factor gene was not expressed, whereas c-met, c-myc and albumin genes were always expressed. In fulminant hepatic failure, hepatocyte growth factor gene was expressed in 1 of 14 cases, c-met in none of 14 cases, c-myc in 10 of 14 cases, and albumin in 3 of 14 cases. By immunofluorescence, c-met protein was revealed in normal but not in fulminant hepatic failure liver tissue. Liver tissue is unlikely to account for high hepatocyte growth factor plasma levels typical for fulminant hepatic failure. Lack of its receptor (c-met) expression may explain a poor response of fulminant hepatic failure livers to exogenous hepatocyte growth factor that normally promotes liver growth and regeneration.

Clinical experience with a bioartificial liver in the treatment of severe liver failure. A phase I clinical trial.

OBJECTIVE: The purpose of this study was to develop a bioartificial liver (BAL) to treat patients with severe liver failure until they can be either transplanted or recover spontaneously. SUMMARY BACKGROUND DATA: Severe acute liver failure is associated with high mortality. Liver transplantation has emerged as an effective therapy for patients who did not respond to standard management. However, because of the donor organ shortage and urgent need for transplantation, many patients die before they can be transplanted and others do not survive after transplantation, primarily because of intracranial hypertension. METHODS: Three groups of patients with severe acute liver failure were treated with the BAL. In group 1 (n = 18) were patients with fulminant hepatic failure (FHF), in group 2 (n = 3) were patients with primary nonfunction (PNF) of a transplanted liver, and in group 3 (n = 10) were patients with acute exacerbation of chronic liver disease. Patients in groups 1 and 2 were candidates for transplantation at the time they entered the study, whereas patients in group 3 were not. RESULTS: In group 1, 16 patients were "bridged" successfully to transplantation, 1 patient was bridged to recovery without a transplant, and 1 patient died because of concomitant severe pancreatitis. In group 2, all patients were bridged successfully to retransplantation. In group 3, two patients were supported to recovery and successful transplants at later dates; the other eight patients, although supported temporarily with the BAL, later died because they were not candidates for transplantation. CONCLUSIONS: The authors' clinical experience with the BAL has yielded encouraging results. A randomized, controlled, prospective trial (phase II-III) is being initiated to determine the efficacy of the system.

Intracranial pressure. Effects of pneumoperitoneum in a large-animal model.

BACKGROUND: The effects of pneumoperitoneum on intracranial pressure (ICP) have received relatively little attention. This study was undertaken to investigate the changes in ICP occurring as a result of increased intraabdominal pressure (IAP) and positioning in animals with normal and elevated ICP. METHOD: Five pigs (average weight 60 lb) were studied. A subarachnoid screw was placed for ICP monitoring. End tidal CO2 was monitored. Ventilation was performed to keep PCO2 between 30 and 50 mmHg. Measurements of arterial blood gases, mean arterial blood pressure, and ICP were recorded at four different levels of intraabdominal pressure (IAP 0, 8, 16, and 24 mmHg), both in the supine and Trendelenburg positions. A Foley catheter was introduced into the subarachnoid space to elevate the intracranial pressure, and the same measurements were performed. RESULTS: There was a significant and linear increase in ICP with increased IAP and Trendelenburg position. The combination of increased IAP of 16 mmHg and Trendelenburg position increased ICP 150% over control levels. CONCLUSIONS: Patient positioning and level of IAP should be taken into consideration when performing laparoscopy on patients with head trauma, cerebral aneurysms, and other conditions associated with increased ICP.

Expression of HGF, its receptor c-met, c-myc, and albumin in cirrhotic and neoplastic human liver tissue.

Hepatocellular carcinoma (HCC) is a common type of cancer, with approximately 260,000 new cases each year, and liver cirrhosis is generally considered a major predisposing factor for HCC. However, specific changes of gene expression in liver cirrhosis and HCC remain obscure. The expression of genes for hepatocyte growth factor (HGF), its receptor c-met proto-oncogene, c-myc proto-oncogene, and albumin was analyzed. Gene expression was studied by PCR in seven normal human livers, nine cases of hepatitis C cirrhosis, 12 cases of alcoholic cirrhosis, two cases of liver adenoma, and 12 cases of HCC. HGF and c-met protein were revealed by immunofluorescent staining. HGF mRNA was not expressed in normal livers but was detected in adenomas, in 80% of HCC, and in some cirrhoses. Paraffin-embedded and fresh-frozen tissue samples yielded similar results. Immunohistochemical data correlated with PCR results regarding the overexpression of the HGF/c-met system in HCC. Albumin gene expression was decreased in HCC vs normal livers, consistent with altered function of tumor hepatocytes. The elevated expression of the HGF/c-met system in HCC may play a role in tumor development and/or progression. Tissue localization studies of HGF and its receptor c-met protein support the existence of both autocrine and paracrine mechanisms of action of HGF in HCC vs only a paracrine mechanism in normal liver.

Neurological and psychological sequelae in transplant recipients after bridging with the bioartificial liver.

Prior to the advent of the bioartificial liver there was little hope to offer the families of comatose patients unless an organ could be found immediately, or xenografting was attempted. The elevated intracranial pressure that develops is more life-threatening than prolonged bleeding times. Over a 2-year period, nine patients were bridged to transplantation using the BAL to keep them neurologically intact prior to surgery. The goal is to maintain the ICP less than 20 mmHg in adults and between 10 and 15 mmHg in children, so that the cerebral perfusion pressure remains above 50 mmHg. The first patients, a 35-year-old woman, arrived in stage II coma. The second patient, a 10-year-old boy in stage IV coma, had decerebrate posturing and anisocoria. The third patient, an 18-year-old girl, had an ICP of 28 mmHg with decerebrate posturing and disconjugate gaze. The fourth patient, a 34-year-old male, had an ICP of > 38 mmHg. The fifth patient, a 24-year-old male, had fixed dilated pupils. The sixth patient, a 50-year-old woman, had readings to 52 mmHg. The seventh patient, a 48-year-old male, had postoperative numbness in his fingertips that remitted. The eighth patient, a 31-year-old female, had decerebrate posturing and an ICP of 64 mmHg transiently. The ninth patient, a 52-year-old woman, had decerebrate posturing with a peak ICP of 50 mmHg. All nine patients survived.